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Sample records for glucose transporter sglt

  1. Sodium glucose transporter 2 (SGLT2 inhibition and ketogenesis

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2015-01-01

    Full Text Available Sodium glucose transporter 2 (SGLT2 inhibitors are a recently developed class of drug that have been approved for use in type 2 diabetes. Their unique extra-pancreatic glucuretic mode of action has encouraged their usage in type 1 diabetes as well. At the same time, reports of pseudo ketoacidosis and ketoacidosis related to their use have been published. No clear mechanism for this phenomenon has been demonstrated so far. This communication delves into the biochemical effects of SGLT2 inhibition, discusses the utility of these drugs and proposes steps to maximize safe usage of the molecules.

  2. A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.

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    Tang, Chunlei; Zhu, Xiaoyun; Huang, Dandan; Zan, Xin; Yang, Baowei; Li, Ying; Du, Xiaoyong; Qian, Hai; Huang, Wenlong

    2012-06-01

    Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

  3. A cell-based fluorescent glucose transporter assay for SGLT2 inhibitor discovery

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    Yi Huan

    2013-04-01

    Full Text Available The sodium/glucose cotransporter 2 (SGLT2 is responsible for the majority of glucose reabsorption in the kidney, and currently, SGLT2 inhibitors are considered as promising hypoglycemic agents for the treatment of type 2 diabetes mellitus. By constructing CHO cell lines that stably express the human SGLT2 transmembrane protein, along with a fluorescent glucose transporter assay that uses 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-ylamino]2-deoxyglucose (2-NBDG as a glucose analog, we have developed a nonradioactive, cell-based assay for the discovery and characterization of SGLT2 inhibitors.

  4. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

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    Rieg, Timo; Masuda, Takahiro; Gerasimova, Maria; Mayoux, Eric; Platt, Kenneth; Powell, David R.; Thomson, Scott C.; Koepsell, Hermann

    2013-01-01

    In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted. PMID:24226519

  5. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects.

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    Norton, Luke; Shannon, Christopher E; Fourcaudot, Marcel; Hu, Cheng; Wang, Niansong; Ren, Wei; Song, Jun; Abdul-Ghani, Muhammad; DeFronzo, Ralph A; Ren, Jimmy; Jia, Weiping

    2017-09-01

    The sodium-glucose co-transporters (SGLTs) are responsible for the tubular reabsorption of filtered glucose from the kidney into the bloodstream. The inhibition of SGLT2-mediated glucose reabsorption is a novel and highly effective strategy to alleviate hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). However, the effectiveness of SGLT2 inhibitor therapy is diminished due, in part, to a compensatory increase in the maximum reabsorptive capacity (Tm) for glucose in patients with T2DM. We hypothesized that this increase in Tm could be explained by an increase in the tubular expression of SGLT and glucose transporters (GLUT) in these patients. To examine this, we obtained human kidney biopsy specimens from patients with or without T2DM and examined the mRNA expression of SGLTs and GLUTs. The expression of SGLT1 is markedly increased in the kidney of patients with T2DM, and SGLT1 mRNA is highly and significantly correlated with fasting and postprandial plasma glucose and HbA1c. In contrast, our data demonstrate that the levels of SGLT2 and GLUT2 mRNA are downregulated in diabetic patients, but not to a statistically significant level. These important findings are clinically significant and may have implications for the treatment of T2DM using strategies that target SGLT transporters in the kidney. © 2017 John Wiley & Sons Ltd.

  6. Isotonic transport by the Na+-glucose cotransporter SGLT1 from humans and rabbit

    DEFF Research Database (Denmark)

    Zeuthen, T; Meinild, A K; Loo, D D

    2001-01-01

    water transport was divided about equally between cotransport, osmosis across the SGLT1 and osmosis across the native oocyte membrane. 6. Coexpression of AQP1 with the SGLT1 increased the water permeability more than 10-fold and steady state isotonic transport was achieved after less than 2 s of sugar......1. In order to study its role in steady state water transport, the Na+-glucose cotransporter (SGLT1) was expressed in Xenopus laevis oocytes; both the human and the rabbit clones were tested. The transport activity was monitored as a clamp current and the flux of water followed optically...... as the change in oocyte volume. 2. SGLT1 has two modes of water transport. First, it acts as a molecular water pump: for each 2 Na+ and 1 sugar molecule 264 water molecules were cotransported in the human SGLT1 (hSGLT1), 424 for the rabbit SGLT1 (rSGLT1). Second, it acts as a water channel. 3. The cotransport...

  7. Sodium-Glucose linked transporter 2 (SGLT2) inhibitors--fighting diabetes from a new perspective.

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    Angelopoulos, Theodoros P; Doupis, John

    2014-06-01

    Sodium-Glucose linked transporter 2 (SGLT2) inhibitors are a new family of antidiabetic pharmaceutical agents whose action is based on the inhibition of the glucose reabsorption pathway, resulting in glucosuria and a consequent reduction of the blood glucose levels, in patients with type 2 diabetes mellitus. Apart from lowering both fasting and postprandial blood glucose levels, without causing hypoglycemia, SGLT2 inhibitors have also shown a reduction in body weight and the systolic blood pressure. This review paper explores the renal involvement in glucose homeostasis providing also the latest safety and efficacy data for the European Medicines Agency and U.S. Food and Drug Administration approved SGLT2 inhibitors, looking, finally, into the future of this novel antidiabetic category of pharmaceutical agents.

  8. Sodium glucose co-transporter 2 (SGLT2) inhibitors: novel antidiabetic agents.

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    Washburn, William N

    2012-05-01

    Maintenance of glucose homeostasis in healthy individuals involves SGLT2 (sodium glucose co-transporter 2)-mediated recovery of glucose from the glomerular filtrate which otherwise would be excreted in urine. Clinical studies indicate that SGLT2 inhibitors provide an insulin-independent means to reduce the hyperglycemia that is the hallmark of type 2 diabetes mellitus (T2DM) with minimal risk of hypoglycemia. The pharmacophore common to the SGLT2 inhibitors currently in development is a diarylmethane C-glucoside which is discussed in this review. The focus is how this pharmacophore was further modified as inferred from the patents publishing from 2009 to 2011. The emphasis is on the strategy that each group employed to circumvent the constraints imposed by prior art and how the resulting SGLT2 potency and selectivity versus SGLT1 compared with that of the lead clinical compound dapagliflozin. SGLT2 inhibitors offer a new fundamentally different approach for treatment of diabetes. To date, the clinical results suggest that for non-renally impaired patients this class of inhibitors could be safely used at any stage of T2DM either alone or in combination with other marketed antidiabetic medications.

  9. The Sodium Glucose Cotransporter SGLT1 Is an Extremely Efficient Facilitator of Passive Water Transport.

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    Erokhova, Liudmila; Horner, Andreas; Ollinger, Nicole; Siligan, Christine; Pohl, Peter

    2016-04-29

    The small intestine is void of aquaporins adept at facilitating vectorial water transport, and yet it reabsorbs ∼8 liters of fluid daily. Implications of the sodium glucose cotransporter SGLT1 in either pumping water or passively channeling water contrast with its reported water transporting capacity, which lags behind that of aquaporin-1 by 3 orders of magnitude. Here we overexpressed SGLT1 in MDCK cell monolayers and reconstituted the purified transporter into proteoliposomes. We observed the rate of osmotic proteoliposome deflation by light scattering. Fluorescence correlation spectroscopy served to assess (i) SGLT1 abundance in both vesicles and plasma membranes and (ii) flow-mediated dilution of an aqueous dye adjacent to the cell monolayer. Calculation of the unitary water channel permeability, pf, yielded similar values for cell and proteoliposome experiments. Neither the absence of glucose or Na(+), nor the lack of membrane voltage in vesicles, nor the directionality of water flow grossly altered pf Such weak dependence on protein conformation indicates that a water-impermeable occluded state (glucose and Na(+) in their binding pockets) lasts for only a minor fraction of the transport cycle or, alternatively, that occlusion of the substrate does not render the transporter water-impermeable as was suggested by computational studies of the bacterial homologue vSGLT. Although the similarity between the pf values of SGLT1 and aquaporin-1 makes a transcellular pathway plausible, it renders water pumping physiologically negligible because the passive flux would be orders of magnitude larger. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Sodium glucose CoTransporter 2 (SGLT2) inhibitors: Current status and future perspective.

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    Madaan, Tushar; Akhtar, Mohd; Najmi, Abul Kalam

    2016-10-10

    Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes. This article covers the mechanism of glucose reabsorption in the kidneys, the mechanism of action of SGLT2 inhibitors, several SGLT2 inhibitors currently available in the market as well as those in various phases of development, their individual pharmacokinetics as well as the discussion about the future role of SGLT2 inhibitors, not only for the treatment of diabetes, but also for various other diseases like obesity, hepatic steatosis, and cardiovascular disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

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    Opie, L H

    2014-08-01

    Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

  12. Sodium-glucose co-transporter 2 (SGLT2 inhibitors: a growing class of anti-diabetic agents

    Directory of Open Access Journals (Sweden)

    Eva M Vivian

    2014-12-01

    Full Text Available Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM. The renal sodium-glucose co-transporter 2 (SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM.

  13. [Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD].

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    Insalaco, Monica; Zanoli, Luca; Rastelli, Stefania; Lentini, Paolo; Rapisarda, Francesco; Fatuzzo, Pasquale; Castellino, Pietro; Granata, Antonio

    2015-01-01

    Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD.

  14. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.

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    Oliva, Raymond V; Bakris, George L

    2014-05-01

    Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 for dapagliflozin and ≥45 mL/min/1.73 m2 for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4-5 years. Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  15. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus

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    Rose, Michael; Gerasimova, Maria; Satriano, Joseph; Platt, Kenneth A.; Koepsell, Hermann; Cunard, Robyn; Sharma, Kumar; Thomson, Scott C.; Rieg, Timo

    2013-01-01

    The Na-glucose cotransporter SGLT2 mediates high-capacity glucose uptake in the early proximal tubule and SGLT2 inhibitors are developed as new antidiabetic drugs. We used gene-targeted Sglt2 knockout (Sglt2−/−) mice to elucidate the contribution of SGLT2 to blood glucose control, glomerular hyperfiltration, kidney growth, and markers of renal growth and injury at 5 wk and 4.5 mo after induction of low-dose streptozotocin (STZ) diabetes. The absence of SGLT2 did not affect renal mRNA expression of glucose transporters SGLT1, NaGLT1, GLUT1, or GLUT2 in response to STZ. Application of STZ increased blood glucose levels to a lesser extent in Sglt2−/− vs. wild-type (WT) mice (∼300 vs. 470 mg/dl) but increased glucosuria and food and fluid intake to similar levels in both genotypes. Lack of SGLT2 prevented STZ-induced glomerular hyperfiltration but not the increase in kidney weight. Knockout of SGLT2 attenuated the STZ-induced renal accumulation of p62/sequestosome, an indicator of impaired autophagy, but did not attenuate the rise in renal expression of markers of kidney growth (p27 and proliferating cell nuclear antigen), oxidative stress (NADPH oxidases 2 and 4 and heme oxygenase-1), inflammation (interleukin-6 and monocyte chemoattractant protein-1), fibrosis (fibronectin and Sirius red-sensitive tubulointerstitial collagen accumulation), or injury (renal/urinary neutrophil gelatinase-associated lipocalin). SGLT2 deficiency did not induce ascending urinary tract infection in nondiabetic or diabetic mice. The results indicate that SGLT2 is a determinant of hyperglycemia and glomerular hyperfiltration in STZ-induced diabetes mellitus but is not critical for the induction of renal growth and markers of renal injury, inflammation, and fibrosis. PMID:23152292

  16. Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation.

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    Jesus, Ana R; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Marques, Ana P; Dore, Timothy M; Rauter, Amélia P

    2017-01-26

    Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC 50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC 50 = 10-19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.

  17. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus.

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    Scheen, André J

    2015-01-01

    Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin

  18. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2 inhibitor for the treatment of type 2 diabetes

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    Joshua J Neumiller

    2014-06-01

    Full Text Available Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2 inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™.

  19. Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans.

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    Lu, Yasong; Griffen, Steven C; Boulton, David W; Leil, Tarek A

    2014-01-01

    In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1/2 modulation.

  20. Expression of Na+/glucose co-transporter 1 (SGLT1) is enhanced by supplementation of the diet of weaning piglets with artificial sweeteners.

    Science.gov (United States)

    Moran, Andrew W; Al-Rammahi, Miran A; Arora, Daleep K; Batchelor, Daniel J; Coulter, Erin A; Daly, Kristian; Ionescu, Catherine; Bravo, David; Shirazi-Beechey, Soraya P

    2010-09-01

    In an intensive livestock production, a shorter suckling period allows more piglets to be born. However, this practice leads to a number of disorders including nutrient malabsorption, resulting in diarrhoea, malnutrition and dehydration. A number of strategies have been proposed to overcome weaning problems. Artificial sweeteners, routinely included in piglets' diet, were thought to enhance feed palatability. However, it is shown in rodent models that when included in the diet, they enhance the expression of Na+/glucose co-transporter (SGLT1) and the capacity of the gut to absorb glucose. Here, we show that supplementation of piglets' feed with a combination of artificial sweeteners saccharin and neohesperidin dihydrochalcone enhances the expression of SGLT1 and intestinal glucose transport function. Artificial sweeteners are known to act on the intestinal sweet taste receptor T1R2/T1R3 and its partner G-protein, gustducin, to activate pathways leading to SGLT1 up-regulation. Here, we demonstrate that T1R2, T1R3 and gustducin are expressed together in the enteroendocrine cells of piglet intestine. Furthermore, gut hormones secreted by the endocrine cells in response to dietary carbohydrates, glucagon-like peptides (GLP)-1, GLP-2 and glucose-dependent insulinotrophic peptide (GIP), are co-expressed with type 1 G-protein-coupled receptors (T1R) and gustducin, indicating that L- and K-enteroendocrine cells express these taste elements. In a fewer endocrine cells, T1R are also co-expressed with serotonin. Lactisole, an inhibitor of human T1R3, had no inhibitory effect on sweetener-induced SGLT1 up-regulation in piglet intestine. A better understanding of the mechanism(s) involved in sweetener up-regulation of SGLT1 will allow the identification of nutritional targets with implications for the prevention of weaning-related malabsorption.

  1. Use systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans

    Directory of Open Access Journals (Sweden)

    Yasong eLu

    2014-12-01

    Full Text Available In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1 and 2 (SGLT2 along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80% of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30-50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al. data (2013, and evaluated against clinical data from the literature (Mogensen, 1971;Wolf et al., 2009;Polidori et al., 2013. The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30-50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to

  2. Use of systems pharmacology modeling to elucidate the operating characteristics of SGLT1 and SGLT2 in renal glucose reabsorption in humans

    Science.gov (United States)

    Lu, Yasong; Griffen, Steven C.; Boulton, David W.; Leil, Tarek A.

    2014-01-01

    In the kidney, glucose in glomerular filtrate is reabsorbed primarily by sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) along the proximal tubules. SGLT2 has been characterized as a high capacity, low affinity pathway responsible for reabsorption of the majority of filtered glucose in the early part of proximal tubules, and SGLT1 reabsorbs the residual glucose in the distal part. Inhibition of SGLT2 is a viable mechanism for removing glucose from the body and improving glycemic control in patients with diabetes. Despite demonstrating high levels (in excess of 80%) of inhibition of glucose transport by SGLT2 in vitro, potent SGLT2 inhibitors, e.g., dapagliflozin and canagliflozin, inhibit renal glucose reabsorption by only 30–50% in clinical studies. Hypotheses for this apparent paradox are mostly focused on the compensatory effect of SGLT1. The paradox has been explained and the role of SGLT1 demonstrated in the mouse, but direct data in humans are lacking. To further explore the roles of SGLT1/2 in renal glucose reabsorption in humans, we developed a systems pharmacology model with emphasis on SGLT1/2 mediated glucose reabsorption and the effects of SGLT2 inhibition. The model was calibrated using robust clinical data in the absence or presence of dapagliflozin (DeFronzo et al., 2013), and evaluated against clinical data from the literature (Mogensen, 1971; Wolf et al., 2009; Polidori et al., 2013). The model adequately described all four data sets. Simulations using the model clarified the operating characteristics of SGLT1/2 in humans in the healthy and diabetic state with or without SGLT2 inhibition. The modeling and simulations support our proposition that the apparent moderate, 30–50% inhibition of renal glucose reabsorption observed with potent SGLT2 inhibitors is a combined result of two physiological determinants: SGLT1 compensation and residual SGLT2 activity. This model will enable in silico inferences and predictions related to SGLT1

  3. MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2

    Science.gov (United States)

    Coady, Michael J.; El Tarazi, Abdulah; Santer, René; Bissonnette, Pierre; Sasseville, Louis J.; Calado, Joaquim; Lussier, Yoann; Dumayne, Christopher; Bichet, Daniel G.

    2017-01-01

    The renal proximal tubule reabsorbs 90% of the filtered glucose load through the Na+-coupled glucose transporter SGLT2, and specific inhibitors of SGLT2 are now available to patients with diabetes to increase urinary glucose excretion. Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that increased SGLT2 activity in RNA-injected Xenopus oocytes by two orders of magnitude. Significant stimulation of SGLT2 activity also occurred in opossum kidney cells cotransfected with SGLT2 and MAP17. Notably, transfection with MAP17 did not change the quantity of SGLT2 protein at the cell surface in either cell type. To confirm the physiologic relevance of the MAP17–SGLT2 interaction, we studied a cohort of 60 individuals with familial renal glucosuria. One patient without any identifiable mutation in the SGLT2 coding gene (SLC5A2) displayed homozygosity for a splicing mutation (c.176+1G>A) in the MAP17 coding gene (PDZK1IP1). In the proximal tubule and in other tissues, MAP17 is known to interact with PDZK1, a scaffolding protein linked to other transporters, including Na+/H+ exchanger 3, and to signaling pathways, such as the A-kinase anchor protein 2/protein kinase A pathway. Thus, these results provide the basis for a more thorough characterization of SGLT2 which would include the possible effects of its inhibition on colocalized renal transporters. PMID:27288013

  4. Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors.

    Science.gov (United States)

    Blaschek, Wolfgang

    2017-08-01

    Glucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glucose absorption, gluconeogenesis, biosynthesis and mobilization of glycogen, glucose consumption in all tissues and glomerular filtration, and reabsorption of glucose in the kidneys. Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the family of facilitative glucose transporters (GLUTs) or to the family of sodium glucose cotransporters (SGLTs). The intestinal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the kidney SGLT2 and SGLT1 are responsible for reabsorption of filtered glucose from the primary urine, and GLUT2 and GLUT1 enable the transport of glucose from epithelial cells back into the blood stream.The flavonoid phlorizin was isolated from the bark of apple trees and shown to cause glucosuria. Phlorizin is an inhibitor of SGLT1 and SGLT2. With phlorizin as lead compound, specific inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of type 2 diabetes. Inhibition of SGLT2 eliminates excess glucose via the urine. In recent times, the dual SGLT1/SGLT2 inhibitory activity of phlorizin has served as a model for the development and testing of new drugs exhibiting both activities.Besides phlorizin, also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes. Georg Thieme Verlag KG Stuttgart · New York.

  5. Renoprotective Effects of SGLT2 Inhibitors: Beyond Glucose Reabsorption Inhibition.

    Science.gov (United States)

    Tsimihodimos, V; Filippatos, T D; Filippas-Ntekouan, S; Elisaf, M

    2017-01-01

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Water transport by Na+-coupled cotransporters of glucose (SGLT1) and of iodide (NIS). The dependence of substrate size studied at high resolution

    DEFF Research Database (Denmark)

    Zeuthen, Thomas; Belhage, Bo; Zeuthen, Emil

    2005-01-01

    and osmosis at the membrane with diffusion in the cytoplasm. The combination of high resolution measurements and precise modelling showed that water transport across the membrane can be explained by cotransport of water in the membrane proteins and that intracellular unstirred layers effects are minute.......The relation between substrate and water transport was studied in Na+-coupled cotransporters of glucose (SGLT1) and of iodide (NIS) expressed in Xenopus oocytes. The water transport was monitored from changes in oocyte volume at a resolution of 20 pl, more than one order of magnitude better than...... previous investigations. The rate of cotransport was monitored as the clamp current obtained from two-electrode voltage clamp. The high resolution data demonstrated a fixed ratio between the turn-over of the cotransporter and the rate of water transport. This applied to experiments in which the rate...

  7. The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer.

    Science.gov (United States)

    Koepsell, Hermann

    2017-02-01

    Orally applied SGLT2 (SLC5A2) inhibitors that enter the blood and decrease renal reabsorption of glucose have been approved as antidiabetic drugs. They decrease blood glucose levels, slightly reduce body weight and blood pressure, and decrease the risk for diabetic nephropathy. The SGLT2 inhibitor empagliflozin has been shown to reduce the risk of severe cardiac failure. This review summarizes knowledge about the functions of SGLT2 and the pathophysiology of type 2 diabetes (T2D) and diabetic follow-up diseases. In addition, proposed pathophysiological mechanisms of therapeutic effects and of side effects of SGLT2 inhibitors are described. A recently investigated strategy to employ orally applied SGLT1 (SLC5A1) inhibitors for treatment of diabetes is discussed. The SGLT1 inhibitors reduce glucose absorption and decrease blood glucose excursions after the intake of glucose-rich food. Knowledge concerning the expression of SGLT1 in different organs is compiled and potential side effects of SGLT1 inhibitors entering the blood are discussed. Because selective targeting of SGLT1 expression presents a strategy to decrease SGLT1-mediated glucose absorption, current knowledge about the regulation of SGLT1 is also discussed. This includes the possibility to decrease SGLT1 abundance in the small intestinal brush-border membrane by a peptide derived from protein RS1 (RSC1A1) that regulates membrane trafficking. Finally the possibility to employ SGLT1 and SGLT2 as targets for anticancer therapy is discussed. SGLT1 and SGLT2 are expressed in various tumors where they supply the tumor cells with glucose for euglycemic glycolysis. Tumor growth of carcinoma expressing SGLT2 can be slowed down by an SGLT2 inhibitor. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. SGLT1-mediated transport in Caco-2 cells is highly dependent on cell bank origin

    DEFF Research Database (Denmark)

    Steffansen, B; Pedersen, Maria; Laghmoch, A M

    2017-01-01

    The Caco-2 cell line is a well-established in vitro model for studying transport phenomena for prediction of intestinal nutrient and drug absorption. However, for substances depending on transporters such predictions are complicated due to variable transporter expression and limited knowledge about...... transporter function during multiple cell passaging and cell thawings. In the case of SGLT1, a key transporter of oral absorption of D-glucose, one reason for compromised prediction could be inadequate expression of SGLT1 in Caco-2 cells and thereby limited sensitivity in the determination of SGLT1-mediated...... permeability (PSGLT1). Here, the objective was to characterize and compare SGLT1-mediated uptake in Caco-2 cells obtained from different cell banks. SGLT1-mediated uptake of the standard SGLT1 substrate, α-MDG, in Caco-2 cells was shown to be highly dependent on cell bank origin. The most robust and reliable...

  9. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Tang, H L; Li, D D; Zhang, J J; Hsu, Y H; Wang, T S; Zhai, S D; Song, Y Q

    2016-12-01

    To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors. Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted. © 2016 John Wiley & Sons Ltd.

  10. Effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Lubin Xu

    2017-06-01

    Full Text Available Aim To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes. Methods We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR and/or urine albumin/creatinine ratio (ACR changes. Data were synthesized using the random-effects model. Results Forty-seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD, −0.33 ml/min per 1.73 m2, 95% CI [−0.90 to 0.23] or in patients with chronic kidney disease (CKD (WMD −0.78 ml/min per 1.73 m2, 95% CI [−2.52 to 0.97]. SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD −0.98 ml/min per 1.73 m2, 95% CI [−1.42 to −0.54], and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]. Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD −7.24 mg/g, 95% CI [−15.54 to 1.06], but was significant in patients with CKD (WMD −107.35 mg/g, 95% CI [−192.53 to −22.18]. Conclusions SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD.

  11. Lycium barbarum L. Polysaccharide (LBP Reduces Glucose Uptake via Down-Regulation of SGLT-1 in Caco2 Cell

    Directory of Open Access Journals (Sweden)

    Huizhen Cai

    2017-02-01

    Full Text Available Lycium barbarum L. polysaccharide (LBP is prepared from Lycium barbarum L. (L. barbarum, which is a traditional Chinese medicine. LPB has been shown to have hypoglycemic effects. In order to gain some mechanistic insights on the hypoglycemic effects of LBP, we investigated the uptake of LBP and its effect on glucose absorption in the human intestinal epithelial cell line Caco2 cell. The uptake of LBP through Caco2 cell monolayer was time-dependent and was inhibited by phloridzin, a competitive inhibitor of SGLT-1. LPB decreased the absorption of glucose in Caco2 cell, and down-regulated the expression of SGLT-1. These results suggest that LBP might be transported across the human intestinal epithelium through SGLT-1 and it inhibits glucose uptake via down-regulating SGLT-1.

  12. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

    Science.gov (United States)

    Vallon, Volker; Edwards, Aurélie

    2016-01-01

    Diabetes increases the reabsorption of Na+ (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption QO2active along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising QO2active by 5–12% in the cortex and medulla. Diabetes increases overall TNa and QO2active by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers QO2active in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises QO2active in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase QO2active by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces QO2active by 33% in S3 segments, and raises QO2active by SGLT2 blockade in diabetes lowers cortical QO2active and raises medullary QO2active, particularly in S3 segments. PMID:26764207

  13. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans.

    Science.gov (United States)

    List, James F; Whaley, Jean M

    2011-03-01

    Glucose is freely filtered in the glomeruli before being almost entirely reabsorbed into circulation from the proximal renal tubules. The sodium-glucose cotransporter 2 (SGLT2), present in the S1 segment of the proximal tubule, is responsible for the majority of glucose reabsorption. SGLT2 inhibitors reduce glucose reabsorption and increase urinary glucose excretion. In animal models and humans with type 2 diabetes, this effect is associated with reduced fasting and postprandial blood glucose levels, and reduced hemoglobin A1c. Animal studies suggest that reduction of hyperglycemia with SGLT2 inhibitors may also improve insulin sensitivity and preserve β-cell function. Urinary excretion of excess calories with SGLT2 inhibitors is also associated with reduction in body weight. Modest reductions in blood pressure have been noted with SGLT2 inhibitors, consistent with a mild diuretic action. Some C-glucoside SGLT2 inhibitors, such as dapagliflozin, have pharmacokinetic properties that make them amenable to once-daily dosing.

  14. Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans?

    Science.gov (United States)

    Liu, Jiwen Jim; Lee, TaeWeon; DeFronzo, Ralph A

    2012-09-01

    Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30-50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible.

  15. Why Do SGLT2 Inhibitors Inhibit Only 30–50% of Renal Glucose Reabsorption in Humans?

    Science.gov (United States)

    Liu, Jiwen (Jim); Lee, TaeWeon; DeFronzo, Ralph A.

    2012-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibition is a novel and promising treatment for diabetes under late-stage clinical development. It generally is accepted that SGLT2 mediates 90% of renal glucose reabsorption. However, SGLT2 inhibitors in clinical development inhibit only 30–50% of the filtered glucose load. Why are they unable to inhibit 90% of glucose reabsorption in humans? We will try to provide an explanation to this puzzle in this perspective analysis of the unique pharmacokinetic and pharmacodynamic profiles of SGLT2 inhibitors in clinical trials and examine possible mechanisms and molecular properties that may be responsible. PMID:22923645

  16. Relevance of sodium/glucose cotransporter-1 (SGLT1) to diabetes mellitus and obesity in dogs.

    Science.gov (United States)

    Batchelor, D J; German, A J; Shirazi-Beechey, S P

    2013-04-01

    Glucose transport across the enterocyte brush border membrane by sodium/glucose cotransporter-1 (SGLT1, coded by Slc5a1) is the rate-limiting step for intestinal glucose transport. The relevance of SGLT1 expression in predisposition to diabetes mellitus and to obesity was investigated in dogs. Cultured Caco-2/TC7 cells were shown to express SGLT1 in vitro. A 2-kbp fragment of the Slc5a1 5' flanking region was cloned from canine genomic DNA, ligated into reporter gene plasmids, and shown to drive reporter gene expression in these cells above control (P obesity (Labrador retriever and cocker spaniel). The Slc5a1 5' flanking region was amplified from 10 healthy individuals of each of these breeds by high-fidelity PCR with the use of breed-labeled primers and sequenced by pyrosequencing. The sequence of the Slc5a1 5' flanking region in all individuals of all breeds tested was identical. On this evidence, variations in Slc5a1 promoter sequence between dogs do not influence the pathogenesis of diabetes mellitus or obesity in these breeds. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.

    Science.gov (United States)

    Vallon, Volker; Thomson, Scott C

    2017-02-01

    Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are

  18. Sodium Glucose Cotransporter 2 (SGLT2 Plays as a Physiological Glucose Sensor and Regulates Cellular Contractility in Rat Mesangial Cells.

    Directory of Open Access Journals (Sweden)

    Masanori Wakisaka

    Full Text Available Mesangial cells play an important role in regulating glomerular filtration by altering their cellular tone. We report the presence of a sodium glucose cotransporter (SGLT in rat mesangial cells. This study in rat mesangial cells aimed to evaluate the expression and role of SGLT2.The SGLT2 expression in rat mesangial cells was assessed by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR. Changes in the mesangial cell surface area at different glucose concentrations and the effects of extracellular Na+ and Ca2+ and of SGLT and Na+/Ca2+ exchanger (NCX inhibitors on cellular size were determined. The cellular sizes and the contractile response were examined during a 6-day incubation with high glucose with or without phlorizin, an SGLT inhibitor.Western blotting revealed an SGLT2 band, and RT-PCR analysis of SGLT2 revealed the predicted 422-bp band in both rat mesangial and renal proximal tubular epithelial cells. The cell surface area changed according to the extracellular glucose concentration. The glucose-induced contraction was abolished by the absence of either extracellular Na+ or Ca2+ and by SGLT and NCX inhibitors. Under the high glucose condition, the cell size decreased for 2 days and increased afterwards; these cells did not contract in response to angiotensin II, and the SGLT inhibitor restored the abolished contraction.These data suggest that SGLT2 is expressed in rat mesangial cells, acts as a normal physiological glucose sensor and regulates cellular contractility in rat mesangial cells.

  19. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose.

    Science.gov (United States)

    Powell, David R; Smith, Melinda; Greer, Jennifer; Harris, Angela; Zhao, Sharon; DaCosta, Christopher; Mseeh, Faika; Shadoan, Melanie K; Sands, Arthur; Zambrowicz, Brian; Ding, Zhi-Ming

    2013-05-01

    LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.

  20. Rates of myocardial infarction and stroke in patients initiated on SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice

    DEFF Research Database (Denmark)

    Kosiborod, Mikhail; Birkeland, Kåre I; Cavender, Matthew A

    2018-01-01

    The multinational, observational CVD-REAL study recently showed that initiation of sodium-glucose co-transporter-2 inhibitors (SGLT-2i) was associated with significantly lower rates of death and heart failure vs. other glucose-lowering drugs (oGLDs). This sub-analysis of CVD-REAL sought to determ...

  1. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Functional expression of sodium-glucose transporters in cancer

    Science.gov (United States)

    Scafoglio, Claudio; Hirayama, Bruce A.; Kepe, Vladimir; Liu, Jie; Ghezzi, Chiara; Satyamurthy, Nagichettiar; Moatamed, Neda A.; Huang, Jiaoti; Koepsell, Hermann; Barrio, Jorge R.; Wright, Ernest M.

    2015-01-01

    Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy. PMID:26170283

  3. Diabetes and kidney disease: the role of sodium-glucose cotransporter-2 (SGLT-2) and SGLT-2 inhibitors in modifying disease outcomes.

    Science.gov (United States)

    Mende, Christian W

    2017-03-01

    Patients with type 2 diabetes (T2D) often have coexisting chronic kidney disease (CKD). However, healthy renal function is crucial in maintaining glucose homeostasis, assuring that almost all of the filtered glucose is reabsorbed by the sodium glucose cotransporters (SGLTs) SGLT-1 and SGLT-2. In diabetes, an increased amount of glucose is filtered by the kidneys and SGLT-2 is upregulated, leading to increased glucose absorption and worsening hyperglycemia. Prolonged hyperglycemia contributes to the development of CKD by inducing metabolic and hemodynamic changes in the kidneys. Due to the importance of SGLT-2 in regulating glucose levels, investigation into SGLT-2 inhibitors was initiated as a glucose-dependent mechanism to control hyperglycemia, and there are three agents currently approved for use in the United States: dapagliflozin, canagliflozin, and empagliflozin. SGLT-2 inhibitors have been shown to reduce glycated hemoglobin (A1C), weight, and blood pressure, which not only affects glycemic control, but may also help slow the progression of renal disease by impacting the underlying mechanisms of kidney injury. In addition, SGLT-2 inhibitors have shown reductions in albuminuria, uric acid, and an increase in magnesium. Caution is advised when prescribing SGLT-2 inhibitors to patients with moderately impaired renal function and those at risk for volume depletion and hypotension. Published data on slowing of the development, as well as progression of CKD, is a hopeful indicator for the possible renal protection potential of this drug class. This narrative review provides an in-depth discussion of the interplay between diabetes, SGLT-2 inhibitors, and factors that affect kidney function.

  4. A 96-well automated method to study inhibitors of human sodium-dependent D-glucose transport.

    Science.gov (United States)

    Castaneda, Francisco; Kinne, Rolf K-H

    2005-12-01

    The sodium-dependent D-glucose transporter (SGLT) family is involved in glucose uptake via intestinal absorption (SGLT1) or renal reabsorption (SGLT1 and SGLT2). Current methods for the screening of inhibitors of SGLT transporters are complex, expensive and very labor intensive, and have not been applied to human SGLT transporters. The purpose of the present study was to develop an alternative 96-well automated method to study the activity of human SGLT1 and SGLT2. Chinese hamster ovary (CHO) Flp-In cells were stably transfected with pcDNA5-SGLT1 or pcDNA5-SGLT2 plasmid and maintained in hygromycin-selection Ham's F12 culture medium until hygromycin-resistant clones were developed. SGLT1 and SGLT2 gene expression was evaluated by relative real-time reverse transcription-polymerase chain reaction (RT-PCR) quantification, Western blotting, and immunocytochemical analysis. The clones with higher expression of SGLT1 and SGLT2 were used for transport studies using [14C]-methyl-alpha-D-glucopyranoside ([14C]AMG). The advantage of using the 96-well format is the low amount of radioactive compounds and inhibitory substances required, and its ability to establish reproducibility because repetition into the assay. This method represents an initial approach in the development of transport-based high-throughput screening in the search for inhibitors of glucose transport. The proposed method can easily be performed to yield quantitative data regarding key aspects of glucose membrane transport and kinetic studies of potential inhibitors of human SGLT1 and SGLT2.

  5. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with Type 2 diabetes

    DEFF Research Database (Denmark)

    Røder, Michael Einar; Storgaard, Heidi; Rungby, Jørgen

    2016-01-01

    The sodium-glucose cotransporter 2 inhibitor (SGLT-2i)-class is efficacious as monotherapy and as add-on therapy with an expected lowering of the glycated haemoglobin (HbA1c) concentration of approximately 7 mmol/mol. Side effects relate to the mode of action, genital infections are the main...... problem. Extremely rare cases of ketoacidosis are reported, mostly in patients with Type 1 diabetes. One SGLT-2i, empagliflozin, has been shown to reduce cardiovascular mortality and progression of kidney disease in patients with Type 2 diabetes and cardiovascular disease. Outcome trials for other SGLT-2i...... are pending. SGLT-2i are now in guidelines as a possible second-line therapy or in case of metformin intolerance....

  6. Sodium-glucose cotransporter (SGLT)-2-inhibitorer til patienter med type 2-diabetes

    DEFF Research Database (Denmark)

    Røder, Michael Einar; Storgaard, Heidi; Rungby, Jørgen

    2016-01-01

    The sodium-glucose cotransporter 2 inhibitor (SGLT-2i)-class is efficacious as monotherapy and as add-on therapy with an expected lowering of the glycated haemoglobin (HbA1c) concentration of approximately 7 mmol/mol. Side effects relate to the mode of action, genital infections are the main...... problem. Extremely rare cases of ketoacidosis are reported, mostly in patients with Type 1 diabetes. One SGLT-2i, empagliflozin, has been shown to reduce cardiovascular mortality and progression of kidney disease in patients with Type 2 diabetes and cardiovascular disease. Outcome trials for other SGLT-2i...... are pending. SGLT-2i are now in guidelines as a possible second-line therapy or in case of metformin intolerance....

  7. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

    Science.gov (United States)

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [14C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [14C]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID:25044127

  8. Novel Hypothesis to Explain Why SGLT2 Inhibitors Inhibit Only 30–50% of Filtered Glucose Load in Humans

    Science.gov (United States)

    Abdul-Ghani, Muhammad A.; DeFronzo, Ralph A.; Norton, Luke

    2013-01-01

    Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis. PMID:24065789

  9. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans.

    Science.gov (United States)

    Abdul-Ghani, Muhammad A; DeFronzo, Ralph A; Norton, Luke

    2013-10-01

    Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis.

  10. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences

    Science.gov (United States)

    Gallo, Linda A; Wright, Ernest M; Vallon, Volker

    2018-01-01

    Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions only excrete ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents. PMID:25616707

  11. Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

    Science.gov (United States)

    Chichger, Havovi; Cleasby, Mark E; Srai, Surjit K; Unwin, Robert J; Debnam, Edward S; Marks, Joanne

    2016-06-01

    What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC

  12. SGLT-2 Inhibitors and Cardiovascular Risk

    DEFF Research Database (Denmark)

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  13. Development and application of a fluorescent glucose uptake assay for the high-throughput screening of non-glycoside SGLT2 inhibitors.

    Science.gov (United States)

    Wu, Szu-Huei; Yao, Chun-Hsu; Hsieh, Chieh-Jui; Liu, Yu-Wei; Chao, Yu-Sheng; Song, Jen-Shin; Lee, Jinq-Chyi

    2015-07-10

    Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are of current interest as a treatment for type 2 diabetes. Efforts have been made to discover phlorizin-related glycosides with good SGLT2 inhibitory activity. To increase structural diversity and better understand the role of non-glycoside SGLT2 inhibitors on glycemic control, we initiated a research program to identify non-glycoside hits from high-throughput screening. Here, we report the development of a novel, fluorogenic probe-based glucose uptake system based on a Cu(I)-catalyzed [3+2] cycloaddition. The safer processes and cheaper substances made the developed assay our first priority for large-scale primary screening as compared to the well-known [(14)C]-labeled α-methyl-D-glucopyranoside ([(14)C]-AMG) radioactive assay. This effort culminated in the identification of a benzimidazole, non-glycoside SGLT2 hit with an EC50 value of 0.62 μM by high-throughput screening of 41,000 compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Na+-glucose cotransporter SGLT1 protein in salivary glands: potential involvement in the diabetes-induced decrease in salivary flow.

    Science.gov (United States)

    Sabino-Silva, R; Freitas, H S; Lamers, M L; Okamoto, M M; Santos, M F; Machado, U F

    2009-03-01

    Oral health complications in diabetes include decreased salivary secretion. The SLC5A1 gene encodes the Na(+)-glucose cotransporter SGLT1 protein, which not only transports glucose, but also acts as a water channel. Since SLC5A1 expression is altered in kidneys of diabetic subjects, we hypothesize that it could also be altered in salivary glands, contributing to diabetic dysfunction. The present study shows a diabetes-induced decrease (p salivary secretion, which was accompanied by enhanced (p diabetic rats revealed that SGLT1 protein expression increased in the luminal membrane of ductal cells, which can stimulate water reabsorption from primary saliva. Furthermore, SGLT1 protein was reduced in myoepithelial cells of the parotid from diabetic animals, and that, by reducing cellular contractile activity, might also be related to reduced salivary flux. Six-day insulin-treated diabetic rats reversed all alterations. In conclusion, diabetes increases SLC5A1 gene expression in salivary glands, increasing the SGLT1 protein content in the luminal membrane of ductal cells, which, by increasing water reabsorption, might explain the diabetes-induced decrease in salivary secretion.

  15. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data.

    Science.gov (United States)

    Kurosaki, Eiji; Ogasawara, Hideaki

    2013-07-01

    Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of the kidneys and plays a key role in renal glucose reabsorption. A novel class of antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM). In this review, we summarize recent animal and human studies on ipragliflozin and other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and luseogliflozin. These agents all show potent and selective SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several advantages over other classes of hypoglycemic agents. Due to their insulin-independent mode of action, SGLT2 inhibitors provide steady glucose control without major risk for hypoglycemia and may also reverse β-cell dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors include a reduction in both body weight and blood pressure. SGLT2 inhibitors are safe and well tolerated and can easily be combined with other classes of antidiabetic medications to achieve tighter glycemic control. The long-term safety and efficacy of these agents are under evaluation. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Development of a novel non-radioactive cell-based method for the screening of SGLT1 and SGLT2 inhibitors using 1-NBDG.

    Science.gov (United States)

    Chang, Hung-Chi; Yang, Su-Fu; Huang, Ching-Chun; Lin, Tzung-Sheng; Liang, Pi-Hui; Lin, Chun-Jung; Hsu, Lih-Ching

    2013-08-01

    Sodium-coupled glucose co-transporters SGLT1 and SGLT2 play important roles in intestinal absorption and renal reabsorption of glucose, respectively. Blocking SGLT2 is a novel mechanism for lowering the blood glucose level by inhibiting renal glucose reabsorption and selective SGLT2 inhibitors are under development for treatment of type 2 diabetes. Furthermore, it has been reported that perturbation of SGLT1 is associated with cardiomyopathy and cancer. Therefore, both SGLT1 and SGLT2 are potential therapeutic targets. Here we report the development of a non-radioactive cell-based method for the screening of SGLT inhibitors using COS-7 cells transiently expressing human SGLT1 (hSGLT1), CHO-K1 cells stably expressing human SGLT2 (hSGLT2), and a novel fluorescent d-glucose analogue 1-NBDG as a substrate. Our data indicate that 1-NBDG can be a good replacement for the currently used isotope-labeled SGLT substrate, (14)C-AMG. The Michaelis constant of 1-NBDG transport (0.55 mM) is similar to that of d-glucose (0.51 mM) and AMG (0.40 mM) transport through hSGLT1. The IC50 values of a SGLT inhibitor phlorizin for hSGLT1 obtained using 1-NBDG and (14)C-AMG were identical (0.11 μM) in our cell-based system. The IC50 values of dapagliflozin, a well-known selective SGLT2 inhibitor, for hSGLT2 and hSGLT1 determined using 1-NBDG were 1.86 nM and 880 nM, respectively, which are comparable to the published results obtained using (14)C-AMG. Compared to (14)C-AMG, the use of 1-NBDG is cost-effective, convenient and potentially more sensitive. Taken together, a non-radioactive system using 1-NBDG has been validated as a rapid and reliable method for the screening of SGLT1 and SGLT2 inhibitors.

  17. SGLT2 inhibitors in the treatment of type 2 diabetes.

    Science.gov (United States)

    Hasan, Farhad M; Alsahli, Mazen; Gerich, John E

    2014-06-01

    The kidney plays an important role in glucose homeostasis via its production, utilization, and, most importantly, reabsorption of glucose from glomerular filtrate which is largely mediated via the sodium glucose co-transporter 2 (SGLT2). Pharmacological inhibition of SGLT2 increases urinary glucose excretion and decreases plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 represent a novel class of drugs, which has recently become available for treatment of type 2 diabetes. This article summarizes the rationale for use of these agents and reviews available clinical data on their efficacy, safety, and risks/benefits. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

    Science.gov (United States)

    Choi, Chang-Ik

    2016-08-27

    Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

  19. Sodium-Glucose Cotransporter 2 (SGLT2 Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents

    Directory of Open Access Journals (Sweden)

    Chang-Ik Choi

    2016-08-01

    Full Text Available Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2 for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

  20. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

    Science.gov (United States)

    Jabbour, S A; Goldstein, B J

    2008-08-01

    The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

  1. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Science.gov (United States)

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  2. Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia.

    Science.gov (United States)

    Yamazaki, Yui; Harada, Shinichi; Wada, Tetsuyuki; Yoshida, Shigeru; Tokuyama, Shogo

    2016-07-01

    We recently demonstrated that the cerebral sodium-glucose transporter (SGLT) is involved in postischaemic hyperglycaemia-induced exacerbation of cerebral ischaemia. However, the associated SGLT-mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT-induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage. [Na+]i was estimated according to sodium-binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT-specific inhibitor phlorizin. SGLT-specific sodium ion influx was induced using a-methyl-D-glucopyranoside (a-MG) treatments, which led to significant concentration-dependent declines in neuronal survival rates and exacerbated hydrogen peroxide-induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a-MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage. © 2016 Royal Pharmaceutical Society.

  3. In vitro characterization of luseogliflozin, a potent and competitive sodium glucose co-transporter 2 inhibitor: Inhibition kinetics and binding studies

    Directory of Open Access Journals (Sweden)

    Saeko Uchida

    2015-05-01

    Full Text Available In this study, we evaluated an inhibition model of luseogliflozin on sodium glucose co-transporter 2 (SGLT2. We also analyzed the binding kinetics of the drug to SGLT2 protein using [3H]-luseogliflozin. Luseogliflozin competitively inhibited human SGLT2 (hSGLT2-mediated glucose uptake with a Ki value of 1.10 nM. In the absence of glucose, [3H]-luseogliflozin exhibited a high affinity for hSGLT2 with a Kd value of 1.3 nM. The dissociation half-time was 7 h, suggesting that luseogliflozin dissociates rather slowly from hSGLT2. These profiles of luseogliflozin might contribute to the long duration of action of this drug.

  4. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.

    Science.gov (United States)

    Scheen, André J

    2014-04-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

  5. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    Science.gov (United States)

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

    2016-01-01

    Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

  6. The effects of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise Lotte; Christensen, Mikkel

    2014-01-01

    INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta......-analyses of randomised clinical trials on SGLT-2i versus placebo, other oral glucose lowering drugs or insulin for patients with type 2 diabetes will be performed. The primary end point will be the glycated haemoglobin. Secondary end points will include changes in body weight, body mass index, fasting plasma glucose...... to the knowledge regarding the beneficial and harmful effects of SGLT-2i in patients with type 2 diabetes. We plan to publish the study irrespective of the results. RESULTS: The study will be disseminated by peer-review publication and conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014008960...

  7. Effects of taurine on plasma glucose concentration and active glucose transport in the small intestine.

    Science.gov (United States)

    Tsuchiya, Yo; Kawamata, Koichi

    2017-11-01

    Taurine lowers blood glucose levels and improves hyperglycemia. However, its effects on glucose transport in the small intestine have not been investigated. Here, we elucidated the effect of taurine on glucose absorption in the small intestine. In the oral glucose tolerance test, addition of 10 mmol/L taurine suppressed the increase in hepatic portal glucose concentrations. To investigate whether the suppressive effect of taurine occurs via down-regulation of active glucose transport in the small intestine, we performed an assay using the everted sac of the rat jejunum. Addition of taurine to the mucosal side of the jejunum suppressed active glucose transport via sodium-glucose cotransporter 1 (SGLT1). After elimination of chloride ions from the mucosal solution, taurine did not show suppressive effects on active glucose transport. These results suggest that taurine suppressed the increase in hepatic portal glucose concentrations via suppression of SGLT1 activity in the rat jejunum, depending on chloride ions. © 2017 Japanese Society of Animal Science.

  8. [Mechanisms and efficacy of SGLT2 inhibitors].

    Science.gov (United States)

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  9. Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy?

    Directory of Open Access Journals (Sweden)

    Usha Panchapakesan

    Full Text Available Sodium/glucose cotransporter 2 (SGLT2 inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC, leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line were exposed to control 5 mM, high glucose (HG 30 mM or the profibrotic cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-κB suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression through phosphorylated smad3.

  10. Glucose transporters are expressed in taste receptor cells.

    Science.gov (United States)

    Merigo, Flavia; Benati, Donatella; Cristofoletti, Mirko; Osculati, Francesco; Sbarbati, Andrea

    2011-08-01

    In the intestine, changes of sugar concentration generated in the lumen during digestion induce adaptive responses of glucose transporters in the epithelium. A close matching between the intestinal expression of glucose transporters and the composition and amount of the diet has been provided by several experiments. Functional evidence has demonstrated that the regulation of glucose transporters into enterocytes is induced by the sensing of sugar of the enteroendocrine cells through activation of sweet taste receptors (T1R2 and T1R3) and their associated elements of G-protein-linked signaling pathways (e.g. α-gustducin, phospholipase C β type 2 and transient receptor potential channel M5), which are signaling molecules also involved in the perception of sweet substances in the taste receptor cells (TRCs) of the tongue. Considering this phenotypical similarity between the intestinal cells and TRCs, we evaluated whether the TRCs themselves possess proteins of the glucose transport mechanism. Therefore, we investigated the expression of the typical intestinal glucose transporters (i.e. GLUT2, GLUT5 and SGLT1) in rat circumvallate papillae, using immunohistochemistry, double-labeling immunofluorescence, immunoelectron microscopy and reverse transcriptase-polymerase chain reaction analysis. The results showed that GLUT2, GLUT5 and SGLT1 are expressed in TRCs; their immunoreactivity was also observed in cells that displayed staining for α-gustducin and T1R3 receptor. The immunoelectron microscopic results confirmed that GLUT2, GLUT5 and SGLT1 were predominantly expressed in cells with ultrastructural characteristics of chemoreceptor cells. The presence of glucose transporters in TRCs adds a further link between chemosensory information and cellular responses to sweet stimuli that may have important roles in glucose homeostasis, contributing to a better understanding of the pathways implicated in glucose metabolism. © 2011 The Authors. Journal of Anatomy © 2011

  11. Molecular analysis of the SGLT2 gene in patients with renal glucosuria

    DEFF Research Database (Denmark)

    Santer, René; Kinner, Martina; Lassen, Christoph L.

    2003-01-01

    The role of SGLT2 (the gene for a renal sodium-dependent glucose transporter) in renal glucosuria was evaluated. Therefore, its genomic sequence and its intron-exon organization were determined, and 23 families with index cases were analyzed for mutations. In 21 families, 21 different SGLT2 mutat...

  12. What Are The Benefits In The Association Of SGLT2 Inhibitors And Other Drugs?

    Directory of Open Access Journals (Sweden)

    Deici Aparecida Gomes Rodrigues

    2017-11-01

    Full Text Available The SGLT2 inhibitors are a class of drugs that blocks the sodium-glucose co-transport, which is responsible for 90% of the nephron glucose. Objective: To show the benefits of the SGLT2 inhibitors in monotherapy and in association with other drugs. Results: The association of SGLT2 inhibitors and other drugs has shown several additional benefits after their interaction, including weight loss, reduction of body fat, reduction of triglycerides level, decrease of glycated hemoglobin, decrease in postprandial glucose level, reduction of arterial pressure, decrease of hypoglycemia risk and improvement of glucose metabolism. Therefore, this is a promising interaction for type 2 diabetes.

  13. Safety of Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2-I During the Month of Ramadan in Muslim Patients with Type 2 Diabetes

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    Alaaeldin Bashier

    2018-03-01

    Full Text Available Objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2-I are a new class of antidiabetic drugs that might increase the risk of dehydration and hypoglycemia, particularly during the month of Ramadan in which Muslims abstain from eating and drinking for 14–16 hours daily. We aimed to provide real-life evidence about the safety of SGLT2-I during Ramadan. Methods: All patients over the age of 18 years on SGLT2-I before Ramadan 2016 who would be fasting during Ramadan were included. Demographic data, detailed medical history including comorbidities and medication profile, and laboratory results were collected before and after Ramadan. We also conducted a phone interview to evaluate the frequency and severity of hypoglycemia and dehydration. Results: Of the total of 417 patients, 113 (27.0% experienced hypoglycemic events, and 93 of these (82.3% checked their blood glucose using a glucometer. Confirmed hypoglycemia (< 70 mg/dL was observed in 78 (83.8%. The hypoglycemic events were significantly more frequent in the SGLT2-I plus insulin-treated group than in those treated with SGLT2-I plus oral hypoglycemic agents group (p < 0.001. Confirmed hypoglycemic events were more frequent in those using SGLT2-I plus intensive insulin compared to those using SGLT2-I plus basal insulin (p = 0.020. Symptoms of dehydration were seen in 9.3% (n = 39 of the total population. We observed statistically significant reductions in glycated hemoglobin and weight by the end of Ramadan (p < 0.001. There were no significant changes in lipid profile and creatinine levels by the end of the study. Conclusions: The use of insulin in combination with SGLT2-I increases the risk of hypoglycemia during Ramadan. Hypoglycemic events were mild and did not require hospital admission. However, careful monitoring during prolonged fasting is warranted. No significant harmful effects on renal function result from treatment with SGLT2-I during Ramadan.

  14. The effects of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise Lotte; Christensen, Mikkel

    2014-01-01

    INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta-analyses of r......INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) increase urinary glucose excretion through a reduced renal glucose reabsorption. We plan to perform a systematic review of SGLT-2i for treatment of type 2 diabetes. METHODS AND ANALYSIS: A systematic review with meta......-analyses of randomised clinical trials on SGLT-2i versus placebo, other oral glucose lowering drugs or insulin for patients with type 2 diabetes will be performed. The primary end point will be the glycated haemoglobin. Secondary end points will include changes in body weight, body mass index, fasting plasma glucose......, plasma cholesterol, kidney and liver blood tests, blood pressure and adverse events. Electronic (the Cochrane Library, MEDLINE, EMBASE and the Science Citation Index) and manual searches will be performed. Meta-analyses will be performed and the results presented as mean differences for continuous...

  15. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis.

    Science.gov (United States)

    Ruanpeng, Darin; Ungprasert, Patompong; Sangtian, Jutarat; Harindhanavudhi, Tasma

    2017-09-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors could potentially alter calcium and phosphate homeostasis and may increase the risk of bone fracture. The current meta-analysis was conducted to investigate the fracture risk among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors. Randomized controlled trials that compared the efficacy of SGLT2 inhibitors to placebo were identified. The risk ratios of fracture among patients who received SGLT2 inhibitors versus placebo were extracted from each study. Pooled risk ratios and 95% confidence intervals were calculated using a random-effect, Mantel-Haenszel analysis. A total of 20 studies with 8286 patients treated with SGLT2 inhibitors were included. The pooled risk ratio of bone fracture in patients receiving SGLT2 inhibitors versus placebo was 0.67 (95% confidence interval, 0.42-1.07). The pooled risk ratio for canagliflozin, dapagliflozin, and empagliflozin was 0.66 (95% confidence interval, 0.37-1.19), 0.84 (95% confidence interval, 0.22-3.18), and 0.57 (95% confidence interval, 0.20-1.59), respectively. Increased risk of bone fracture among patients with type 2 diabetes mellitus treated with SGLT2 inhibitors compared with placebo was not observed in this meta-analysis. However, the results were limited by short duration of treatment/follow-up and low incidence of the event of interest. Copyright © 2017 John Wiley & Sons, Ltd.

  16. SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy

    Science.gov (United States)

    Wang, Xiaoxin X.; Levi, Jonathan; Luo, Yuhuan; Myakala, Komuraiah; Herman-Edelstein, Michal; Qiu, Liru; Wang, Dong; Peng, Yingqiong; Grenz, Almut; Lucia, Scott; Dobrinskikh, Evgenia; D'Agati, Vivette D.; Koepsell, Hermann; Kopp, Jeffrey B.; Rosenberg, Avi Z.; Levi, Moshe

    2017-01-01

    There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-β, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice. PMID:28196866

  17. Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

    Science.gov (United States)

    Demin, Oleg; Yakovleva, Tatiana; Kolobkov, Dmitry; Demin, Oleg

    2014-01-01

    The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family). PMID:25352807

  18. Analysis of efficacy of SGLT2 inhibitors using semi-mechanistic model

    Directory of Open Access Journals (Sweden)

    Oleg eDemin Jr

    2014-10-01

    Full Text Available Renal sodium-dependent glucose co-transporter 2 (SGLT2 is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies. All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: 1 the site of action of SGLT2 inhibitors is not in the lumen of the kidney’s proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells; and 2 there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family.

  19. Quality of methodological reporting of randomized clinical trials of sodium-glucose cotransporter-2 (sglt2 inhibitors

    Directory of Open Access Journals (Sweden)

    Hadeel Alfahmi

    2017-01-01

    Full Text Available Sodium-glucose cotransporter-2 (SGLT2 inhibitors are a new class of medicines approved recently for the treatment of type 2 diabetes. To improve the quality of randomized clinical trial (RCT reports, the Consolidated Standards of Reporting Trials (CONSORT statement for methodological features was created. For achieving our objective in this study, we assessed the quality of methodological reporting of RCTs of SGLT2 inhibitors according to the 2010 CONSORT statement. We reviewed and analyzed the methodology of SGLT2 inhibitors RCTs that were approved by the Food & Drug Administration (FDA. Of the 27 trials, participants, eligibility criteria, and additional analyses were reported in 100% of the trials. In addition, trial design, interventions, and statistical methods were reported in 96.3% of the trials. Outcomes were reported in 93.6% of the trials. Settings were reported in 85.2% of the trials. Blinding and sample size were reported in 66.7 and 59.3% of the trials, respectively. Sequence allocation and the type of randomization were reported in 63 and 74.1% of the trials, respectively. Besides those, a few methodological items were inadequate in the trials. Allocation concealment was inadequate in most of the trials. It was reported only in 11.1% of the trials. The majority of RCTs have high percentage adherence for more than half of the methodological items of the 2010 CONSORT statement.

  20. De novo expression of sodium-glucose cotransporter SGLT2 in Bowman's capsule coincides with replacement of parietal epithelial cell layer with proximal tubule-like epithelium.

    Science.gov (United States)

    Tabatabai, Niloofar M; North, Paula E; Regner, Kevin R; Kumar, Suresh N; Duris, Christine B; Blodgett, Amy B

    2014-08-01

    In kidney nephron, parietal epithelial cells line the Bowman's capsule and function as a permeability barrier for the glomerular filtrate. Bowman's capsule cells with proximal tubule epithelial morphology have been found. However, the effects of tubular metaplasia in Bowman's capsule on kidney function remain poorly understood. Sodium-glucose cotransporter 2 (SGLT2) plays a major role in reabsorption of glucose in the kidney and is expressed on brush border membrane (BBM) of epithelial cells in the early segment of the proximal tubule. We hypothesized that SGLT2 is expressed in tubularized Bowman's capsule and used our novel antibody to test this hypothesis. Immunohistochemical analysis was performed with our SGLT2 antibody on C57BL/6 mouse kidney prone to have tubularized Bowman's capsules. Cell membrane was examined with periodic acid-Schiff (PAS) stain. The results showed that SGLT2 was localized on BBM of the proximal tubules in young and adult mice. Bowman's capsules were lined mostly with normal brush border-less parietal epithelial cells in young mice, while they were almost completely covered with proximal tubule-like cells in adult mice. Regardless of age, SGLT2 was expressed on BBM of the tubularized Bowman's capsule but did not co-localize with nephrin in the glomerulus. SGLT2-expressing tubular cells expanded from the urinary pole toward the vascular pole of the Bowman's capsule. This study identified the localization of SGLT2 in the Bowman's capsule. Bowman's capsules with tubular metaplasia may acquire roles in reabsorption of filtered glucose and sodium.

  1. Euglycemic Diabetic Ketoacidosis with Elevated Acetone in a Patient Taking a Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor.

    Science.gov (United States)

    Andrews, Tory J; Cox, Robert D; Parker, Christina; Kolb, James

    2017-02-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitor medications are a class of antihyperglycemic agents that increase urinary glucose excretion by interfering with the reabsorption of glucose in the proximal renal tubules. In May of 2015, the U.S. Food and Drug Administration released a warning concerning a potential increased risk of ketoacidosis and ketosis in patients taking these medications. We present a case of a 57-year-old woman with type 2 diabetes mellitus taking a combination of canagliflozin and metformin who presented with progressive altered mental status over the previous 2 days. Her work-up demonstrated a metabolic acidosis with an anion gap of 38 and a venous serum pH of 7.08. The serum glucose was 168 mg/dL. The urinalysis showed glucose > 500 mg/dL and ketones of 80 mg/dL. Further evaluation demonstrated an elevated serum osmolality of 319 mOsm/kg and an acetone concentration of 93 mg/dL. She was treated with intravenous insulin and fluids, and the metabolic abnormalities and her altered mental status resolved within 36 h. This was the first episode of diabetic ketoacidosis (DKA) for this patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Diabetic patients on SGLT2 inhibitor medications are at risk for ketoacidosis. Due to the renal glucose-wasting properties of these drugs, they may present with ketoacidosis with only mild elevations in serum glucose, potentially complicating the diagnosis. Acetone is one of the three main ketone bodies formed during DKA and it may be present at considerable concentrations, contributing to the serum osmolality. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes.

    Science.gov (United States)

    Nauck, Michael A

    2014-01-01

    The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter type 2 (SGLT2) inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit-risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration.

  3. The design and synthesis of novel SGLT2 inhibitors: C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties.

    Science.gov (United States)

    Guo, Cheng; Hu, Min; DeOrazio, Russell J; Usyatinsky, Alexander; Fitzpatrick, Kevin; Zhang, Zhenjun; Maeng, Jun-Ho; Kitchen, Douglas B; Tom, Susan; Luche, Michele; Khmelnitsky, Yuri; Mhyre, Andrew J; Guzzo, Peter R; Liu, Shuang

    2014-07-01

    The sodium glucose co-transporter 2 (SGLT2) has received considerable attention in recent years as a target for the treatment of type 2 diabetes mellitus. This report describes the design, synthesis and structure-activity relationship (SAR) of C-glycosides with benzyltriazolopyridinone and phenylhydantoin as the aglycone moieties as novel SGLT2 inhibitors. Compounds 5p and 33b demonstrated high potency in inhibiting SGLT2 and high selectivity against SGLT1. The in vitro ADMET properties of these compounds will also be discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. SGLT2 inhibitors: molecular design and potential differences in effect.

    Science.gov (United States)

    Isaji, Masayuki

    2011-03-01

    The physiological and pathological handling of glucose via sodium-glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs.

  5. SGLT2 inhibitors: are they safe?

    Science.gov (United States)

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  6. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry.

    Science.gov (United States)

    Sawada, Yoshikazu; Izumida, Yoshihiko; Takeuchi, Yoshinori; Aita, Yuichi; Wada, Nobuhiro; Li, EnXu; Murayama, Yuki; Piao, Xianying; Shikama, Akito; Masuda, Yukari; Nishi-Tatsumi, Makiko; Kubota, Midori; Sekiya, Motohiro; Matsuzaka, Takashi; Nakagawa, Yoshimi; Sugano, Yoko; Iwasaki, Hitoshi; Kobayashi, Kazuto; Yatoh, Shigeru; Suzuki, Hiroaki; Yagyu, Hiroaki; Kawakami, Yasushi; Kadowaki, Takashi; Shimano, Hitoshi; Yahagi, Naoya

    2017-11-04

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Substrate binding to SGLT1 investigated by single molecule force spectroscopy

    International Nuclear Information System (INIS)

    Neundlinger, I. J.

    2010-01-01

    D-glucose serves as one of the most important fuels in various organism due to its fundamental role in ATP-, protein and lipid synthesis. Thus, sustaining glucose homeostasis is a crucial issue of life as disorders can cause severe malfunctions such as glucose-galactose-malabsorbtion (GGM). Sodium-glucose co-transporter, SGLTs, especially the high affinity transporter SGLT1, play a crucial role in accumulation of glucose in the cell as they facilitate transport of the sugar into the cytoplasma across the cell membrane by a Na+-electrochemical potential. Even recently, members of the SGLT transporter family have become a therapeutic target for the treatment of hyperglycemia in type 2 diabetes. Hence, it is of particular importance to gain insights on the dynamic behavior of SGLTs during substrate binding and transport across the cell membrane on the single molecular level. In the present study, the Atomic Force Microscope (AFM) was employed to investigate the dynamic properties of the sodium-glucose co-transporter SGLT1 upon substrate binding under nearly physiological conditions. Hereto, new glucose derivatives were synthesized in order to probe the recognition efficiency of these molecules to SGLT1 embedded in the plasma membrane of living cells. A well established coupling protocol was used to covalently link (i) amino-modified D-glucose owning a conserved pyranose ring, (ii) 1-thio-β-D-glucose having a sulphur atom at C1 of the pyranose ring and (iii) the competitive inhibitor phlorizin to the AFM tip via poly(ethylene)glycol (PEG)-tether using different functional end groups and varying lengths. Binding characteristics, e.g. binding probability, interaction forces, influence of substances (glucose, phlorizin, sodium) and of molecule-linker compounds were obtained by performing single molecular recognition force spectroscopy (SMRFS) measurements. Moreover, temperature controlled radioactive binding/transport assays and SMRFS experiments yielded insights into

  8. The renal effects of SGLT2 inhibitors and a mini-review of the literature.

    Science.gov (United States)

    Andrianesis, Vasileios; Glykofridi, Spyridoula; Doupis, John

    2016-12-01

    Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.

  9. Role of SGLT2 Inhibitors in Patients with Diabetes Mellitus and Heart Failure.

    Science.gov (United States)

    Verbrugge, Frederik H

    2017-08-01

    This review aims to summarize the evidence on cardiovascular risks and benefits of glucose-lowering drugs in diabetic patients, with a particular focus on the role of sodium-glucose transporter-2 (SGLT-2) inhibitors and their promising potential as a heart failure treatment. The SGLT-2 inhibitor empagliflozin has emerged as the first glucose-lowering drug to lower cardiovascular mortality in diabetes with an unprecedented 38% relative risk reduction. In addition, empagliflozin significantly reduced the rate of heart failure admissions with 35% when compared to placebo in diabetic patients with established atherosclerosis. SGLT-2 inhibitors should be considered as a first-line drug to achieve glycemic control in diabetic patients at high risk for cardiovascular diseases and heart failure in particular. As SGLT-2 inhibitors target different pathophysiological pathways in heart failure, they might even be considered in the broader population without diabetes, but this remains the topic of further study.

  10. SGLT2 inhibitors to control glycemia in type 2 diabetes mellitus: a new approach to an old problem.

    Science.gov (United States)

    Jabbour, Serge A

    2014-01-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent mechanism of action. The SGLT2 is a transporter found in the proximal tubule of the kidney and is responsible for approximately 90% of renal glucose reabsorption. The SGLT2 inhibitors reduce reabsorption of glucose in the kidney, resulting in glucose excretion in the urine (50-90 g of ~180 g filtered by the kidneys daily), which in turn lowers plasma glucose levels in people with diabetes. The insulin-independent mechanism of action of SGLT2 inhibitors dictates that they are associated with a very low risk of hypoglycemia and can be used in patients with any degree of β-cell function or insulin sensitivity. Clinical trials have shown that SGLT2 inhibitors are effective at reducing blood glucose levels, body weight, and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus. Treatment with SGLT2 inhibitors is generally well tolerated, although these agents have been associated with an increased incidence of genital infections. The SGLT2 inhibitors have become a valuable addition to the armory of drugs used to treat patients with type 2 diabetes mellitus, and several agents within the class are currently under investigation in phase III clinical trials.

  11. SGLT5 Reabsorbs Fructose in the Kidney but Its Deficiency Paradoxically Exacerbates Hepatic Steatosis Induced by Fructose

    OpenAIRE

    Fukuzawa, Taku; Fukazawa, Masanori; Ueda, Otoya; Shimada, Hideaki; Kito, Aki; Kakefuda, Mami; Kawase, Yosuke; Wada, Naoko A.; Goto, Chisato; Fukushima, Naoshi; Jishage, Kou-ichi; Honda, Kiyofumi; King, George L.; Kawabe, Yoshiki

    2013-01-01

    Although excessive fructose intake is epidemiologically linked with dyslipidemia, obesity, and diabetes, the mechanisms regulating plasma fructose are not well known. Cells transfected with sodium/glucose cotransporter 5 (SGLT5), which is expressed exclusively in the kidney, transport fructose in vitro; however, the physiological role of this transporter in fructose metabolism remains unclear. To determine whether SGLT5 functions as a fructose transporter in vivo, we established a line of mic...

  12. Stimulation of Na+/K+ ATPase activity and Na+ coupled glucose transport by β-catenin

    International Nuclear Information System (INIS)

    Sopjani, Mentor; Alesutan, Ioana; Wilmes, Jan; Dermaku-Sopjani, Miribane; Lam, Rebecca S.; Koutsouki, Evgenia; Jakupi, Muharrem; Foeller, Michael; Lang, Florian

    2010-01-01

    Research highlights: → The oncogenic transcription factor β-catenin stimulates the Na + /K + -ATPase. → β-Catenin stimulates SGLT1 dependent Na + , glucose cotransport. → The effects are independent of transcription. → β-Catenin sensitive transport may contribute to properties of proliferating cells. -- Abstract: β-Catenin is a multifunctional protein stimulating as oncogenic transcription factor several genes important for cell proliferation. β-Catenin-regulated genes include the serum- and glucocorticoid-inducible kinase SGK1, which is known to stimulate a variety of transport systems. The present study explored the possibility that β-catenin influences membrane transport. To this end, β-catenin was expressed in Xenopus oocytes with or without SGLT1 and electrogenic transport determined by dual electrode voltage clamp. As a result, expression of β-catenin significantly enhanced the ouabain-sensitive current of the endogeneous Na + /K + -ATPase. Inhibition of vesicle trafficking by brefeldin A revealed that the stimulatory effect of β-catenin on the endogenous Na + /K + -ATPase was not due to enhanced stability of the pump protein in the cell membrane. Expression of β-catenin further enhanced glucose-induced current (Ig) in SGLT1-expressing oocytes. In the absence of SGLT1 Ig was negligible irrespective of β-catenin expression. The stimulating effect of β-catenin on both Na + /K + ATPase and SGLT1 activity was observed even in the presence of actinomycin D, an inhibitor of transcription. The experiments disclose a completely novel function of β-catenin, i.e. the regulation of transport.

  13. Targeting the kidney and glucose excretion with dapagliflozin: preclinical and clinical evidence for SGLT2 inhibition as a new option for treatment of type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Whaley JM

    2012-07-01

    Full Text Available Jean M Whaley,1 Mark Tirmenstein,2 Timothy P Reilly,2 Simon M Poucher,3 JoAnne Saye,4 Shamik Parikh,5 James F List61Bristol-Myers Squibb, Metabolic Disease Discovery Biology, Research and Development, Princeton, NJ, USA; 2Bristol-Myers Squibb, Drug Safety Evaluation, Research and Development, New Brunswick and Princeton, NJ, USA; 3AstraZeneca, Cardiovascular and Gastrointestinal Innovative Medicines Science Unit, Alderley Park, Macclesfield, Cheshire, UK; 4AstraZeneca, Global Safety Assessment, Research and Development, Wilmington, DE, USA; 5AstraZeneca, Cardiovascular, Clinical Development, Wilmington, DE, USA; 6Bristol-Myers Squibb, Global Clinical Development, Research and Development, Princeton, NJ, USAAbstract: Sodium-glucose cotransporter-2 (SGLT2 inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a

  14. Evidence for the involvement of Ala 166 in coupling Na(+) to sugar transport through the human Na(+)/glucose cotransporter

    DEFF Research Database (Denmark)

    Meinild, A K; Loo, D D; Hirayama, B A

    2001-01-01

    . The affinity for Na(+) was unchanged compared to that of hSGLT1, whereas the sugar affinity was reduced and sugar specificity was altered. There was a reduction in the turnover rate of the transporter, and in contrast to that of hSGLT1, the turnover rate depended on the sugar molecule. Exposure of A166C......We mutated residue 166, located in the putative Na(+) transport pathway between transmembrane segments 4 and 5 of human Na(+)/glucose cotransporter (hSGLT1), from alanine to cysteine (A166C). A166C was expressed in Xenopus laevis oocytes, and electrophysiological methods were used to assay function...... to MTSEA and MTSET, but not MTSES, abolished sugar transport. Accessibility of A166C to alkylating reagents was independent of protein conformation, indicating that the residue is always accessible from the extracellular surface. Sugar and phlorizin did not protect the residue from being alkylated...

  15. Safety of Sodium-Glucose Co-Transporter 2 Inhibitors during Ramadan Fasting: Evidence, Perceptions and Guidelines

    Directory of Open Access Journals (Sweden)

    Salem A. Beshyah

    2016-06-01

    Full Text Available Sodium-glucose co-transporter 2 (SGLT2 inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients.  One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients’ education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis.

  16. Fluorine-Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes.

    Science.gov (United States)

    Sadurní, Anna; Kehr, Gerald; Ahlqvist, Marie; Wernevik, Johan; Sjögren, Helena Peilot; Kankkonen, Cecilia; Knerr, Laurent; Gilmour, Ryan

    2018-02-26

    Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga ® ) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Nauck MA

    2014-09-01

    Full Text Available Michael A Nauck Department of Internal Medicine, Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany Abstract: The importance of the kidney's role in glucose homeostasis has gained wider understanding in recent years. Consequently, the development of a new pharmacological class of anti-diabetes agents targeting the kidney has provided new treatment options for the management of type 2 diabetes mellitus (T2DM. Sodium glucose co-transporter type 2 (SGLT2 inhibitors, such as dapagliflozin, canagliflozin, and empagliflozin, decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated hemoglobin concentrations. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral anti-diabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefit–risk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration. Keywords: anti-diabetes agents, efficacy, hyperglycemia, safety, sodium glucose co-transporter type 2 inhibitors, type 2 diabetes mellitus

  18. SGLT5 Reabsorbs Fructose in the Kidney but Its Deficiency Paradoxically Exacerbates Hepatic Steatosis Induced by Fructose

    Science.gov (United States)

    Fukuzawa, Taku; Fukazawa, Masanori; Ueda, Otoya; Shimada, Hideaki; Kito, Aki; Kakefuda, Mami; Kawase, Yosuke; Wada, Naoko A.; Goto, Chisato; Fukushima, Naoshi; Jishage, Kou-ichi; Honda, Kiyofumi; King, George L.; Kawabe, Yoshiki

    2013-01-01

    Although excessive fructose intake is epidemiologically linked with dyslipidemia, obesity, and diabetes, the mechanisms regulating plasma fructose are not well known. Cells transfected with sodium/glucose cotransporter 5 (SGLT5), which is expressed exclusively in the kidney, transport fructose in vitro; however, the physiological role of this transporter in fructose metabolism remains unclear. To determine whether SGLT5 functions as a fructose transporter in vivo, we established a line of mice lacking the gene encoding SGLT5. Sodium-dependent fructose uptake disappeared in renal brush border membrane vesicles from SGLT5-deficient mice, and the increased urinary fructose in SGLT5-deficient mice indicated that SGLT5 was the major fructose reabsorption transporter in the kidney. From this, we hypothesized that urinary fructose excretion induced by SGLT5 deficiency would ameliorate fructose-induced hepatic steatosis. To test this hypothesis we compared SGLT5-deficient mice with wild-type mice under conditions of long-term fructose consumption. Paradoxically, however, fructose-induced hepatic steatosis was exacerbated in the SGLT5-deficient mice, and the massive urinary fructose excretion was accompanied by reduced levels of plasma triglycerides and epididymal fat but fasting hyperinsulinemia compared with fructose-fed wild-type mice. There was no difference in food consumption, water intake, or plasma fructose between the two types of mice. No compensatory effect by other transporters reportedly involved in fructose uptake in the liver and kidney were indicated at the mRNA level. These surprising findings indicated a previously unrecognized link through SGLT5 between renal fructose reabsorption and hepatic lipid metabolism. PMID:23451068

  19. SGLT2 inhibitors: their potential reduction in blood pressure.

    Science.gov (United States)

    Maliha, George; Townsend, Raymond R

    2015-01-01

    The sodium glucose co-transporter 2 (SGLT2) inhibitors represent a promising treatment option for diabetes and its common comorbidity, hypertension. Emerging data suggests that the SGLT2 inhibitors provide a meaningful reduction in blood pressure, although the precise mechanism of the blood pressure drop remains incompletely elucidated. Based on current data, the blood pressure reduction is partially due to a combination of diuresis, nephron remodeling, reduction in arterial stiffness, and weight loss. While current trials are underway focusing on cardiovascular endpoints, the SGLT2 inhibitors present a novel treatment modality for diabetes and its associated hypertension as well as an opportunity to elucidate the pathophysiology of hypertension in diabetes. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  20. The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes.

    Science.gov (United States)

    Pafili, K; Maltezos, E; Papanas, N

    2016-10-01

    There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion. In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM. Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.

  1. SGLT2 inhibition in the diabetic kidney – an update

    Science.gov (United States)

    Novikov, Aleksandra; Vallon, Volker

    2016-01-01

    Purpose of review The sodium glucose cotransporter SGLT2 reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption thereby lowering blood glucose levels and have been approved as new anti-hyperglycemic drugs. While the therapeutic strategy is very promising, many questions remain. Recent findings Using validated antibodies SGLT2 expression was localized to the brush border of the early proximal tubule in human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional glucose reabsorption of 40–50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alpha cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers GFR in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy. Summary The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors. PMID:26575393

  2. Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice.

    Science.gov (United States)

    Suzuki, Masayuki; Honda, Kiyofumi; Fukazawa, Masanori; Ozawa, Kazuharu; Hagita, Hitoshi; Kawai, Takahiro; Takeda, Minako; Yata, Tatsuo; Kawai, Mio; Fukuzawa, Taku; Kobayashi, Takamitsu; Sato, Tsutomu; Kawabe, Yoshiki; Ikeda, Sachiya

    2012-06-01

    Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.

  3. Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise L; Bennett, Cathy

    2016-01-01

    OBJECTIVE: Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND STUDY......, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. RESULTS: Meta-analysis of 34 RCTs with 9,154 patients showed...... to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). CONCLUSION: This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable...

  4. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  5. SGLT-2 inhibitors and the risk of lower-limb amputation: Is this a class effect?

    Science.gov (United States)

    Khouri, Charles; Cracowski, Jean-Luc; Roustit, Matthieu

    2018-06-01

    Inhibitors of the sodium-glucose co-transporter-2 (SGLT-2) are a novel class of glucose-lowering agents that show promising results. However, the use of canagliflozin has been associated with an increased risk of lower-limb amputation. Whether this risk concerns other SGLT-2 inhibitors is unclear, and our objective was to address this issue. We performed a disproportionality analysis using the WHO global database of individual case safety reports (VigiBase). Among the 8 293 886 reports available between January 2013 and December 2017, we identified 79 reports of lower-limb amputation that were associated with SGLT-2 inhibitors. Among all blood glucose lowering drugs, the proportional reporting ratio (PRR) was increased only for SGLT-2 inhibitors (5.55 [4.23, 7.29]). While we observed an expected signal for canagliflozin (7.09 [5.25, 9.57]), the PRR was also high for empagliflozin (4.96 [2.89, 8.50]) and, for toe amputations only, for dapagliflozin (2.62 [1.33, 5.14]). In conclusion, our results reveal a positive disproportionality signal for canagliflozin, and also for empagliflozin, and, for toe amputations only, for dapagliflozin. However, our analysis relies on a limited number of cases and is exposed to the biases inherent to pharmacovigilance studies. Further prospective data are therefore needed to better characterize the risk of amputations with different SGLT-2 inhibitors. © 2018 John Wiley & Sons Ltd.

  6. Flozins, inhibitors of type 2 renal sodium-glucose co-transporter – not only antihyperglycemic drugs

    Directory of Open Access Journals (Sweden)

    Mizerski Grzegorz

    2015-09-01

    Full Text Available The kidneys play a crucial role in the regulation of the carbohydrate metabolism. In normal physiological conditions, the glucose that filters through the renal glomeruli is subsequently nearly totally reabsorbed in the proximal renal tubules. Two transporters are engaged in this process: sodium-glucose co-transporter type 1 (SGLT1, and sodium-glucose co-transporter type type 2 (SGLT2 - this being located in the luminal membrane of the renal tubular epithelial cells. It was found that the administration of dapagliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes, is associated with the reduction of HbA1c concentration by 0.45-1.11%. Additional benefits from the treatment with dapagliflozin are the reduction of arterial blood pressure and a permanent reduction of body weight. This outcome is related to the effect of osmotic diuresis and to the considerable loss of the glucose load by way of urine excretion. Dapagliflozin may be successfully applied in type 2 diabetes monotherapy, as well as in combined therapy (including insulin, where it is equally effective as other oral anti-diabetic drugs. Of note: serious adverse effects of dapagliflozin administration are rarely observed. What is more, episodes of severe hypoglycaemia related with the treatment occur only sporadically, most often in the course of diabetes polytherapy. The most frequent effects of the SGLT2 inhibitors are inseparably associated with the mechanism of their action (the glucuretic effect, and cover urogenital infections with a mild clinical course. At present, clinical trials are being continued of the administration of several subsequent drugs from this group, the most advanced of these being the use of canagliflozin and empagliflozin.

  7. SGLT2 Inhibitors in Diabetes Mellitus Treatment.

    Science.gov (United States)

    Rosas-Guzman, Juan; Rosas-Saucedo, Juan; Romero-Garcia, Alma R J

    2017-01-01

    Type 2 Diabetes Mellitus (T2DM) is a chronic illness with high prevalence in Mexico, Latin- America, and the world and is associated to high morbidity, disability, and mortality rate, especially in developing countries. T2DM physiopathology is very complex; insulin resistance in the muscle, liver, and adipose tissue, a reduction in the production of incretins (mainly GLP-1) in the intestine, increased glucagon synthesis, an insufficient response of insulin generation, and increased glucose reabsorption in the kidney lead all together to an hyperglycemic state, which has been closely associated with the development of micro and macrovascular complications. Sodium Glucose Linked Transporter 2 inhibitors (SGLT2i) are the most recent therapeutic class available for treating T2DM. SGLT2i central effect is a glycosuric action, and they can reverse the deleterious effect of tubular reabsorption of glucose in the diabetic patient resulting in greater hyperglycemia. Because their mechanism of action is completely different to current drugs, they can be considered as monotherapy or in combination with any other oral or parenteral medication, including different types of insulin or its analogues. This therapeutic synergy accomplishes a greater percentage of patients achieving glycemic control goals. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. De novo expression of sodium-glucose cotransporter SGLT2 in Bowman’s capsule coincides with replacement of parietal epithelial cell layer with proximal tubule-like epithelium

    OpenAIRE

    Tabatabai, Niloofar M.; North, Paula E.; Regner, Kevin R.; Kumar, Suresh N.; Duris, Christine B.; Blodgett, Amy B.

    2014-01-01

    In kidney nephron, parietal epithelial cells line the Bowman’s capsule and function as a permeability barrier for the glomerular filtrate. Bowman’s capsule cells with proximal tubule epithelial morphology have been found. However, the effects of tubular metaplasia in Bowman’s capsule on kidney function remain poorly understood. Sodium-glucose cotransporter 2 (SGLT2) plays a major role in reabsorption of glucose in the kidney and is expressed on brush border membrane of epithelial cells in the...

  9. Approaching to DM2 through sodium-glucose cotransporter-2: does it make sense?

    Science.gov (United States)

    Segura, Julián

    2016-11-01

    The kidney is involved in glucose homeostasis through three main mechanisms: renal gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most relevant physiological functions of the kidney, through which filtered glucose is fully recovered, urine is free of glucose, and calorie loss is prevented. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where GLUT2 and SGLT2 transporters are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters. In patients with hyperglycaemia, the kidney continues reabsorbing glucose, and hyperglycaemia is maintained. Most renal glucose reabsorption is mediated by the SGLT2 transporter. Several experimental and clinical studies suggest that pharmacological blockade of this transporter might be beneficial in the management of hyperglycemia in patients with type 2 diabetes. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  10. SGLT2 inhibitors with cardiovascular benefits: Transforming clinical care in Type 2 diabetes mellitus.

    Science.gov (United States)

    d'Emden, Michael; Amerena, John; Deed, Gary; Pollock, Carol; Cooper, Mark E

    2018-02-01

    Cardiovascular risk reduction in individuals with Type 2 diabetes mellitus (T2DM) is a key part of clinical management. Sodium-glucose co-transporter (SGLT2) inhibitors improve glycaemic control, reduce body weight and decrease blood pressure. In addition, the SGLT2 inhibitors empagliflozin and canagliflozin reduced the risk of composite cardiovascular events in high-risk individuals with T2DM in the EMPA-REG OUTCOME trial and the CANVAS Program, respectively. Empagliflozin also reduced cardiovascular deaths and improved renal outcomes. This class of agents should be considered in people with established cardiovascular disease, usually in combination with other glucose lowering medications, when satisfactory glycaemic control has not been achieved. The dose of insulin or sulfonylureas may need to be lowered when used with SGLT2 inhibitors, to reduce the risk of hypoglycaemia. Genitourinary infections can occur with SGLT2 inhibitors in a small proportion of people. In people with osteoporosis or prior amputation, it may be prudent to use empagliflozin rather than canagliflozin, based on the increased risk for bone fractures and amputations observed with canagliflozin in the CANVAS Program. SGLT2 inhibitors have the potential to transform the clinical care of persons with T2DM by not only improving glycaemic control but also reducing blood pressure, body weight and diabetes-related end-organ complications. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. SGLT-2 Inhibitors: Is There a Role in Type 1 Diabetes Mellitus Management?

    Science.gov (United States)

    Ahmed-Sarwar, Nabila; Nagel, Angela K; Leistman, Samantha; Heacock, Kevin

    2017-09-01

    The purpose of this review is to identify and evaluate disease management of patients with type 1 diabetes mellitus (T1DM) who were treated with a sodium-glucose cotransporter 2 (SGLT-2) inhibitor as an adjunct to insulin therapy. A PubMed (1969 to March 2017) and Ovid (1946 to March 2017) search was performed for articles published utilizing the following MESH terms: canagliflozin, empagliflozin, dapagliflozin, type 1 diabetes mellitus, insulin dependent diabetes, insulin, sodium-glucose transporter 2. There were no limitations placed on publication type. All English-language articles were evaluated for association of SGLT-2 inhibitors and type 1 diabetes. Further studies were identified by review of pertinent manuscript bibliographies. All 3 SGLT-2 inhibitors, when combined with insulin, resulted in an overall reduction of hemoglobin A1C (up to 0.49%), lower total daily insulin doses, and a reduction in weight (up to 2.7 kg). The combination therapy of insulin and SGLT-2 inhibitors also resulted in a lower incidence of hypoglycemia. Study duration varied from 2 to 18 weeks. A review of the identified literature indicated that there is a potential role for the combination of SGLT-2 inhibitors with insulin in T1DM for improving glycemic control without increasing the risk of hypoglycemia. The short duration and small sample sizes limit the ability to fully evaluate the incidences of diabetic ketoacidosis and urogenital infections. The risks associated with this combination of medications require further evaluation.

  12. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis.

    Science.gov (United States)

    Packer, Milton

    2018-06-01

    Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin. © 2018 John Wiley & Sons Ltd.

  13. SGLT2 Inhibitors and the Diabetic Kidney.

    Science.gov (United States)

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

  14. Glucose transport in brain - effect of inflammation.

    Science.gov (United States)

    Jurcovicova, J

    2014-01-01

    Glucose is transported across the cell membrane by specific saturable transport system, which includes two types of glucose transporters: 1) sodium dependent glucose transporters (SGLTs) which transport glucose against its concentration gradient and 2) sodium independent glucose transporters (GLUTs), which transport glucose by facilitative diffusion in its concentration gradient. In the brain, both types of transporters are present with different function, affinity, capacity, and tissue distribution. GLUT1 occurs in brain in two isoforms. The more glycosylated GLUT1 is produced in brain microvasculature and ensures glucose transport across the blood brain barrier (BBB). The less glycosylated form is localized in astrocytic end-feet and cell bodies and is not present in axons, neuronal synapses or microglia. Glucose transported to astrocytes by GLUT1 is metabolized to lactate serving to neurons as energy source. Proinflammatory cytokine interleukin (IL)-1β upregulates GLUT1 in endothelial cells and astrocytes, whereas it induces neuronal death in neuronal cell culture. GLUT2 is present in hypothalamic neurons and serves as a glucose sensor in regulation of food intake. In neurons of the hippocampus, GLUT2 is supposed to regulate synaptic activity and neurotransmitter release. GLUT3 is the most abundant glucose transporter in the brain having five times higher transport capacity than GLUT1. It is present in neuropil, mostly in axons and dendrites. Its density and distribution correlate well with the local cerebral glucose demands. GLUT5 is predominantly fructose transporter. In brain, GLUT5 is the only hexose transporter in microglia, whose regulation is not yet clear. It is not present in neurons. GLUT4 and GLUT8 are insulin-regulated glucose transporters in neuronal cell bodies in the cortex and cerebellum, but mainly in the hippocampus and amygdala, where they maintain hippocampus-dependent cognitive functions. Insulin translocates GLUT4 from cytosol to plasma

  15. Stimulation of Na{sup +}/K{sup +} ATPase activity and Na{sup +} coupled glucose transport by {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Sopjani, Mentor [Department of Physiology, University of Tuebingen (Germany); Department of Chemistry, University of Prishtina, Kosovo (Country Unknown); Alesutan, Ioana; Wilmes, Jan [Department of Physiology, University of Tuebingen (Germany); Dermaku-Sopjani, Miribane [Department of Physiology, University of Tuebingen (Germany); Faculty of Medicine, University of Prishtina, Kosovo (Country Unknown); Lam, Rebecca S. [Department of Physiology, University of Tuebingen (Germany); Department of Molecular Neurogenetics, Max Planck Institute of Biophysics, Frankfurt/Main (Germany); Koutsouki, Evgenia [Department of Physiology, University of Tuebingen (Germany); Jakupi, Muharrem [Faculty of Medicine, University of Prishtina, Kosovo (Country Unknown); Foeller, Michael [Department of Physiology, University of Tuebingen (Germany); Lang, Florian, E-mail: florian.lang@uni-tuebingen.de [Department of Physiology, University of Tuebingen (Germany)

    2010-11-19

    Research highlights: {yields} The oncogenic transcription factor {beta}-catenin stimulates the Na{sup +}/K{sup +}-ATPase. {yields} {beta}-Catenin stimulates SGLT1 dependent Na{sup +}, glucose cotransport. {yields} The effects are independent of transcription. {yields} {beta}-Catenin sensitive transport may contribute to properties of proliferating cells. -- Abstract: {beta}-Catenin is a multifunctional protein stimulating as oncogenic transcription factor several genes important for cell proliferation. {beta}-Catenin-regulated genes include the serum- and glucocorticoid-inducible kinase SGK1, which is known to stimulate a variety of transport systems. The present study explored the possibility that {beta}-catenin influences membrane transport. To this end, {beta}-catenin was expressed in Xenopus oocytes with or without SGLT1 and electrogenic transport determined by dual electrode voltage clamp. As a result, expression of {beta}-catenin significantly enhanced the ouabain-sensitive current of the endogeneous Na{sup +}/K{sup +}-ATPase. Inhibition of vesicle trafficking by brefeldin A revealed that the stimulatory effect of {beta}-catenin on the endogenous Na{sup +}/K{sup +}-ATPase was not due to enhanced stability of the pump protein in the cell membrane. Expression of {beta}-catenin further enhanced glucose-induced current (Ig) in SGLT1-expressing oocytes. In the absence of SGLT1 Ig was negligible irrespective of {beta}-catenin expression. The stimulating effect of {beta}-catenin on both Na{sup +}/K{sup +} ATPase and SGLT1 activity was observed even in the presence of actinomycin D, an inhibitor of transcription. The experiments disclose a completely novel function of {beta}-catenin, i.e. the regulation of transport.

  16. Sodium-Glucose Linked Transporter-2 Inhibitors in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    L. Zanoli

    2015-01-01

    Full Text Available SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD.

  17. Distribution of glucose transporters in renal diseases

    OpenAIRE

    Szablewski, Leszek

    2017-01-01

    Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney. Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three famil...

  18. Glucose transport machinery reconstituted in cell models.

    Science.gov (United States)

    Hansen, Jesper S; Elbing, Karin; Thompson, James R; Malmstadt, Noah; Lindkvist-Petersson, Karin

    2015-02-11

    Here we demonstrate the production of a functioning cell model by formation of giant vesicles reconstituted with the GLUT1 glucose transporter and a glucose oxidase and hydrogen peroxidase linked fluorescent reporter internally. Hence, a simplified artificial cell is formed that is able to take up glucose and process it.

  19. [SGLT2 inhibitors: a new therapeutic class for the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Dagan, Amir; Dagan, Bracha; SegaL, Gad

    2015-03-01

    SGLT2 (Sodium Glucose co-Transporter 2 Inhibitors) inhibitors are a new group of oral medications for the treatment of type 2 diabetes mellitus patients. These medications interfere with the process of glucose reabsorption in the proximal convoluted tubules in the kidneys, therefore increasing both glucose and water diuresis. SGLT2 inhibitors were found to be effective in lowering HbA1c levels in double-blinded studies, both as monotherapy and in combination with other oral hypoglycemic medications of various other mechanisms of action. SGLT2 Inhibitors are not a risk factor for hypoglycemia and are suitable for combination with insulin therapy. Their unique mode of action, relying on glomerular filtration, make these medication unsuitable for usage as treatment for type 2 diabetes patients who are also suffering from moderate to severe renal failure. Their main adverse effects are increased risk for urinary and genital tract infections. The following review describes the relevant pathophysiology addressed by these novel medications, evidence for efficacy and the safety profile of SGLT2 Inhibitors.

  20. SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.

    Science.gov (United States)

    Zou, Honghong; Zhou, Baoqin; Xu, Gaosi

    2017-05-16

    Diabetic kidney disease (DKD) is the most common cause of end stage renal disease. The comprehensive management of DKD depends on combined target-therapies for hyperglycemia, hypertension, albuminuria, and hyperlipaemia, etc. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the most recently developed oral hypoglycemic agents acted on renal proximal tubules, suppress glucose reabsorption and increase urinary glucose excretion. Besides improvements in glycemic control, they presented excellent performances in direct renoprotective effects and the cardiovascular (CV) safety by decreasing albuminuria and the independent CV risk factors such as body weight and blood pressure, etc. Simultaneous use of SGLT-2 inhibitors and renin-angiotensin-aldosterone system (RAAS) blockers are novel strategies to slow the progression of DKD via reducing inflammatory and fibrotic markers induced by hyperglycaemia more than either drug alone. The available population and animal based studies have described SGLT2 inhibitors plus RAAS blockers. The present review was to systematically review the potential renal benefits of SGLT2 inhibitors combined with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and especially the angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

  1. Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial

    Science.gov (United States)

    Mordi, Natalie A; Mordi, Ify R; Singh, Jagdeep S; Baig, Fatima; Choy, Anna-Maria; McCrimmon, Rory J; Struthers, Allan D; Lang, Chim C

    2017-01-01

    Introduction Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium–glucose cotransporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics are limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics and the benefits of SGLT2 inhibitors may extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters. The effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study. Methods and analysis To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF (Renal and Cardiovascular Effects of SGLT2 inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure) trial is a single-centre, randomised, double-blind, placebo-controlled, cross-over trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 and 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 and 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio and urinary albumin/creatinine ratio when compared with placebo. Ethics and dissemination Ethics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer

  2. Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Gluud, Lise L.; Bennett, Cathy; Grøndahl, Magnus F.; Christensen, Mikkel B.; Knop, Filip K.; Vilsbøll, Tina

    2016-01-01

    Objective Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. Design Systematic review and meta-analysis. Data Sources and Study Selection We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. Results Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to ‘low quality’ due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence). Conclusion

  3. Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Sodium-glucose co-transporter-2 inhibitors (SGLT-2i are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from −0.5 to −0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism.

  4. Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors.

    Science.gov (United States)

    Rahelić, Dario; Javor, Eugen; Lucijanić, Tomo; Skelin, Marko

    2017-02-01

    Elevated hemoglobin A 1c (HbA 1c ) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors. Key messages Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs. The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM.

  5. [Acidosis without marked hyperglycemia : Euglycemic diabetic ketoacidosis associated with SGLT2-Inhibitors].

    Science.gov (United States)

    Valek, R; Von der Mark, J

    2017-03-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new antidiabetic drugs that regulate blood glucose levels by increasing urinary glucose excretion. In May 2015, the U.S. Food and Drug Administration (FDA) issued a warning that SGLT2 inhibitors may lead to ketoacidosis. In this report, we describe a case of life-threatening euglycemic ketoacidosis associated with SGLT2 inhibition and evaluate possible mechanisms and triggers.

  6. Elucidation of the glucose transport pathway in glucose transporter 4 via steered molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Aswathy Sheena

    Full Text Available BACKGROUND: GLUT4 is a predominant insulin regulated glucose transporter expressed in major glucose disposal tissues such as adipocytes and muscles. Under the unstimulated state, GLUT4 resides within intracellular vesicles. Various stimuli such as insulin translocate this protein to the plasma membrane for glucose transport. In the absence of a crystal structure for GLUT4, very little is known about the mechanism of glucose transport by this protein. Earlier we proposed a homology model for GLUT4 and performed a conventional molecular dynamics study revealing the conformational rearrangements during glucose and ATP binding. However, this study could not explain the transport of glucose through the permeation tunnel. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the molecular mechanism of glucose transport and its energetic, a steered molecular dynamics study (SMD was used. Glucose was pulled from the extracellular end of GLUT4 to the cytoplasm along the pathway using constant velocity pulling method. We identified several key residues within the tunnel that interact directly with either the backbone ring or the hydroxyl groups of glucose. A rotation of glucose molecule was seen near the sugar binding site facilitating the sugar recognition process at the QLS binding site. CONCLUSIONS/SIGNIFICANCE: This study proposes a possible glucose transport pathway and aids the identification of several residues that make direct interactions with glucose during glucose transport. Mutational studies are required to further validate the observation made in this study.

  7. Recent Developments of C-Aryl Glucoside SGLT2 Inhibitors.

    Science.gov (United States)

    Zhang, Yang; Liu, Zhao-Peng

    2016-01-01

    Sodium-glucose cotransporter 2 (SGLT2) is almost exclusively expressed in the proximal renal tubules. It is responsible for about 90% of the glucose reabsorption from tubular fluid. Selective inhibition of SGLT2 is expected to favor in the normalization of plasma glucose levels in T2DM patients through the prevention of renal glucose reabsorption and the promotion of glucose excretion from urine. Selective SGLT2 inhibitors have the merits to minimize the gastrointestinal side effects associated with SGLT1 inhibition, and selective SGLT2 inhibition may have a low risk of hypoglycemia. Since the C-aryl glucosides are metabolically more stable than the O-glucosides, numerous efforts have been made in the development of potent and selective C-aryl glucoside SGLT2 inhibitors, and a number of them are now used as anti-diabetes drugs in clinic or at various stages of clinical developments. Based on their structural features, in this review, these SGLT2 inhibitors are classified as three types: the phenyl/arylmethylphenyl C-glucosides, with an emphasis on the modifications on the proximal and/or the distal phenyl ring, and the spacer; the heteroarylmethylphenyl Cglucosides, with a replacement of the distal phenyl ring by a heterocycle like pyridazine, pyrimidine, thiophene and benzothiophene, thiazole, 1,3,4-thiadiazole, and triazolopyridinone; and the glucose-modified Caryl glucosides, including the glucose C-1 derived O-spiroketals, C-4 gem-difluoro analogues, C-5 and C-6 modified derivatives, dioxa-bicyclo[3.2.1]octane bridged ketals, the thioglucosides, and carbasugars. The structure-activity relationships (SARs) of each type along with their inhibitory potency against human SGLT2 and selectivity over human SGLT1 are discussed.

  8. SGLT2 Inhibitors: Glucotoxicity and Tumorigenesis Downstream the Renal Proximal Tubule?

    Science.gov (United States)

    Bertinat, Romina; Nualart, Francisco; Yáñez, Alejandro J

    2016-08-01

    At present, diabetes mellitus is the main cause of end-stage renal disease. Effective glycaemic management is the most powerful tool to delay the establishment of diabetic complications, such as diabetic kidney disease. Together with reducing blood glucose levels, new anti-diabetic agents are expected not only to control the progression but also to restore known defects of the diabetic kidney. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising anti-diabetic agents that reduce hyperglycaemia by impairing glucose reabsorption in proximal tubule of the kidney and increasing glucosuria. SGLT2 inhibitors have shown to reduce glucotoxicity in isolated proximal tubule cells and also to attenuate expression of markers of overall kidney damage in experimental animal models of diabetes, but the actual renoprotective effect for downstream nephron segments is still unknown and deserves further attention. Here, we briefly discuss possible undesired effects of enhanced glucosuria and albuminuria in nephron segments beyond the proximal tubule after SGLT2 inhibitor treatment, offering new lines of research to further understand the renoprotective action of these anti-diabetic agents. Strategies blocking glucose reabsorption by renal proximal tubule epithelial cells (RPTEC) may be protective for RPTEC, but downstream nephron segments will still be exposed to high glucose and albumin levels through the luminal face. The actual effect of constant enhanced glucosuria over distal nephron segments remains to be established. J. Cell. Physiol. 231: 1635-1637, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  9. Glucose stimulates neurotensin secretion from the rat small intestine by mechanisms involving SGLT1 and GLUT2 leading to cell depolarization and calcium influx

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Bechmann, Louise Ellegaard; Hartmann, Bolette

    2015-01-01

    of secretion. Luminal glucose (20% wt/vol) stimulated secretion but vascular glucose (5, 10, or 15 mmol/l) was without effect. The underlying mechanisms depend on membrane depolarization and calcium influx, since the voltage-gated calcium channel inhibitor nifedipine and the KATP channel opener diazoxide......, suggesting that glucose stimulates secretion by initial uptake by this transporter. However, secretion was also sensitive to GLUT2 inhibition (by phloretin) and blockage of oxidative phosphorylation (2-4-dinitrophenol). Direct KATP channel closure by sulfonylureas stimulated secretion. Therefore, glucose...

  10. [Contribution of the kidney to glucose homeostasis].

    Science.gov (United States)

    Segura, Julián; Ruilope, Luis Miguel

    2013-09-01

    The kidney is involved in glucose homeostasis through three major mechanisms: renal gluconeogenesis, renal glucose consumption, and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most important physiological functions of the kidney, allowing full recovery of filtered glucose, elimination of glucose from the urine, and prevention of calorie loss. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where glucose transporter-2 (GLUT2) and sodium-glucose transporter-2 (SGLT2) are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters. In patients with hyperglycemia, the kidney continues to reabsorb glucose, thus maintaining hyperglycemia. Most of the renal glucose reabsorption is mediated by SGLT2. Several experimental and clinical studies suggest that pharmacological blockade of this transporter might be beneficial in the management of hyperglycemia in patients with type 2 diabetes. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  11. [Sodium-glucose co-transporter-2 inhibitors: from the bark of apple trees and familial renal glycosuria to the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Mauricio, Dídac

    2013-09-01

    The therapeutic armamentarium for the treatment of hyperglycemia in type 2 diabetes mellitus is still inadequate. We are currently witnessing the introduction of a new mode of hypoglycemic treatment through induction of glycosuria to decrease the availability of the metabolic substrate, i.e. glucose. Clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors are as efficacious as other oral hypoglycemic drugs. This article discusses the basic features of this new treatment concept and the efficacy and safety of this new drug group. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  12. Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry.

    Science.gov (United States)

    Cai, Wenqing; Jiang, Linlin; Xie, Yafei; Liu, Yuqiang; Liu, Wei; Zhao, Guilong

    2015-01-01

    A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin, a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships (SAR) of the SGLT2 inhibitors are also discussed.

  13. Long-term efficacy and safety of sodium-glucose cotransporter-2 inhibitors as add-on to metformin treatment in the management of type 2 diabetes mellitus

    Science.gov (United States)

    Li, Jian; Gong, Yanping; Li, Chunlin; Lu, Yanhui; Liu, Yu; Shao, Yinghong

    2017-01-01

    Abstract Background: Drug intensification is often required for patients with type 2 diabetes mellitus on stable metformin therapy. Among the potential candidates for a combination therapy, sodium-glucose transporter-2 (SGLT2) inhibitors have shown promising outcomes. This meta-analysis was performed to compare the efficacy and safety of SGLT2 inhibitors with non-SGLT2 combinations as add-on treatment to metformin. Methods: Literature search was carried out in multiple electronic databases for the acquisition of relevant randomized controlled trials (RCTs) by following a priori eligibility criteria. After the assessment of quality of the included RCTs, meta-analyses of mean differences or odds ratios (OR) were performed to achieve overall effect sizes of the changes from baseline in selected efficacy and safety endpoints reported in the individual studies. Between-studies heterogeneity was estimated with between-studies statistical heterogeneity (I2) index. Results: Six RCTs fulfilled the eligibility criteria. SGLT2 inhibitors as add-on to metformin treatment reduced % HbA1c significantly more than non-SGLT2 combinations after 52 weeks (P = .002) as well as after 104 weeks (P SGLT2 inhibitors also reduced fasting plasma glucose levels, body weight, systolic, and diastolic blood pressures after 52 weeks and 104 weeks significantly (P SGLT2 combinations. Incidence of hypoglycemia was significantly lower (P = .02) but incidence of suspected or confirmed genital tract infections was significantly higher (P SGLT2 inhibitors treated in comparison with non-SGLT2 combinations. Conclusion: As add-on to metformin treatment, SGLT2 inhibitors are found significantly more efficacious than non-SGLT2 inhibitor combinations in the management of type 2 diabetes mellitus, although, SGLT2 inhibitor therapy is associated with significantly higher incidence of suspected or confirmed genital tract infections. PMID:28682870

  14. Use of SGLT2 inhibitors for diabetes and risk of infection: Analysis using general practice records from the NPS MedicineWise MedicineInsight program.

    Science.gov (United States)

    Gadzhanova, Svetla; Pratt, Nicole; Roughead, Elizabet

    2017-08-01

    To explore the feasibility of MedicineInsight data to support risk management plan evaluation, focusing on sodium glucose co-transporter 2 (SGLT2) inhibitors for type 2 diabetes. A retrospective study using de-identified electronic general practitioner records. Patients who initiated SGLT2 inhibitor between 1 Jan 2012 to 1 Sep 2015 were compared to patients who initiated dipeptidyl peptidase 4 (DPP-4) inhibitors. The two cohorts were followed-up for six months. Risk of urinary-tract (UT) and genital infections was evaluated. The indication for use of SGLT2 inhibitors, recommended prior diabetes therapies and recommended monitoring were investigates. There were 1977 people in the SGLT2 cohort (with 93% initiated on dapagliflozin) and 1964 people in the DPP-4 cohort. Of the SGLT2 initiators, 54% had a documented indication for use as type 2 diabetes; 86% had used metformin and/or a sulfonylurea in the prior 12months. Renal function monitoring was documented for only 25% in the 6months initiation. The frequency of UTI in the 6months post SGLT2 initiation was not significantly increased compared to the DPP-4 cohort (3.6%vs 4.9%; aHR=0.90, 95% CI 0.66-1.24). Genital infection were more frequent in the SGLT2 than in the DPP-4 cohort (2.9% vs 0.9%, aHR=3.50, 95% CI 1.95-5.89). Similar to existing evidence, we found a higher risk of genital infection associated with SGLT2 inhibitors (primarily dapagliflozin) but no increased risk of UTIs compared to DPP-4 use. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Are SGLT2 inhibitors reasonable antihypertensive drugs and renoprotective?

    Science.gov (United States)

    Lovshin, J A; Gilbert, R E

    2015-06-01

    By eliminating glucose in the urine, the sodium-glucose-linked cotransporter-2 (SGLT2) inhibitors act as osmotic diuretics to lower blood pressure in addition to reducing plasma glucose and assisting with weight loss. While not approved as antihypertensive agents, the ability of this new class of antihyperglycemic agents to lower blood pressure is not insubstantial, and while not used primarily for this indication, they may assist diabetic individuals in attaining currently recommended blood pressure targets. In addition to lowering systemic pressure, preclinical and exploratory human studies suggest that SGLT2 inhibitors may also lower intraglomerular pressure, potentially reducing the rate of GFR decline in patients with diabetic nephropathy. However, given the lack of clinically meaningful endpoint data, the use of SGLT2 inhibitors, primarily, as either antihypertensive or renoprotective agents would, at present, be premature. Fortunately, further insight will be garnered from large, randomized controlled trials that will assess the effects of various SGLT2 inhibitors on cardiovascular and renal outcomes.

  16. Resveratrol Inhibits Porcine Intestinal Glucose and Alanine Transport: Potential Roles of Na+/K+-ATPase Activity, Protein Kinase A, AMP-Activated Protein Kinase and the Association of Selected Nutrient Transport Proteins with Detergent Resistant Membranes

    Directory of Open Access Journals (Sweden)

    Stefanie Klinger

    2018-03-01

    Full Text Available Background: Beneficial effects of Resveratrol (RSV have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. Methods: Porcine jejunum and ileum were incubated with RSV (300 µM, 30 min in Ussing chambers (functional studies and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs. Results: RSV reduced alanine and glucose-induced short circuit currents (ΔIsc and influenced forskolin-induced ΔIsc. The phosphorylation of sodium–glucose-linked transporter 1 (SGLT1, AMP-activated protein kinase (AMPK, protein kinase A substrates (PKA-S and liver kinase B1 (LKB1 increased but a causative relation to the inhibitory effects could not directly be established. The DRM association of SGLT1, peptide transporter 1 (PEPT1 and (phosphorylated Na+/H+-exchanger 3 (NHE3 did not change. Conclusion: RSV influences the intestinal transport of glucose, alanine and chloride and is likely to affect other transport processes. As the effects of protein kinase activation vary between the intestinal localizations, it would appear that increasing cyclic adenosine monophosphate (cAMP levels are part of the mechanism. Nonetheless, the physiological responses depend on cell type-specific structures.

  17. Effects of dietary glucose and sodium chloride on intestinal glucose absorption of common carp (Cyprinus carpio L.).

    Science.gov (United States)

    Qin, Chaobin; Yang, Liping; Zheng, Wenjia; Yan, Xiao; Lu, Ronghua; Xie, Dizhi; Nie, Guoxing

    2018-01-08

    The co-transport of sodium and glucose is the first step for intestinal glucose absorption. Dietary glucose and sodium chloride (NaCl) may facilitate this physiological process in common carp (Cyprinus carpio L.). To test this hypothesis, we first investigated the feeding rhythm of intestinal glucose absorption. Carps were fed to satiety once a day (09:00 a.m.) for 1 month. Intestinal samples were collected at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00. Result showed that food intake greatly enhanced sodium/glucose cotransporter 1 (SGLT1) and glucose transporter type 2 (GLUT2) expressions, and improved glucose absorption, with highest levels at 09:00 a.m.. Then we designed iso-nitrogenous and iso-energetic diets with graded levels of glucose (10%, 20%, 30%, 40% and 50%) and NaCl (0%, 1%, 3% and 5%), and submitted to feeding trial for 10 weeks. The expressions of SGLT1 and GLUT2, brush border membrane vesicles (BBMVs) glucose transport and intestinal villus height were determined after the feeding trial. Increasing levels of dietary glucose and NaCl up-regulated mRNA and protein levels of SGLT1 and GLUT2, enhanced BBMVs glucose transport in the proximal, mid and distal intestine. As for histological adaptive response, however, high-glucose diet prolonged while high-NaCl diet shrank intestinal villus height. Furthermore, we also found that higher mRNA levels of SGLT1 and GLUT2, higher glucose transport capacity of BBMVs, and higher intestinal villus were detected in the proximal and mid intestine, compared to the distal part. Taken together, our study indicated that intestinal glucose absorption in carp was primarily occurred in the proximal and mid intestine, and increasing levels of dietary glucose and NaCl enhanced intestinal glucose absorption in carp. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle

    DEFF Research Database (Denmark)

    Ploug, T; Stallknecht, B M; Pedersen, O

    1990-01-01

    exhaustive single exercise session the day before experiment both maximum insulin- and contraction-stimulated transport rates were increased in all muscle types in trained rats. Accordingly, the increased glucose transport capacity in trained muscle was not due to a residual effect of the last training...... session. Half-times for reversal of contraction-induced glucose transport were similar in trained and untrained muscles. The concentrations of mRNA for GLUT-1 (the erythrocyte-brain-Hep G2 glucose transporter) and GLUT-4 (the adipocyte-muscle glucose transporter) were increased approximately twofold......The effect of 10 wk endurance swim training on 3-O-methylglucose (3-MG) uptake (at 40 mM 3-MG) in skeletal muscle was studied in the perfused rat hindquarter. Training resulted in an increase of approximately 33% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers...

  19. Efficacy and Safety of SGLT2 Inhibitors in Patients with Type 1 Diabetes: A Meta-analysis of Randomized Controlled Trials.

    Science.gov (United States)

    Yang, Yingying; Pan, Hui; Wang, Bo; Chen, Shi; Zhu, Huijuan

    2017-04-10

    Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2 (SGLT2) inhibitor-SGLT2 inhibitors, in combination with insulin for type 1 diabetes mellitus (T1DM). Methods We searched Medline, Embase, and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration (FDA) data and ClinicalTrials (http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria: randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin (HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin, and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items: fasting blood glucose, HbA1c, glycosuria, or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3.Results Three trials including 178 patients were enrolled. As compared to the placebo group, SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences (MD) -2.47 mmol/L, 95% confidence interval (CI) -3.65 to -1.28, PSGLT2 inhibitors could also increase the excretion of urine glucose (MD 131.09 g/24 h, 95%CI 91.79 to 170.39, PSGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.

  20. Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

    Science.gov (United States)

    Egger, Andrea; Kraenzlin, Marius E; Meier, Christian

    2016-12-01

    Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

  1. Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle

    International Nuclear Information System (INIS)

    Ploug, T.; Stallknecht, B.M.; Pedersen, O.; Kahn, B.B.; Ohkuwa, T.; Vinten, J.; Galbo, H.

    1990-01-01

    The effect of 10 wk endurance swim training on 3-O-methylglucose (3-MG) uptake (at 40 mM 3-MG) in skeletal muscle was studied in the perfused rat hindquarter. Training resulted in an increase of approximately 33% for maximum insulin-stimulated 3-MG transport in fast-twitch red fibers and an increase of approximately 33% for contraction-stimulated transport in slow-twitch red fibers compared with nonexercised sedentary muscle. A fully additive effect of insulin and contractions was observed both in trained and untrained muscle. Compared with transport in control rats subjected to an almost exhaustive single exercise session the day before experiment both maximum insulin- and contraction-stimulated transport rates were increased in all muscle types in trained rats. Accordingly, the increased glucose transport capacity in trained muscle was not due to a residual effect of the last training session. Half-times for reversal of contraction-induced glucose transport were similar in trained and untrained muscles. The concentrations of mRNA for GLUT-1 (the erythrocyte-brain-Hep G2 glucose transporter) and GLUT-4 (the adipocyte-muscle glucose transporter) were increased approximately twofold by training in fast-twitch red muscle fibers. In parallel to this, Western blot demonstrated a approximately 47% increase in GLUT-1 protein and a approximately 31% increase in GLUT-4 protein. This indicates that the increases in maximum velocity for 3-MG transport in trained muscle is due to an increased number of glucose transporters

  2. [Contributions of SGLT-2 and new drugs under investigation].

    Science.gov (United States)

    Mediavilla Bravo, J J

    2014-07-01

    DeFronzo spoke of the "ominous octet", in which he referred to the existence of distinct pathways and organs related to the physiopathology of type 2 diabetes mellitus (DM2). One of these key organs is the kidney, which plays an important role in regulating glucose metabolism through gluconeogenesis and through glomerular filtration and glucose reabsorption in the proximal convoluted tubules. Approximately 180 g of glucose are filtered to the renal tubule from the blood stream through the glomerulus. The filtrate is subsequently reabsorbed from the tubules to the peritubular capillaries through the action of sodium glucose cotransporters (SGLT). There are 2 main cotransporters in the kidney, SGLT1 and SGLT2, which reabsorb the glucose (10% and 90%, respectively) and return it to the blood. In persons with DM2, SGLT2 is increased, leading to greater renal absorption of glucose, which has adverse effects as it contributes to the maintenance of hyperglycemia. Selective pharmacological SGLT2 inhibition increases renal glucose excretion and secondarily reduces its plasma values. SGLT2 inhibitors act exclusively on the kidney, reduce glycosylated hemoglobin (HbA1c) by about 0.66%, decrease blood pressure, and induce a weight loss of approximately 1.8 kg. These drugs have a low risk of hypoglycemia but carry an increased risk of genitourinary infections. Several clinical trials have shown that dapagliflozin (10mg/day), the first SGLT2 inhibitor commercialized in Spain, produces a statistically significant reduction in HbA1c of 0.82-0.97%, both in monotherapy and in combination with metformin, glimepiride, pioglitazone, or insulin. Its use produces a weight loss of between 2 and 3 kg and reduces both systolic and diastolic blood pressure, while the risk of hypoglycemias is low. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  3. SGLT2 Inhibitors: Benefit/Risk Balance.

    Science.gov (United States)

    Scheen, André J

    2016-10-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.

  4. SGLT-2 Inhibitors: Are They a Promising Treatment Option in T2DM Patients with NAFLD?

    Directory of Open Access Journals (Sweden)

    Dimitrios Patoulias

    2018-04-01

    Full Text Available Sodium glucose co-transporter type 2 inhibitors (SGLT-2 inhibitors are a class of antidiabetics, recently approved for the treatment of patients with T2DM. They feature cardioprotective and renoprotective action, while they exert beneficial effects on metabolic parameters. Non-alcoholic fatty liver disease (NAFLD is a frequent co-morbidity in diabetic patients. Its prevalence reaches up to 70%. Since there is no specific treatment approved for NAFLD, both experimental and clinical studies have been recently conducted highlighting the efficacy and safety of SGLT-2 inhibitors mainly in animal models and secondarily in patients with T2DM and NAFLD. This class of antidiabetics seems very attractive, improving both glycemic control and liver function tests, while inhibiting NAFLD progression. However, further investigation is required to establish them as a first-line treatment option in T2DM patients with NAFLD, after thorough assessment of their efficacy and safety in clinical practice.

  5. Passive water and ion transport by cotransporters

    DEFF Research Database (Denmark)

    Loo, D D; Hirayama, B A; Meinild, A K

    1999-01-01

    the Lp of control oocytes. Passive Na+ transport (Na+ leak) was obtained from the blocker-sensitive Na+ currents in the absence of substrates (glucose and GABA). 2. Passive Na+ and water transport through SGLT1 were blocked by phlorizin with the same sensitivity (inhibitory constant (Ki), 3-5 micro......1. The rabbit Na+-glucose (SGLT1) and the human Na+-Cl--GABA (GAT1) cotransporters were expressed in Xenopus laevis oocytes, and passive Na+ and water transport were studied using electrical and optical techniques. Passive water permeabilities (Lp) of the cotransporters were determined from......M). When Na+ was replaced with Li+, phlorizin also inhibited Li+ and water transport, but with a lower affinity (Ki, 100 microM). When Na+ was replaced by choline, which is not transported, the SGLT1 Lp was indistinguishable from that in Na+ or Li+, but in this case water transport was less sensitive...

  6. Benefits of SGLT2 Inhibitors beyond glycemic control - A focus on metabolic, cardiovascular, and renal outcomes.

    Science.gov (United States)

    Minze, Molly G; Will, Kayley; Terrell, Brian T; Black, Robin L; Irons, Brian K

    2017-08-16

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new pharmacotherapeutic class for the treatment of type 2 diabetes mellitus (T2DM). To evaluate beneficial effects of the SGLT2 inhibitors on metabolic, cardiovascular, and renal outcomes. A Pub-Med search (1966 to July 2017) was performed of published English articles using keywords sodium-glucose co-transporter 2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin. A review of literature citations provided further references. The search identified 17clinical trials and 2 meta-analysis with outcomes of weight loss and blood pressure reduction with dapagliflozin, canagliflozin, or empagliflozin. Three randomized trials focused on either empagliflozin or canagliflozin and reduction of cardiovascular disease and progression of renal disease. SGLT2 inhibitors have a beneficial profile in the treatment of T2DM. They have evidence of reducing weight between 2.9 kilograms when used as monotherapy to 4.7 kilograms when used in combination with metformin, and reduce systolic blood pressure between 3 to 5 mmHg and reduce diastolic blood pressure approximately 2 mmHg. To date, reduction of cardiovascular events was seen specifically with empagliflozin in patients with T2DM and a history of cardiovascular disease. In the same population, empagliflozin was associated with slowing the progression of kidney disease. Moreover, patients with increased risk of cardiovascular disease treated with canagliflozin has decreased risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Data regarding these outcomes with dapagliflozin are underway. SGLT2 inhibitors demonstrate some positive metabolic effects. In addition, empagliflozin specifically has demonstrated reduction in cardiovascular events and delay in the progression of kidney disease in patients with T2DM and a history of cardiovascular disease. Further data is needed to assess if this is a class effect. Copyright© Bentham Science Publishers

  7. The kidney and type 2 diabetes mellitus: therapeutic implications of SGLT2 inhibitors.

    Science.gov (United States)

    Weir, Matthew R

    2016-01-01

    Understanding the role of the kidneys in type 2 diabetes mellitus (T2DM) has taken on an increased importance in recent years with the arrival of sodium-glucose co-transporter 2 (SGLT2) inhibitors - antihyperglycemic agents (AHAs) that specifically target the kidneys. This review includes an update on the physiology of the kidneys, their role in the pathophysiology of T2DM, and the mechanisms implicated in the development and progression of diabetic kidney disease, such as glomerular hyperfiltration and inflammation. It also discusses renal issues that could influence the choice of AHA for patients with T2DM, including special populations such as patients with concomitant chronic kidney disease. The most recent data published on the clinical efficacy and safety of the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin and their effects on renal function are presented, showing how the renally mediated mechanisms of action of these agents translate into clinical benefits, including the potential for renoprotection. The observed positive effects of these agents on measures such as glucose control, estimated glomerular filtration rate, albumin-to-creatinine ratio, blood pressure, and body weight in patients both with and without impaired renal function suggest that SGLT2 inhibitors represent an important extension to the diabetes treatment armamentarium.

  8. Effects of SGLT2 inhibitors on weight loss in patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Ribola, F A; Cançado, F B; Schoueri, J H M; De Toni, V F; Medeiros, V H R; Feder, D

    2017-01-01

    SGLT2 (sodium-glucose cotransporter type 2) inhibitors are a new class of drugs which reversibly block the glucose reabsorption that occurs in the kidneys. Since their mechanisms of action do not rely on insulin secretion, they constitute a complementary alternative to the classic treatment of type 2 diabetes mellitus. A glycemic level reduction in patients who used SGLT2 inhibitors due to the reversible block of their transporters could be observed. Associated with this, there was a reduction in body weight and blood pressure (BP) caused by osmotic diuresis. Few adverse effects and low drug interaction combined with antihyperglycemic effects are some of the benefits of these inhibitors widely discussed in clinical trials. Patients with history of urogenital infections or those on diuretics must be carefully evaluated before the administration of these drugs. While a promising class of drugs indicated as a treatment for patients with type 2 diabetes mellitus, SGLT2 inhibitors should not be prescribed for individuals with severe renal or hepatic impairment. Therefore, as there are only a few situations in which they should not be indicated, the efficacy, safety and tolerability of these inhibitors allow them to be used in a wide range of patients. Nevertheless, further researches are required so that the possible long-term risks can be studied and the benefits associated with their use can be more objectively elucidated.

  9. Screening for Inhibitors of Essential Leishmania Glucose Transporters

    Science.gov (United States)

    2013-07-01

    Leishmania Glucose Transporters PRINCIPAL INVESTIGATOR: Scott M. Landfear, Ph.D. CONTRACTING ORGANIZATION: Oregon Health & Science...COVERED 1 July 2009- 30 June 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Screening for Inhibitors of Essential Leishmania Glucose Transporters 5b...The objective of this project was to identify compounds that selectively inhibit the essential Leishmania glucose transporters and could hence serve

  10. Glucose transporter 1 localisation throughout pregnancy in the carnivore placenta

    DEFF Research Database (Denmark)

    Wooding, F.B.P.; Dantzer, Vibeke; Klisch, K.

    2007-01-01

    Glucose is one of the major fetal nutrients. Maternofetal transfer requires transport across the several placental membranes. This transfer is mediated by one or more of the fourteen known isoforms of glucose transporter. So far only Glucose Transporters 1 and 3 (GT1, GT3) have been shown to be l...

  11. Glucose transporters: expression, regulation and cancer

    Directory of Open Access Journals (Sweden)

    RODOLFO A. MEDINA

    2002-01-01

    Full Text Available Mammalian cells depend on glucose as a major substrate for energy production. Glucose is transported into the cell via facilitative glucose transporters (GLUT present in all cell types. Many GLUT isoforms have been described and their expression is cell-specific and subject to hormonal and environmental control. The kinetic properties and substrate specificities of the different isoforms are specifically suited to the energy requirements of the particular cell types. Due to the ubiquitousness of these transporters, their differential expression is involved in various disease states such as diabetes, ischemia and cancer. The majority of cancers and isolated cancer cell lines over-express the GLUT family members which are present in the respective tissue of origin under non-cancerous conditions. Moreover, due to the requirement of energy to feed uncontrolled proliferation, cancer cells often express GLUTs which under normal conditions would not be present in these tissues. This over-expression is predominantly associated with the likelihood of metastasis and hence poor patient prognosis. This article presents a review of the current literature on the regulation and expression of GLUT family members and has compiled clinical and research data on GLUT expression in human cancers and in isolated human cancer cell lines.

  12. Activity-Dependent Regulation of Surface Glucose Transporter-3

    OpenAIRE

    Ferreira, Jainne M.; Burnett, Arthur L.; Rameau, Gerald A.

    2011-01-01

    Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation o...

  13. Sodium-glucose co-transporter-2 inhibitors, the latest residents on the block: Impact on glycaemic control at a general practice level in England.

    Science.gov (United States)

    Heald, Adrian H; Fryer, Anthony A; Anderson, Simon G; Livingston, Mark; Lunt, Mark; Davies, Mark; Moreno, Gabriela Y C; Gadsby, Roger; Young, Robert J; Stedman, Mike

    2018-03-08

    To determine, using published general practice-level data, how differences in Type 2 diabetes mellitus (T2DM) prescribing patterns relate to glycaemic target achievement levels. Multiple linear regression modelling was used to link practice characteristics and defined daily dose (DDD) of different classes of medication in 2015/2016 and changes between that year and the year 2014/2015 in medication to proportion of patients achieving target glycaemic control (glycated haemoglobin A1c [HbA1c] ≤58 mmol/mol [7.5%]) and proportion of patients at high glycaemic risk (HbA1c >86 mmol/mol [10.0%]) for practices in the National Diabetes Audit with >100 people with T2DM on their register. Overall, HbA1c outcomes were not different between the years studied. Although, in percentage terms, most practices increased their use of sodium-glucose co-transporter-2 (SGLT2) inhibitors (96%), dipeptidyl peptidase-4 (DPP-4) inhibitors (76%) and glucagon-like peptide 1 (GLP-1) analogues (53%), there was wide variation in the use of older and newer therapies. For example, 12% of practices used >200% of the national average for some newer agents. In cross-sectional analysis, greater prescribing of metformin and analogue insulin were associated with a higher proportion of patients achieving HbA1c ≤58 mmol/mol; the use of SGLT2 inhibitors and metformin was associated with a reduced proportion of patients with HbA1c >86 mol/mol; otherwise associations for sulphonylureas, GLP-1 analogues, SGLT2 inhibitors and DPP-4 inhibitors were neutral or negative. In year-on-year analysis there was ongoing deterioration in glycaemic control, which was offset to some extent by increased use of SGLT2 inhibitors and GLP-1 analogues, which were associated with a greater proportion of patients achieving HbA1c levels ≤58 mmol/mol and a smaller proportion of patients with HbA1c levels >86 mmol/mol. SGLT2 inhibitor prescribing was associated with significantly greater improvements than those found

  14. Glucose transport and milk secretion during manipulated plasma insulin and glucose concentrations and during LPS-induced mastitis in dairy cows.

    Science.gov (United States)

    Gross, J J; van Dorland, H A; Wellnitz, O; Bruckmaier, R M

    2015-08-01

    In dairy cows, glucose is essential as energy source and substrate for milk constituents. The objective of this study was to investigate effects of long-term manipulated glucose and insulin concentrations in combination with a LPS-induced mastitis on mRNA abundance of glucose transporters and factors involved in milk composition. Focusing on direct effects of insulin and glucose without influence of periparturient endocrine adaptations, 18 dairy cows (28 ± 6 weeks of lactation) were randomly assigned to one of three infusion treatments for 56 h (six animals each). Treatments included a hyperinsulinemic hypoglycaemic clamp (HypoG), a hyperinsulinemic euglycaemic clamp (EuG) and a control group (NaCl). After 48 h of infusions, an intramammary challenge with LPS from E. coli was performed and infusions continued for additional 8 h. Mammary gland biopsies were taken before, at 48 (before LPS challenge) and at 56 h (after LPS challenge) of infusion, and mRNA abundance of genes involved in mammary gland metabolism was measured by RT-qPCR. During the 48 h of infusions, mRNA abundance of glucose transporters GLUT1, 3, 4, 8, 12, SGLT1, 2) was not affected in HypoG, while they were downregulated in EuG. The mRNA abundance of alpha-lactalbumin, insulin-induced gene 1, κ-casein and acetyl-CoA carboxylase was downregulated in HypoG, but not affected in EuG. Contrary during the intramammary LPS challenge, most of the glucose transporters were downregulated in NaCl and HypoG, but not in EuG. The mRNA abundance of glucose transporters in the mammary gland seems not to be affected by a shortage of glucose, while enzymes and milk constituents directly depending on glucose as a substrate are immediately downregulated. During LPS-induced mastitis in combination with hypoglycaemia, mammary gland metabolism was more aligned to save glucose for the immune system compared to a situation without limited glucose availability during EuG. Journal of Animal Physiology and Animal

  15. The expression and regulation of glucose transporters in tumor cells

    Directory of Open Access Journals (Sweden)

    Pengfei Zhao

    2016-12-01

    Full Text Available Glucose transporter proteins are involved in many physiological and biochemical processes. In particular, the high expressions of sodium-glucose cotransporter and glucose transporter proteins in tumor cells show that these two transporters play a key role in tumor cell metabolism. Studying the crystal structure and conformation of human glucose transporter proteins has enabled the development of drugs based on specific binding sites, opening up a new path towards more effective cancer treatments. This mini review serves to summarize our existing understanding of the metabolic pathways of tumor cells, focusing on the roles of glucose transporter proteins.

  16. SGLT2 inhibitors as adjunct therapy to insulin in type 1 diabetes: Meta analysis

    Directory of Open Access Journals (Sweden)

    Jiao CHEN

    2017-02-01

    Full Text Available Objective To evaluate the efficacy and safety of sodium glucose co-transporter-2 (SGLT-2 inhibitors as adjunct therapy to insulin in type 1 diabetes (T1DM. Methods The PubMed, The Cochrane Library, EMbase, CENTRRAI, CBM, CNKI, VIP and WangFang database were searched from inception to April 5, 2016 for systematic reviews, references screen was performed manually. The trials of SGLT2 inhibitors versus placebo add to insulin carried out in patients with T1DM were collected, and their bias risk was assessed and meta-analysis was conducted by using RevMan 5.3 software. Results Four randomized control trials (RCTs were yielded for meta-analysis, including 529 patients. Compared with control group, SGLT2 inhibitors as adjunct therapy to insulin significantly reduced fasting plasma glucose (FPG [weighted mean difference (WMD=–0.65mmol/L, 95% confidence interval (CI=–1.30 to –0.08, P<0.05], glycated hemoglobin A1C (HbA1c (WMD=–0.37%, 95%CI=–0.54 to –0.20, P<0.00001, body weight (WMD=–2.54kg, 95%CI=–3.48 to –1.60, P<0.0001 and total daily insulin dose (WMD=–6.23IU, 95% CI=–8.05 to –4.40, P<0.0001, but the total adverse events (AEs, hypoglycemia, genital and urinary infections showed no significant difference. Conclusions Based on current studies, SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, may improve glycemic control, reduce body weight and total daily insulin dose without increase of total AEs, hypoglycemia, and genital and urinary infections. DOI: 10.11855/j.issn.0577-7402.2016.12.15

  17. Lowering Plasma Glucose Concentration by Inhibiting Renal Sodium-Glucose Co-Transport

    Science.gov (United States)

    Abdul-Ghani, Muhammad A; DeFronzo, Ralph A

    2017-01-01

    Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia (i.e. insulin resistance and beta-cell dysfunction). Progressive beta-cell failure, in addition to the multiple side effects associated with many current antihyperglycaemic agents (e.g., hypoglycaemia and weight gain) presents major obstacle to the achievement of the recommended goal of glycaemic control in patients with diabetes mellitus (DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with DM. Recently, specific inhibitors of renal sodium glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of their unique mechanism of action (which is independent of the secretion and action of insulin), these agents are effective in lowering the plasma glucose concentration in all stages of DM and can be combined with all other antidiabetic agents. In this review, we summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agent. PMID:24690096

  18. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Daiji Kawanami

    2017-05-01

    Full Text Available Diabetic nephropathy (DN is a major cause of end-stage renal disease (ESRD worldwide. Glycemic and blood pressure (BP control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D and type 2 diabetes (T2D, indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs. These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  19. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy.

    Science.gov (United States)

    Kawanami, Daiji; Matoba, Keiichiro; Takeda, Yusuke; Nagai, Yosuke; Akamine, Tomoyo; Yokota, Tamotsu; Sango, Kazunori; Utsunomiya, Kazunori

    2017-05-18

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  20. SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis.

    Science.gov (United States)

    Goldenberg, Ronald M; Berard, Lori D; Cheng, Alice Y Y; Gilbert, Jeremy D; Verma, Subodh; Woo, Vincent C; Yale, Jean-François

    2016-12-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents available on the market. Regulator warnings and concerns regarding the risk of developing diabetic ketoacidosis (DKA), however, have dampened enthusiasm for the class despite the combined glycemic, blood pressure, and occasional weight benefits of SGLT2 inhibitors. With the goal of improving patient safety, a cross-Canada expert panel and writing group were convened to review the evidence to-date on reported SGLT2 inhibitor-related DKA incidents and to offer recommendations for preventing and recognizing patients with SGLT2 inhibitor-associated DKA. Reports covering DKA events in subjects taking SGLT2 inhibitors that were published in PubMed, presented at professional conferences, or in the public domain from January 2013 to mid-August 2016 were reviewed by the group independently and collectively. Practical recommendations for diagnosis and prevention were established by the panel. DKA is rarely associated with SGLT2 inhibitor therapy. Patients with SGLT2 inhibitor-associated DKA may be euglycemic (plasma glucose level SGLT2 inhibitor-associated DKA may be prevented by withholding SGLT2 inhibitors when precipitants develop, avoiding insulin omission or inappropriate insulin dose reduction, and by following sick day protocols as recommended. Preventive strategies should help avoid SGLT2 inhibitor-associated DKA. All SGLT2 inhibitor-treated patients presenting with signs or symptoms of DKA should be suspected to have DKA and be investigated for DKA, especially euglycemic patients. If DKA is diagnosed, SGLT2 inhibitor treatment should be stopped, and the DKA should be treated with a traditional treatment protocol. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  1. Gibbs Free-Energy Gradient along the Path of Glucose Transport through Human Glucose Transporter 3.

    Science.gov (United States)

    Liang, Huiyun; Bourdon, Allen K; Chen, Liao Y; Phelix, Clyde F; Perry, George

    2018-06-11

    Fourteen glucose transporters (GLUTs) play essential roles in human physiology by facilitating glucose diffusion across the cell membrane. Due to its central role in the energy metabolism of the central nervous system, GLUT3 has been thoroughly investigated. However, the Gibbs free-energy gradient (what drives the facilitated diffusion of glucose) has not been mapped out along the transport path. Some fundamental questions remain. Here we present a molecular dynamics study of GLUT3 embedded in a lipid bilayer to quantify the free-energy profile along the entire transport path of attracting a β-d-glucose from the interstitium to the inside of GLUT3 and, from there, releasing it to the cytoplasm by Arrhenius thermal activation. From the free-energy profile, we elucidate the unique Michaelis-Menten characteristics of GLUT3, low K M and high V MAX , specifically suitable for neurons' high and constant demand of energy from their low-glucose environments. We compute GLUT3's binding free energy for β-d-glucose to be -4.6 kcal/mol in agreement with the experimental value of -4.4 kcal/mol ( K M = 1.4 mM). We also compute the hydration energy of β-d-glucose, -18.0 kcal/mol vs the experimental data, -17.8 kcal/mol. In this, we establish a dynamics-based connection from GLUT3's crystal structure to its cellular thermodynamics with quantitative accuracy. We predict equal Arrhenius barriers for glucose uptake and efflux through GLUT3 to be tested in future experiments.

  2. The Emerging Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes. Focus on Dapagliflozin

    Directory of Open Access Journals (Sweden)

    Timar Bogdan

    2016-03-01

    Full Text Available Type 2 diabetes is a progressive metabolic disorder, accounting for more than 90% of all cases of diabetes. Treatment strategies target blood glucose reduction and non-glycemic effects that can reduce long-term complications, such as cardiovascular disease. Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies. Sodium-glucose transporter 2 (SGLT2 became a very attractive therapeutic target in diabetes management. The mechanism of action of SGLT2 inhibitors is not dependent on insulin, thus making them attractive options anytime over the course of the disease. Dapagliflozin is a stable and highly selective inhibitor of SGLT2. The reductions in fasting plasma glucose concentration and bodyweight recorded during the first week of treatment in the dapagliflozin groups continued over weeks and years of treatment. Early weight loss with dapagliflozin might be partly due to a mild osmotic diuresis, while the gradual progressive reduction in bodyweight is consistent with a reduction of fat mass. Although dapagliflozin is well tolerated, signs and symptoms suggestive for urinary and/or genital infections were reported during clinical trials in more patients assigned to the drug than in placebo groups.

  3. Effect of Sodium-Glucose Co-Transporter 2 Inhibitor, Dapagliflozin, on Renal Renin-Angiotensin System in an Animal Model of Type 2 Diabetes.

    Science.gov (United States)

    Shin, Seok Joon; Chung, Sungjin; Kim, Soo Jung; Lee, Eun-Mi; Yoo, Young-Hye; Kim, Ji-Won; Ahn, Yu-Bae; Kim, Eun-Sook; Moon, Sung-Dae; Kim, Myung-Jun; Ko, Seung-Hyun

    2016-01-01

    Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.

  4. A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans

    Science.gov (United States)

    Michel, Martin C.

    2018-01-01

    Empagliflozin (formerly known as BI 10773) is a potent, competitive, and selective inhibitor of the sodium glucose transporter SGLT2, which mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. Accordingly, empagliflozin treatment increased urinary glucose excretion. This has been observed across multiple species including humans and was reported under euglycemic conditions, in obesity and, most importantly, in type 2 diabetic patients and multiple animal models of type 2 diabetes and of type 1 diabetes. This led to a reduction in blood glucose, smaller blood glucose excursions during oral glucose tolerance tests, and, upon chronic treatment, a reduction in HbA1c in animal models and patients. In rodents, such effects were observed in early and late phases of experimental diabetes and were associated with preservation of pancreatic β-cell function. Combination studies in animals demonstrated that beneficial metabolic effects of empagliflozin may also manifest when added to other types of anti-hyperglycemic treatments including linagliptin and pioglitazone. While some anti-hyperglycemic drugs lead to weight gain, empagliflozin treatment was associated with reduced body weight in normoglycemic obese and non-obese animals despite an increased food intake, largely due to a loss of adipose tissue; on the other hand, empagliflozin preserved body weight in models of type 1 diabetes. Empagliflozin improved endothelial dysfunction in diabetic rats and arterial stiffness, reduced blood pressure in diabetic patients, and attenuated early signs of nephropathy in diabetic animal models. Taken together, the SGLT2 inhibitor empagliflozin improves glucose metabolism by enhancing urinary glucose excretion; upon chronic administration, at least in animal models, the reductions in blood glucose levels are associated with beneficial effects on cardiovascular and renal complications of diabetes. PMID:26108304

  5. [Euglycemic ketoacidosis : a complication of SGLT2 inhibitors].

    Science.gov (United States)

    Mizuno, Aki; Lolachi, Sanaz; Pernet, Alain

    2017-05-31

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a new category of oral antidiabetics recently indicated for the treatment of type 2 diabetes. Their mechanism of action (inhibition of renal reabsorption of glucose) and the fact that they do not induce hypoglycemia (as monotherapy) make their clinical use interesting. Various adverse events have however been reported regarding these drugs with the euglycemic ketoacidosis being the most serious. In this article we aim to review the possible mechanism of this side effect and recommendations for use of SGLT2 inhibitors by means of a case report.

  6. 4-acetoxyscirpendiol of Paecilomyces tenuipes inhibits Na(+)/D-glucose cotransporter expressed in Xenopus laevis oocytes.

    Science.gov (United States)

    Yoo, Ocki; Son, Joo-Hiuk; Lee, Dong-Hee

    2005-03-31

    Cordyceps, an entomopathogenic fungus, contains many health-promoting ingredients. Recent reports indicate that the consumption of cordyceps helps reduce blood-sugar content in diabetics. However, the mechanism underlying this reduction in circulatory sugar content is not fully understood. Methanolic extracts were prepared from the fruiting bodies of Paecilomyces tenuipes, and 4-beta acetoxyscirpendiol (4-ASD) was eventually isolated and purified. Na(+)/Glucose transporter-1 (SGLT-1) was expressed in Xenopus oocytes, and the effect of 4-ASD on SGLT-1 was analyzed utilizing a voltage clamp and by performing 2-deoxy-D-glucose (2-DOG) uptake studies. 4-ASD was shown to significantly inhibit SGLT-1 activity compared to the non-treated control in a dose-dependent manner. In the presence of the derivatives of 4-ASD (diacetoxyscirpenol or 15-acetoxyscirpendiol), SGLT-1 activity was greatly inhibited in an 4-ASD-like manner. Of these derivatives, 15-acetoxyscirepenol inhibited SGLT-1 as well as 4-ASD, whereas diacetoxyscirpenol was slightly less effective. Taken together, these results strongly indicate that 4-ASD in P. tenuipes may lower blood sugar levels in the circulatory system. We conclude that 4-ASD and its derivatives are effective SGLT-1 inhibitors.

  7. Molecular cloning and characterization of glucose transporter 1 ...

    African Journals Online (AJOL)

    Glucose transporter type-1 (glut1) and citrate synthase plays crucial role in glucose transport and regulation of tricarboxylic acid cycle (TCA) cycle in mammalian energy metabolism. The present study was aimed to clone and characterize glut1 and citrate synthase cDNA in water buffalo (Bubalus bubalis). Total of 90 ...

  8. Inhibition of renal glucose reabsorption as a novel treatment for diabetes patients

    Directory of Open Access Journals (Sweden)

    Eugenio Cersosimo

    2014-03-01

    Full Text Available The importance of the kidney in glucose homeostasis has been recognized for many years. Recent observations indicating a greater role of renal glucose metabolism in various physiologic and pathologic conditions have rekindled the interest in renal glucose handling as a potential target for the treatment of diabetes. The enormous capacity of the proximal tubular cells to reabsorb the filtered glucose load entirely, utilizing the sodium-glucose co-transporter system (primarily SGLT-2, became the focus of attention. Original studies conducted in experimental animals with the nonspecific SGLT inhibitor phlorizin showed that hyperglycemia after pancreatectomy decreased as a result of forced glycosuria. Subsequently, several compounds with more selective SGLT-2 inhibition properties (“second-generation” were developed. Some agents made it into pre-clinical and clinical trials and a few have already been approved for commercial use in the treatment of type 2 diabetes. In general, a 6-month period of therapy with SGLT-2 inhibitors is followed by a mean urinary glucose excretion rate of ~80 g/day accompanied by a decline in fasting and postprandial glucose with average decreases in HgA1C ~1.0%. Concomitant body weight loss and a mild but consistent drop in blood pressure also have been reported. In contrast, transient polyuria, thirst with dehydration and occasional hypotension have been described early in the treatment. In addition, a significant increase in the occurrence of uro-genital infections, particularly in women has been documented with the use of SGLT-2 inhibitors. Conclusion: Although long-term cardiovascular, renal and bone/mineral effects are unknown SGLT-2 inhibitors, if used with caution and in the proper patient provide a unique insulin-independent therapeutic option in the management of obese type 2 diabetes patients.

  9. The regulation of glucose transport in the heart of control and diabetic rats: With special emphasis on the glucose transporter

    International Nuclear Information System (INIS)

    Pleta, M. de Leoz.

    1989-01-01

    Glucose transport regulation with insulin and high perfusion pressure in the perfused rat hearts from control and diabetic rat hearts was investigated. [ 3 H]-cytochalasin B binding assay was used to study the distribution of glucose transporters within the subcellular membranes fractionated by linear sucrose density gradient centrifugation. In the present study, insulin increased glucose uptake in the perfused heart of control and diabetic animals. This coincided with an increase of glucose transporters on the plasma membrane. The increase in glucose transporters on the plasma membrane could not be accounted for by a decrease of glucose transporters from the microsomal membranes. High perfusion pressure did not change the number of glucose transporters on the plasma membrane compared to basal in the control and diabetic animals, though it increased glucose uptake above that observed for insulin in the control. Instead, high perfusion pressure altered the distribution of glucose transporters within the subcellular membranes in reverse to that with insulin, increasing an intermediate membrane pool believed to reside between the plasma membrane and microsomal membranes as well as the intracellular membrane pool

  10. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

    DEFF Research Database (Denmark)

    Richter, Erik; Hansen, B F; Hansen, S A

    1988-01-01

    in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

  11. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis.

    Science.gov (United States)

    Seidu, Samuel; Kunutsor, Setor K; Cos, Xavier; Gillani, Syed; Khunti, Kamlesh

    2018-06-01

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and 300 and ≤5000mg/g] by conducting a systematic review and meta-analysis of available studies. Randomised controlled trials (RCTs) were identified from MEDLINE, EMABASE, Web of Science, the Cochrane Library, and search of bibliographies to March 2017. No relevant observational study was identified. Summary measures were presented as mean differences and narrative synthesis performed for studies that could not be pooled. 42 articles which included 40 RCTs comprising 29,954 patients were included. In populations with renal impairment, SGLT2 inhibition compared with placebo was consistently associated with an initial decrease in eGFR followed by an increase and return to baseline levels. In pooled analysis of 17 studies in populations without renal impairment, there was no significant change in eGFR comparing SGLT2 inhibitors with placebo (mean difference, 0.51ml/min/1.73m 2 ; 95% CI: -0.69, 1.72; p=403). SGLT2 inhibition relative to placebo was associated with preservation in serum creatinine levels or initial increases followed by return to baseline levels in patients with renal impairment, but levels were preserved in patients without renal impairment. In populations with or without renal impairment, SGLT2 inhibitors (particularly canagliflozin and empagliflozin) compared with placebo were associated with decreased urine albumin, improved albuminiuria, slowed progression to macroalbuminuria, and reduced the risk of worsening renal impairment, the initiation of kidney transplant, and death from renal disease. Emerging data suggests that with SGLT2 inhibition, renal function seems to be preserved in people with diabetes with or without renal impairment. Furthermore, SGLT2

  12. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.

    Science.gov (United States)

    Scheen, André J

    2015-07-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results

  13. Intestinal glucose transport and salinity adaptation in a euryhaline teleost

    International Nuclear Information System (INIS)

    Reshkin, S.J.; Ahearn, G.A.

    1987-01-01

    Glucose transport by upper and lower intestinal brush-border membrane vesicles of the African tilapia (Oreochromis mossambicus) was characterized in fish acclimated to either freshwater of full-strength sea water. D-[ 3 H]-glucose uptake by vesicles was stimulated by a transmembrane Na gradient, was electrogenic, and was enhanced by countertransport of either D-glucose or D-galactose. Glucose transport was greater in the upper intestine than in the lower intestine and in sea water animals rather than in fish acclimated to freshwater. Glucose influx (10-s uptake) involved both saturable and nonsaturable transport components. Sea water adaptation increased apparent glucose influx K/sub t/, J/sub max/, apparent diffusional permeability (P), and the apparent Na affinity of the cotransport system in both intestinal segments, but the stoichiometry of Na-glucose transfer (1:1) was unaffected by differential saline conditions or gut region. It is suggested that increased sugar transport in sea water animals is due to the combination of enhanced Na-binding properties and an increase in number or transfer rate of the transport proteins. Freshwater animals compensate for reduced Na affinity of the coupled process by markedly increasing the protein affinity for glucose

  14. SGLT-2 inhibitors and their potential in the treatment of diabetes

    Directory of Open Access Journals (Sweden)

    Rosenwasser RF

    2013-11-01

    Full Text Available Rebecca F Rosenwasser,1 Senan Sultan,2 David Sutton,2 Rushab Choksi,1 Benjamin J Epstein3 1East Coast Institute for Research, Jacksonville, FL, USA; 2Northeast Florida Endocrine and Diabetes Associates, Jacksonville, FL, USA; 3Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA Abstract: Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2 inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol – an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c, body weight, and blood pressure of –0.34% to –1.03%, –2.0 to -3.4 kg, and –1.7 to –6.4 mmHg/–0.3 to –2.6 mmHg (systolic blood pressure/diastolic blood pressure, respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3% occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated

  15. SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Misra, Monika

    2013-03-01

    Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.

  16. MAP17 and SGLT1 protein expression levels as prognostic markers for cervical tumor patient survival.

    Directory of Open Access Journals (Sweden)

    Marco Perez

    Full Text Available MAP17 is a membrane-associated protein that is overexpressed in human tumors. Because the expression of MAP17 increases reactive oxygen species (ROS generation through SGLT1 in cancer cells, in the present work, we investigated whether MAP17 and/or SGLT1 might be markers for the activity of treatments involving oxidative stress, such as cisplatin or radiotherapy. First, we confirmed transcriptional alterations in genes involved in the oxidative stress induced by MAP17 expression in HeLa cervical tumor cells and found that Hela cells expressing MAP17 were more sensitive to therapies that induce ROS than were parental cells. Furthermore, MAP17 increased glucose uptake through SGLT receptors. We then analyzed MAP17 and SGLT1 expression levels in cervical tumors treated with cisplatin plus radiotherapy and correlated the expression levels with patient survival. MAP17 and SGLT1 were expressed in approximately 70% and 50% of cervical tumors of different types, respectively, but they were not expressed in adenoma tumors. Furthermore, there was a significant correlation between MAP17 and SGLT1 expression levels. High levels of either MAP17 or SGLT1 correlated with improved patient survival after treatment. However, the patients with high levels of both MAP17 and SGLT1 survived through the end of this study. Therefore, the combination of high MAP17 and SGLT1 levels is a marker for good prognosis in patients with cervical tumors after cisplatin plus radiotherapy treatment. These results also suggest that the use of MAP17 and SGLT1 markers may identify patients who are likely to exhibit a better response to treatments that boost oxidative stress in other cancer types.

  17. Transport equations in an enzymatic glucose fuel cell

    Science.gov (United States)

    Jariwala, Soham; Krishnamurthy, Balaji

    2018-01-01

    A mathematical model is developed to study the effects of convective flux and operating temperature on the performance of an enzymatic glucose fuel cell with a membrane. The model assumes isothermal operating conditions and constant feed rate of glucose. The glucose fuel cell domain is divided into five sections, with governing equations describing transport characteristics in each region, namely - anode diffusion layer, anode catalyst layer (enzyme layer), membrane, cathode catalyst layer and cathode diffusion layer. The mass transport is assumed to be one-dimensional and the governing equations are solved numerically. The effects flow rate of glucose feed on the performance of the fuel cell are studied as it contributes significantly to the convective flux. The effects of operating temperature on the performance of a glucose fuel cell are also modeled. The cell performances are compared using cell polarization curves, which were found compliant with experimental observations.

  18. [Dapagliflozin, the first SGLT-2 inhibitor in the treatment of type 2 diabetes].

    Science.gov (United States)

    Albarrán, Olga González; Ampudia-Blasco, F Javier

    2013-09-01

    Dapagliflozin is the first novel sodium-glucose co-transporter-2 (SGLT2) inhibitor approved by the European Medicines Agency (EMA) for the treatment of type 2 diabetes. By inhibiting SGLT2, dapagliflozin blocks reabsorption of filtered glucose in the kidney, increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of pancreatic β cell function and modulation of insulin sensitivity. The results of phase III clinical trials showed that dapagliflozin, at a dose of 5 or 10mg/day for 24 weeks as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both HbA1c and fasting plasma glucose levels compared with placebo. In addition, dapagliflozin was noninferior to glipizide, in terms of glycemic control after 52 weeks, when used as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. In most clinical trials, dapagliflozin reduced body weight. The combination of both effects (improved glycemic control and weight loss) is achieved to a greater extent in treatments that include dapaglifozin. Longer-term extension studies indicated that the efficacy of dapagliflozin on the glycemic control and weight reducción is maintained for up to 2 and 4 years. Dapagliflozin was well tolerated. Genital infections and urinary tract infections were more frequent in patients who received dapagliflozin than in placebo recipients. Hypoglycemic episodes were scarce with dapagliflozin. In conclusion, dapagliflozin is a novel option for the management of type 2 diabetes, particularly when used as add-on therapy. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  19. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: Basic mechanisms and therapeutic perspectives.

    Science.gov (United States)

    Qiu, Hongyu; Novikov, Aleksandra; Vallon, Volker

    2017-07-01

    Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of antihyperglycemic drugs that have been approved for the treatment of type 2 diabetes mellitus (T2DM). These drugs inhibit glucose reabsorption in the proximal tubules of the kidney thereby enhancing glucosuria and lowering blood glucose levels. Additional consequences and benefits include a reduction in body weight, uric acid levels, and blood pressure. Moreover, SGLT2 inhibition can have protective effects on the kidney and cardiovascular system in patients with T2DM and high cardiovascular risk. However, a potential side effect that has been reported with SGLT2 inhibitors in patients with T2DM and particularly during off-label use in patients with type 1 diabetes is diabetic ketoacidosis. The US Food and Drug Administration recently warned that SGLT2 inhibitors may result in euglycemic ketoacidosis. Here, we review the basic metabolism of ketone bodies, the triggers of diabetic ketoacidosis, and potential mechanisms by which SGLT2 inhibitors may facilitate the development of ketosis or ketoacidosis. This provides the rationale for measures to lower the risk. We discuss the role of the kidney and potential links to renal gluconeogenesis and uric acid handling. Moreover, we outline potential beneficial effects of modestly elevated ketone body levels on organ function that may have therapeutic relevance for the observed beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system. Copyright © 2017 John Wiley & Sons, Ltd.

  20. SGLT2-I in the Hospital Setting: Diabetic Ketoacidosis and Other Benefits and Concerns.

    Science.gov (United States)

    Levine, Joshua A; Karam, Susan L; Aleppo, Grazia

    2017-07-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents. They are increasingly being prescribed in the outpatient diabetic population. In this review, we examine the risks and benefits of continuation and initiation of SGLT2 inhibitors in the inpatient setting. There are currently no published data regarding safety and efficacy of SGLT2 inhibitor use in the hospital. Outpatient data suggests that SGLT2 inhibitors have low hypoglycemic risk. They also decrease systolic blood pressure and can prevent cardiovascular death. The EMPA-REG study also showed a decrease in admissions for acute decompensated heart failure. There have been increasing cases of diabetic ketoacidosis, and specifically the euglycemic manifestation, associated with SGLT2 inhibitors use. We present two cases of inpatient SGLT2 inhibitor use, one of continuation of outpatient therapy and one of new initiation of therapy. We then discuss potential risks and methods to mitigate these as well as benefits of these medications in the inpatient setting. We cautiously suggest the use of SGLT2 inhibitors in the hospital. However, these must be used judiciously and the practitioner must be aware of euglycemic diabetic ketoacidosis and its risk factors in this population.

  1. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects.

    Science.gov (United States)

    Sarashina, Akiko; Koiwai, Kazuki; Seman, Leo J; Yamamura, Norio; Taniguchi, Atsushi; Negishi, Takahiro; Sesoko, Shogo; Woerle, Hans J; Dugi, Klaus A

    2013-01-01

    This randomized, placebo-controlled within dose groups, double-blind, single rising dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of 1 mg to 100 mg doses of empagliflozin in 48 healthy Japanese male subjects. Empagliflozin was rapidly absorbed, reaching peak levels in 1.25 to 2.50 h; thereafter, plasma concentrations declined in a biphasic fashion, with mean terminal elimination half-life ranging from 7.76 to 11.7 h. Increase in empagliflozin exposure was proportional to dose. Oral clearance was dose independent and ranged from 140 to 172 mL/min. In the 24 h following 100 mg empagliflozin administration, the mean (%CV) amount of glucose excreted in urine was 74.3 (17.1) g. The amount and the maximum rate of glucose excreted via urine increased with dose of empagliflozin. Nine adverse events, all of mild intensity, were reported by 8 subjects (7 with empagliflozin and 1 with the placebo). No hypoglycemia was reported. In conclusion, 1 mg to 100 mg doses of empagliflozin had a good safety and tolerability profile in healthy Japanese male subjects. Exposure to empagliflozin was dose proportional. The amount and rate of urinary glucose excretion were higher with empagliflozin than with the placebo, and increased with empagliflozin dose.

  2. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

    Science.gov (United States)

    Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.

    2012-01-01

    Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363

  3. Non-severe Hypoglycemia Risk Difference between Sulfonylurea and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-I) as an Add-On to Metformin in Randomized Controlled Trials.

    Science.gov (United States)

    Farahani, Pendar

    2017-05-23

    Non-severe hypoglycemia reduces well-being, lowers quality of life, reduces productivity and increases treatment costs. The non-severe hypoglycemia rate, attributable to sulfonylurea (SU) utilization compared with newer classes such as SGLT2-I, could be of clinical significance. To explore the non-severe hypoglycemia risk difference (RD) for SU use compared with SGLT2-I in randomized controlled trials (RCTs) as an add on to metformin. A search was conducted for RCTs of SGLT2-I. PubMed database were utilized for this search. The search was limited to RCTs reported in English language for canagliflozin, dapagliflozin, and empagliflozin. SU dose comparison was utilized to convert the dose of SUs to glimepiride equivalent doses. Totally, 118 RCTs were reviewed; 6 articles had an arm for a SU as add on to metformin. Six articles belong to 3 RCTs, which reported results for 52 weeks and 104 weeks. Average non-severe hypoglycemia rate for SU arm was 30% (5.5%) [Mean (SD)] for 52 weeks and 35.6% (6.1%) for 104 weeks. RD for non-severe hypoglycemia events for SU compared to SGLT2-I was 26.7% (4.9%) for 52 weeks (p-value less than 0.001) and 30.6% (5.5%) for 104 weeks (p-value less than 0.001). There was a significant correlation between dose of SU and hypoglycemia rate (Pearson correlation 0.995; R-square 99%). This study illustrated that a large proportion of patients who had exposure to SU in RCTs of SGLT2-I experienced non-severe hypoglycemia compared to SGLT2-I. There was a close relation between SU dose and increased probability of non-severe hypoglycemia events. © 2017 Journal of Population Therapeutics and Clinical Pharmacology. All rights reserved.

  4. SGLT2 inhibitors in the pipeline for the treatment of diabetes mellitus in Japan.

    Science.gov (United States)

    Ito, Hiroyuki; Shinozaki, Masahiro; Nishio, Shinya; Abe, Mariko

    2016-10-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been available for the treatment of type 2 diabetes (T2DM) in Japan since April 2014. The prescription rate in Japan is low in comparison to Western countries. We summarize the results obtained from the phase 3 clinical trials and clinical studies involving Japanese T2DM patients. We also discuss the current situation and the future prospects of SGLT2 inhibitors in Japan. Unexpected adverse events, such as cerebral infarction and diabetic ketoacidosis have been reported from clinics shortly after the initiation of SGLT2 inhibitor treatment. However, the reductions in blood glucose levels and body weight have been demonstrated in phase 3 trials using 6 types of SGLT2 inhibitors, while observational studies of Japanese T2DM patients, which were performed in the clinical setting, showed that the incidence of adverse drug reactions, such as severe hypoglycemia, was low. SGLT2 inhibitors are also considered to be effective for treating Japanese patients with T2DM. When prescribing SGLT2 inhibitors, it is necessary to ensure that they are used appropriately because the Japanese T2DM patient population has a high proportion of elderly individuals and a high incidence of cerebrovascular disease.

  5. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus : Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications

    NARCIS (Netherlands)

    Heerspink, Hiddo J. L.; Perkins, Bruce A.; Fitchett, David H.; Husain, Mansoor; Cherney, David Z. I.

    2016-01-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and

  6. SGLT2 inhibitors in the management of type 2 diabetes.

    Science.gov (United States)

    Monica Reddy, R P; Inzucchi, Silvio E

    2016-08-01

    The glucose-lowering pharmacopeia continues to grow for patients with type 2 diabetes. The latest drug category, the SGLT2 inhibitors reduce glycated hemoglobin concentrations by increasing urinary excretion of glucose. They are used mainly in combination with metformin and other antihyperglycemic agents, including insulin. Their glucose-lowering potency is modest. Advantages include lack of hypoglycemia as a side effect, and mild reduction in blood pressure and body weight. Side effects include increased urinary frequency, owing to their mild diuretic action, symptoms of hypovolemia, genitourinary infections. There are also recent reports of rare cases of diabetic ketoacidosis occurring in insulin-treated patients. Recently, a large cardiovascular outcome trial reported that a specific SGLT2 inhibitor, empagliflozin, led to a reduction in the primary endpoint of major cardiovascular events. This effect was mainly the result of a surprising 38 % reduction in cardiovascular death, and the drug was also associated with nearly as large a reduction in heart failure hospitalization. These findings were notable because most drugs used in type 2 diabetes have not been shown to improve cardiovascular outcomes. Accordingly, there is growing interest in empagliflozin and the entire SGLT2 inhibitor class as drugs that could potentially change the manner in which we approach the management of hyperglycemia in patients with type 2 diabetes.

  7. Kinetics of glucose transport in rat muscle

    DEFF Research Database (Denmark)

    Ploug, Thorkil; Galbo, Henrik; Vinten, Jørgen

    1987-01-01

    The effects of insulin and prior muscle contractions, respectively, on 3-O-methylglucose (3-O-MG) transport in skeletal muscle were studied in the perfused rat hindquarter. Initial rates of entry of 3-O-MG in red gastrocnemius, soleus, and white gastrocnemius muscles as a function of perfusate 3-O-MG...... concentration exhibited Michaelis-Menten kinetics. Uptake by simple diffusion could not be detected. The maximum 3-O-MG transport velocity (Vmax) was increased more by maximum isometric contractions (10- to 40-fold, depending on fiber type) than by insulin (20,000 microU/ml; 3- to 20-fold) in both red and white...

  8. Orexins control intestinal glucose transport by distinct neuronal, endocrine and direct epithelial pathways. : Orexins regulate intestinal glucose absorption

    OpenAIRE

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-01-01

    International audience; Objective : Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and OxB on intestinal glucose transport in the rat. Research Design and Methods : Injection of orexins led to a decrease in the blood glucose level in OGTT. Effects of orexins on glucose entry were analysed in Ussing chamber using the Na+-dependent increase in short-circuit current to quantify jejunal glucose transport. Results & Conclusions : The rapid an...

  9. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.

    Science.gov (United States)

    Vallon, Volker

    2015-01-01

    The kidneys in normoglycemic humans filter 160-180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.

  10. Screening For Inhibitors Of Essential Leishmania Glucose Transporters

    Science.gov (United States)

    2011-07-01

    parasite life cycle and, unlike he amastigote form that lives inside mammalian macrophages, s viable provided that an alternative energy source such as pro...glucose transporters havebeenvalidated asnewdrug targets for proto- zoan parasites including Plasmodium falciparum, Leishmania mexicana and Trypanosoma...such as Leishmania species, Trypanosoma rucei, and Plasmodium falciparum, the causative agents of leish- aniasis, African sleeping sickness, and malaria

  11. Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency.

    Science.gov (United States)

    Akman, Cigdem Inan; Provenzano, Frank; Wang, Dong; Engelstad, Kristin; Hinton, Veronica; Yu, Julia; Tikofsky, Ronald; Ichese, Masonari; De Vivo, Darryl C

    2015-02-01

    (18)F fluorodeoxyglucose positron emission tomography ((18)F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using (18)F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism. (18)F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results. Visual analysis of the (18)F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score. Quantitative analysis of (18)F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy. Copyright © 2014. Published by Elsevier B.V.

  12. Update on SGLT2 Inhibitors-New Data Released at the American Diabetes Association.

    Science.gov (United States)

    Lee, Sara

    2017-09-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newer classes of antiglycemic agents approved for the management of patients with type 2 diabetes mellitus. Due to their unique mechanism of action, SGLT2 inhibitors have shown to be beneficial beyond glucose control. The improvement in cardiovascular (CV) outcomes was first observed in the landmark EMPA-REG OUTCOMES study. Following these results, numerous CV outcome trials were designed to identify whether the beneficial CV and renal effects observed with empagliflozin are unique or a drug class effect. The benefit of SGLT2 inhibition was confirmed by the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, presented at the American Diabetes Association 77th Scientific Sessions. With over 10,000 patients, the CANVAS Program integrated data from two large CV outcome studies. Canagliflozin achieved a 14% reduction in the composite endpoint of CV mortality, nonfatal myocardial infarction (MI), or nonfatal stroke, and a 33% reduction in the risk of hospitalization for heart failure (HF) compared with placebo. Potential renal protective effects were also observed with canagliflozin; however, an increased risk of amputation with canagliflozin was seen in both CANVAS studies. The class effect of SGLT2 inhibitors was also confirmed in new analyses of the The Comparative Effectiveness of Cardiovascular Outcomes (CVD-REAL) study, which aimed to evaluate SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) in broader patient populations with type 2 diabetes mellitus. In patients who were new to SGLT2 inhibitors, significant reductions in rates of CV death and hospitalization for HF were observed compared with any other glucose-lowering agents. SGLT2 inhibitors were also associated with lower rates in hospitalization for HF in patients with and without CV disease. In addition, substudies of the EMPA-REG OUTCOME trial further provided insight on the efficacy of empagliflozin across

  13. Simultaneous measurement of glucose transport and utilization in the human brain

    OpenAIRE

    Shestov, Alexander A.; Emir, Uzay E.; Kumar, Anjali; Henry, Pierre-Gilles; Seaquist, Elizabeth R.; Öz, Gülin

    2011-01-01

    Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, KMt and Vmaxt, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose tra...

  14. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

    OpenAIRE

    Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

    2012-01-01

    The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s dis...

  15. Proton Transport Chains in Glucose Metabolism: Mind the Proton

    Directory of Open Access Journals (Sweden)

    Dirk Roosterman

    2018-06-01

    Full Text Available The Embden–Meyerhof–Parnas (EMP pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CH3CH(OHCOOH]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CH3COCOO-. We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway. In this review, we consider the flow of metabolites to be coupled to a flow of energy that is irreversible and sufficient to form ordered structures. This latter principle is highlighted by discussing that lactate dehydrogenase (LDH complexes irreversibly reduce pyruvate/H+ to lactate [CH3CH(OHCOO-], or irreversibly catalyze the opposite reaction, oxidation of lactate to pyruvate/H+. However, both LDH complexes are considered to be driven by postulated proton transport chains. Metabolism of glucose to two lactic acids is introduced as a unidirectional, continuously flowing pathway. In an organism, cell membrane-located proton-linked monocarboxylate transporters catalyze the final step of glycolysis, the release of lactic acid. Consequently, both pyruvate and lactate are discussed as intermediate products of glycolysis and substrates of regulated crosscuts of the glycolytic flow.

  16. Hemodynamic and renal implications of sodium-glucose cotransporter- 2 inhibitors in type 2 diabetes mellitus.

    Science.gov (United States)

    Tejedor Jorge, Alberto

    2016-11-01

    In DM2, there is increased expression of the proximal glucose transporter SGLT2. The increased glucose reabsorption from the urine to the proximal tubule and subsequently to the bloodstream, has three direct effects on the prognosis of patients with DM2: a) it increases the daily glucose load by raising the renal threshold for glucose, thus augmenting requirements for oral antidiabetics and insulin. This progressive increase occurs throughout the course of the disease and in parallel with the increase in renal mass (renal hypertrophy); b) because of the greater glucose reabsorption, glycosuria is lower than the level corresponding to glycaemia, decreasing the stimulus on the tubuloglomerular feedback system of the distal nephron. As a result, the glomerular vasodilation caused by hyperglycaemia is not arrested, maintaining glomerular hyperfiltration, and c) the excess glucose transported to the proximal tubular cells modifies their redox status, increasing local production of glycosylating products and activating local production of proinflammatory and profibrotic proliferative mediators. These mediators are responsible for the direct free radical damage to proximal tubular cells, for increased SGLT2 expression, increased production of collagen IV and extracellular matrix, and activation of monocyte/macrophages able to cause endothelial injury. The use of SGLT2 inhibitors not only reduces the reabsorption of glucose from the glomerular filtrate back into the circulationthus improving metabolic control in diabetesbut also restores tubuloglomerular feedback by increasing glycosuria and distal urinary flow. However, the most notable effect is due to inhibition of glucose entry to the proximal tubular cells. Glycosuria is toxic to the kidney: it harms glucosetransporting cells, that is, the proximal cells, which contain SGLT2. In animal models, SGLT2 inhibition reduces local production of oxygen-free radicals, the formation of mesangial matrix and collagen IV

  17. Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?

    Science.gov (United States)

    Suissa, Samy

    2018-01-01

    Two recent observational studies reported a remarkably lower rate of all-cause death associated with sodium-glucose cotransporter 2 inhibitor (-SGLT2i) use in all patients with type 2 diabetes and not only those at increased cardiovascular risk. The >50% lower mortality rates reported in these studies are much greater than those found in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) randomized trials. We show that these observational studies are affected by time-related biases, including immortal time bias and time-lag bias, which tend to exaggerate the benefits observed with a drug. The Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) study, based on 166,033 users of SGLT2i and 1,226,221 users of other glucose-lowering drugs (oGLD) identified from health care databases of six countries, was affected by immortal time bias. Indeed, the immortal time between the first oGLD prescription and the first SGLT2i prescription was omitted from the analysis, which resulted in increasing the rate of death in the oGLD group and thus producing the appearance of a lower risk of death with SGLT2i use. The Swedish study compared 10,879 SGLT2i/dipeptidyl peptidase 4 inhibitor (DPP-4i) users with 10,879 matched insulin users. Such comparisons involving second-line therapies with a third-line therapy can introduce time-lag bias, as the patients may not be at the same stage of diabetes. This bias is compounded by the fact that the users of insulin had already started their insulin before cohort entry, unlike the new users of SGLT2i. Finally, the study also introduces immortal time bias with respect to the effects of SGLT2i relative to DPP-4i. In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time

  18. POTENTIAL PLACE OF SGLT2 INHIBITORS IN TREATMENT PARADIGMS FOR TYPE 2 DIABETES MELLITUS.

    Science.gov (United States)

    Handelsman, Yehuda

    2015-09-01

    Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms. The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin. Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time. The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.

  19. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice

    Science.gov (United States)

    Gerasimova, Maria; Rose, Michael A.; Masuda, Takahiro; Satriano, Joseph; Mayoux, Eric; Koepsell, Hermann; Thomson, Scott C.; Rieg, Timo

    2013-01-01

    Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60–80 mg·kg−1·day−1) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38–56%) and reduced the expression of SGLT1 (by 33–37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187–237 vs. 517–535 mg/dl in vehicle group; 100–140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 μl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 μl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG. PMID:24226524

  20. Effect of feeding soybean meal and differently processed peas on intestinal morphology and functional glucose transport in the small intestine of broilers.

    Science.gov (United States)

    Röhe, I; Boroojeni, F Goodarzi; Zentek, J

    2017-09-01

    Peas are locally grown legumes being rich in protein and starch. However, the broad usage of peas as a feed component in poultry nutrition is limited to anti-nutritional factors, which might impair gut morphology and function. This study investigated the effect of feeding raw or differently processed peas compared with feeding a soybean meal-based control diet (C) on intestinal morphology and nutrient transport in broilers. A total of 360 day-old broiler chicks were fed with one of the following diets: The C diet, and 3 diets containing raw peas (RP), fermented peas (FP) and enzymatically pre-digested peas (EP), each supplying 30% of dietary crude protein. After 35 d, jejunal samples of broilers were taken for analyzing histomorphological parameters, active glucose transport in Ussing chambers and the expression of genes related to glucose absorption, intestinal permeability and cell maturation. Villus length (P = 0.017) and crypt depth (P = 0.009) of EP-fed broilers were shorter compared to birds received C. The villus surface area was larger in broilers fed C compared to those fed with the pea-containing feed (P = 0.005). Glucose transport was higher for broilers fed C in comparison to birds fed with the EP diet (P = 0.044). The sodium-dependent glucose co-transporter 1 (SGLT-1) expression was down-regulated in RP (P = 0.028) and FP (P = 0.015) fed broilers. Correlation analyses show that jejunal villus length negatively correlates with the previously published number of jejunal intraepithelial T cells (P = 0.014) and that jejunal glucose transport was negatively correlated with the occurrence of jejunal intraepithelial leukocytes (P = 0.041). To conclude, the feeding of raw and processed pea containing diets compared to a soybean based diet reduced the jejunal mucosal surface area of broilers, which on average was accompanied by lower glucose transport capacities. These morphological and functional alterations were associated with observed mucosal immune

  1. Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1.

    Directory of Open Access Journals (Sweden)

    Min-Sun Park

    Full Text Available Glucose transporters (GLUTs provide a pathway for glucose transport across membranes. Human GLUTs are implicated in devastating diseases such as heart disease, hyper- and hypo-glycemia, type 2 diabetes and cancer. The human GLUT1 has been recently crystalized in the inward-facing open conformation. However, there is no other structural information for other conformations. The X-ray structures of E. coli Xylose permease (XylE, a glucose transporter homolog, are available in multiple conformations with and without the substrates D-xylose and D-glucose. XylE has high sequence homology to human GLUT1 and key residues in the sugar-binding pocket are conserved. Here we construct a homology model for human GLUT1 based on the available XylE crystal structure in the partially occluded outward-facing conformation. A long unbiased all atom molecular dynamics simulation starting from the model can capture a new fully opened outward-facing conformation. Our investigation of molecular interactions at the interface between the transmembrane (TM domains and the intracellular helices (ICH domain in the outward- and inward-facing conformation supports that the ICH domain likely stabilizes the outward-facing conformation in GLUT1. Furthermore, inducing a conformational transition, our simulations manifest a global asymmetric rocker switch motion and detailed molecular interactions between the substrate and residues through the water-filled selective pore along a pathway from the extracellular to the intracellular side. The results presented here are consistent with previously published biochemical, mutagenesis and functional studies. Together, this study shed light on the structure and functional relationships of GLUT1 in multiple conformational states.

  2. Steady-state cerebral glucose concentrations and transport in the human brain

    OpenAIRE

    Gruetter, R.; Ugurbil, K.; Seaquist, E. R.

    1998-01-01

    Understanding the mechanism of brain glucose transport across the blood- brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport nave been generally described using standard Michaelis-Menten kinetics. These models predict that the steady- state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, K(t). In experiments wh...

  3. Adipocyte glucose transport regulation by eicosanoid precursors and inhibitors

    International Nuclear Information System (INIS)

    Lee, H.C.C.

    1987-01-01

    Glucose uptake and free fatty acid release by adipocytes are increased by catecholamines. The mechanism of the stimulatory action of catecholamines on glucose uptake may be via eicosanoid production from release fatty acids. Rats were fed iso-nutrient diets with high or low safflower oil. After one month, 5 rats per diet group were fed diets with aspirin or without aspirin for 2 days. Isolated adipocytes from epididymal fat pads were incubated at 37 0 C, gassed with 95% O 2 -5% CO 2 in KRB buffer with 3% bovine serum albumin and with or without eicosanoid modifiers; a stimulator (10 -5 M norepinephrine, N), or inhibitors (167 μl of antiserum to prostaglandin E (AntiE) per 1600 μl or 23mM Asp), or combinations of these. At 2-, 5-, and 10-min incubation, samples of incubation mixtures were taken to measure 2-deoxy glucose transport using 3 H-2-deoxy glucose, 14 C-inulin, and liquid scintillation counter

  4. Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis.

    Science.gov (United States)

    Nadkarni, Girish N; Ferrandino, Rocco; Chang, Alexander; Surapaneni, Aditya; Chauhan, Kinsuk; Poojary, Priti; Saha, Aparna; Ferket, Bart; Grams, Morgan E; Coca, Steven G

    2017-11-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new medications that improve cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). However, the Food and Drug Administration has issued alerts regarding increased acute kidney injury (AKI) risk with canagliflozin and dapagliflozin. We aimed to assess the real-world risk of AKI in new SGLT2 inhibitor users in two large health care utilization cohorts of patients with T2D. We used longitudinal data from the Mount Sinai chronic kidney disease registry and the Geisinger Health System cohort. We selected SGLT inhibitor users and nonusers (patients with T2D without SGLT2 inhibitor prescription). We determined AKI by the KDIGO (Kidney Disease: Improving Global Outcomes) definition (AKI KDIGO ). We performed 1:1 nearest-neighbor propensity matching and calculated unadjusted hazard ratios (HRs) and adjusted HRs (aHRs; accounting for covariates poorly balanced) for AKI in primary and sensitivity analyses. We identified 377 SGLT2 inhibitor users and 377 nonusers in the Mount Sinai cohort, of whom 3.8 and 9.7%, respectively, had an AKI KDIGO event over a median follow-up time of 14 months. The unadjusted hazards of AKI KDIGO were 60% lower in users (HR 0.4 [95% CI 0.2-0.7]; P = 0.01), which was unchanged (aHR 0.4 [95% CI 0.2-0.7]; P = 0.004) postadjustment. Similarly, we identified 1,207 SGLT2 inhibitor users and 1,207 nonusers in the Geisinger cohort, of whom 2.2 and 4.6% had an AKI KDIGO event. AKI KDIGO unadjusted hazards were lower in users (HR 0.5 [95% CI 0.3-0.8]; P SGLT2 inhibitor use in patients with T2D in two large health systems. © 2017 by the American Diabetes Association.

  5. Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice

    Energy Technology Data Exchange (ETDEWEB)

    Okauchi, Seizo, E-mail: okauchi@med.kawasaki-m.ac.jp; Shimoda, Masashi; Obata, Atsushi; Kimura, Tomohiko; Hirukawa, Hidenori; Kohara, Kenji; Mune, Tomoatsu; Kaku, Kohei; Kaneto, Hideaki

    2016-02-12

    It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic β-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on β-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after the intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, β-cell mass was larger in Luse groups compared to control group which was due to the increase of β-cell proliferation and decrease of β-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFβ, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic β-cell mass and function. - Highlights: • SGLT2 inhibitor luseogliflozin ameliorates glycemic control in db/db mice. • Luseogliflozin increases β-cell proliferation and decreases β-cell apoptosis. • Luseogliflozin preserves various β-cell-specific gene expression. • Luseogliflozin decreases various fibrosis-related factors in db

  6. Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice

    International Nuclear Information System (INIS)

    Okauchi, Seizo; Shimoda, Masashi; Obata, Atsushi; Kimura, Tomohiko; Hirukawa, Hidenori; Kohara, Kenji; Mune, Tomoatsu; Kaku, Kohei; Kaneto, Hideaki

    2016-01-01

    It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic β-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on β-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after the intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, β-cell mass was larger in Luse groups compared to control group which was due to the increase of β-cell proliferation and decrease of β-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFβ, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic β-cell mass and function. - Highlights: • SGLT2 inhibitor luseogliflozin ameliorates glycemic control in db/db mice. • Luseogliflozin increases β-cell proliferation and decreases β-cell apoptosis. • Luseogliflozin preserves various β-cell-specific gene expression. • Luseogliflozin decreases various fibrosis-related factors in db

  7. Modulation of olfactory sensitivity and glucose sensing by the feeding state in obese Zucker rats.

    Directory of Open Access Journals (Sweden)

    Pascaline eAimé

    2014-09-01

    Full Text Available The Zucker fa/fa rat has been widely used as an animal model to study obesity, since it recapitulates most of its behavioral and metabolic dysfunctions, such as hyperphagia, hyperglycemia and insulin resistance. Although it is well established that olfaction is under nutritional and hormonal influences, little is known about the impact of metabolic dysfunctions on olfactory performances and glucose-sensing in the olfactory system of the obese Zucker rat. In the present study, using a behavioral paradigm based on a conditioned olfactory aversion, we have shown that both obese and lean Zucker rats have a better olfactory sensitivity when they are fasted than when they are satiated. Interestingly, the obese Zucker rats displayed a higher olfactory sensitivity than their lean controls. By investigating the molecular mechanisms involved in glucose-sensing in the olfactory system, we demonstrated that sodium-coupled glucose transporters 1 (SGLT1 and insulin dependent glucose transporters 4 (GLUT4 are both expressed in the olfactory bulb (OB. By comparing the expression of GLUT4 and SGLT1 in OB of obese and lean Zucker rats, we found that only SGLT1 is regulated in genotype-dependent manner. Next, we used glucose oxidase biosensors to simultaneously measure in vivo the extracellular fluid glucose concentrations ([Gluc]ECF in the OB and the cortex. Under metabolic steady state, we have determined that the OB contained twice the amount of glucose found in the cortex. In both regions, the [Gluc]ECF was 2 fold higher in obese rats compared to their lean controls. Under induced dynamic glycemia conditions, insulin injection produced a greater decrease of [Gluc]ECF in the OB than in the cortex. Glucose injection did not affect OB [Gluc]ECF in Zucker fa/fa rats. In conclusion, these results emphasize the importance of glucose for the OB network function and provide strong arguments towards establishing the OB glucose-sensing as a key factor for sensory

  8. Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

    International Nuclear Information System (INIS)

    Blomqvist, G.; Widen, L.; Hellstrand, E.; Gutniak, M.; Grill, V.

    1991-01-01

    The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using D-glucose 11 C(ul) as tracer. To rule out any effects of insulin, the plasma insulin concentration was maintained at the same level under normo- and hypoglycaemic conditions. Reduction of blood glucose by 55% increased the glucose clearance through the blood-brain barrier by 50% and reduced brain glucose consumption by 40%. Blood flow was not affected. The results are consistent with facilitated transport of glucose from blood to brain in humans. The maximal transport rate of glucose from blood to brain was found to be 62±19 (mean±SEM) μmol hg -1 min -1 , and the half-saturation constant was found to be 4.1±3.2 mM. (orig.)

  9. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic)

    DEFF Research Database (Denmark)

    Birkeland, Kåre I.; Jørgensen, Marit E.; Carstensen, Bendix

    2017-01-01

    , and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40...... with the results of clinical trials in patients at high cardiovascular risk. Funding AstraZeneca....

  10. A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment.

    Science.gov (United States)

    Consoli, Agostino; Formoso, Gloria; Baldassarre, Maria Pompea Antonia; Febo, Fabrizio

    2018-03-01

    Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials. Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile. Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes. Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a 'similar' safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.

  11. A Review on the Relationship between SGLT2 Inhibitors and Cancer

    Directory of Open Access Journals (Sweden)

    Hao-Wen Lin

    2014-01-01

    Full Text Available Risk of increasing breast and bladder cancer remains a safety issue of SGLT2 (sodium glucose cotransporter type 2 inhibitors, a novel class of antidiabetic agent. We reviewed related papers published before January 29, 2014, through Pubmed search. Dapagliflozin and canagliflozin are the first two approved SGLT2 inhibitors for diabetes therapy. Although preclinical animal toxicology did not suggest a cancer risk of dapagliflozin and overall tumor did not increase, excess numbers of female breast cancer and male bladder cancer were noted in preclinical trials (without statistical significance. This concern of cancer risk hindered its approval by the US FDA in January, 2012. New clinical data suggested that the imbalance of bladder and breast cancer might be due to early diagnosis rather than a real increase of cancer incidence. No increased risk of overall bladder or breast cancer was noted for canagliflozin. Therefore, the imbalance observed with dapagliflozin treatment should not be considered as a class effect of SGLT2 inhibitors and the relationship with cancer for each specific SGLT2 inhibitor should be examined individually. Relationship between SGLT2 inhibition and cancer formation is still inconclusive and studies with larger sample size, longer exposure duration, and different ethnicities are warranted.

  12. A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor

    Directory of Open Access Journals (Sweden)

    Chang Hee Jung

    2014-08-01

    Full Text Available Type 2 diabetes mellitus (T2DM is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2 inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.

  13. Effect of erythropoietin on the glucose transport of rat erythrocytes and bone marrow cells

    International Nuclear Information System (INIS)

    Ghosal, J.; Chakraborty, M.; Biswas, T.; Ganguly, C.K.; Datta, A.G.

    1987-01-01

    The effect of Ep on radioactive glucose and methyl-alpha-D-glucoside transport by rat erythrocytes and bone marrow cells were studied. There is initial linearity followed by saturation kinetics of [ 14 C]glucose transport by the erythrocytes of starved and starved plus Ep-treated rats at different concentrations of glucose. Starvation caused slight inhibition of glucose transport which increased markedly on Ep administration to starved rats. Normal animals failed to show any significant change in glucose transport after Ep treatment. Methyl-alpha-D-glucoside inhibited the Ep-stimulated glucose transport significantly. Ep also stimulated the transport of radioactive methyl-alpha-D-glucoside which was competitively inhibited in presence of D-glucose. Glucose transport in erythrocytes was found to be sensitive to metabolic inhibitors like azide and DNP. A sulfhydryl reagent and ouabain also inhibited the transport process. Ep stimulated glucose and methyl-alpha-D-glucoside transport in the bone marrow cells of starved rats. The sugar analog competitively inhibited the glucose transport in bone marrow cells and vice versa

  14. The Role of Glucose Transporters in Brain Disease: Diabetes and Alzheimer’s Disease

    Science.gov (United States)

    Shah, Kaushik; DeSilva, Shanal; Abbruscato, Thomas

    2012-01-01

    The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain. PMID:23202918

  15. Steviol Glycosides Modulate Glucose Transport in Different Cell Types

    Science.gov (United States)

    Rizzo, Benedetta; Zambonin, Laura; Leoncini, Emanuela; Vieceli Dalla Sega, Francesco; Prata, Cecilia; Fiorentini, Diana; Hrelia, Silvana

    2013-01-01

    Extracts from Stevia rebaudiana Bertoni, a plant native to Central and South America, have been used as a sweetener since ancient times. Currently, Stevia extracts are largely used as a noncaloric high-potency biosweetener alternative to sugar, due to the growing incidence of type 2 diabetes mellitus, obesity, and metabolic disorders worldwide. Despite the large number of studies on Stevia and steviol glycosides in vivo, little is reported concerning the cellular and molecular mechanisms underpinning the beneficial effects on human health. The effect of four commercial Stevia extracts on glucose transport activity was evaluated in HL-60 human leukaemia and in SH-SY5Y human neuroblastoma cells. The extracts were able to enhance glucose uptake in both cellular lines, as efficiently as insulin. Our data suggest that steviol glycosides could act by modulating GLUT translocation through the PI3K/Akt pathway since treatments with both insulin and Stevia extracts increased the phosphorylation of PI3K and Akt. Furthermore, Stevia extracts were able to revert the effect of the reduction of glucose uptake caused by methylglyoxal, an inhibitor of the insulin receptor/PI3K/Akt pathway. These results corroborate the hypothesis that Stevia extracts could mimic insulin effects modulating PI3K/Akt pathway. PMID:24327825

  16. Diabetic Hyperglycemia: Link to Impaired Glucose Transport in Pancreatic β Cells

    Science.gov (United States)

    Unger, Roger H.

    1991-03-01

    Glucose uptake into pancreatic β cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal β-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of β cells to hyperglycemia may improve the management and prevention of diabetes.

  17. Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential

    Science.gov (United States)

    Røder, Michael E.

    2017-01-01

    Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed. PMID:29344329

  18. Inhibition of sodium glucose cotransporter-I expressed in Xenopus laevis oocytes by 4-acetoxyscirpendiol from Cordyceps takaomantana (anamorph = Paecilomyces tenuipes).

    Science.gov (United States)

    Yoo, Ocki; Lee, Dong-Hee

    2006-02-01

    Cordyceps contains many health-promoting constituents. Recent studies revealed that the fruiting body of cordyceps significantly alleviates hyperglycemia which usually accompanies diabetes mellitus. The mechanism of the anti-hyperglycemic effect by cordyceps, however, is not fully understood. In this study, methanolic extracts were prepared from fruiting bodies of Paecilomyces tenuipes, and 4-beta acetoxyscirpendiol (ASD) was eventually purified from the extracts. The Na+/ glucose transporter-1 (SGLT-1) was expressed in Xenopus oocytes, and the effect of ASD on it was analyzed using voltage clamp and 2-deoxy-D-glucose (2-DOG) uptake studies. Fluorescence microscopy was performed to monitor the effect of ASD on glucose uptake using HEK293 cells expressing recombinant SGLT-1. ASD inhibited SGLT-1 activity, and its two derivatives (2-acetoxyscirpenol and 15-acetoxyscirpendiol), were also effective; 15-acetoxyscirepenol was as inhibitory as ASD while diacetoxyscirpenol had less effect. Thus, the ASD in P. tenuipes may play an important role in lowering blood sugar in the circulatory system along with its derivatives as specific inhibitors of SGLT-1.

  19. Effect of physical training on glucose transporter protein and mRNA levels in rat adipocytes

    DEFF Research Database (Denmark)

    Stallknecht, B; Andersen, P H; Vinten, J

    1993-01-01

    Physical training increases insulin-stimulated glucose transport and the number of glucose transporters in adipocytes measured by cytochalasin B binding. In the present study we used immunoblotting to measure the abundance of two glucose transporters (GLUT-4, GLUT-1) in white adipocytes from....../or intrinsic activity). GLUT-1 protein and mRNA levels/adipocyte volume did not change with age or training....

  20. Sugar transporter genes of the brown planthopper, Nilaparvata lugens: A facilitated glucose/fructose transporter.

    Science.gov (United States)

    Kikuta, Shingo; Kikawada, Takahiro; Hagiwara-Komoda, Yuka; Nakashima, Nobuhiko; Noda, Hiroaki

    2010-11-01

    The brown planthopper (BPH), Nilaparvata lugens, attacks rice plants and feeds on their phloem sap, which contains large amounts of sugars. The main sugar component of phloem sap is sucrose, a disaccharide composed of glucose and fructose. Sugars appear to be incorporated into the planthopper body by sugar transporters in the midgut. A total of 93 expressed sequence tags (ESTs) for putative sugar transporters were obtained from a BPH EST database, and 18 putative sugar transporter genes (Nlst1-18) were identified. The most abundantly expressed of these genes was Nlst1. This gene has previously been identified in the BPH as the glucose transporter gene NlHT1, which belongs to the major facilitator superfamily. Nlst1, 4, 6, 9, 12, 16, and 18 were highly expressed in the midgut, and Nlst2, 7, 8, 10, 15, 17, and 18 were highly expressed during the embryonic stages. Functional analyses were performed using Xenopus oocytes expressing NlST1 or 6. This showed that NlST6 is a facilitative glucose/fructose transporter that mediates sugar uptake from rice phloem sap in the BPH midgut in a manner similar to NlST1. Copyright © 2010 Elsevier Ltd. All rights reserved.

  1. Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure.

    Science.gov (United States)

    Rahman, Asadur; Hitomi, Hirofumi; Nishiyama, Akira

    2017-06-01

    Improvement in cardiovascular (CV) morbidity and mortality in the EMPA-REG OUTCOME study provides new insight into the therapeutic use of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. Although SGLT2 inhibitors have several pleiotropic effects, the underlying mechanism responsible for their cardioprotective effects remains undetermined. In this regard, the absence of a nocturnal fall in blood pressure (BP), that is, non-dipping BP, is a common phenomenon in type 2 diabetes and has a crucial role in the pathogenesis of CV morbidity and mortality. In most clinical trials, SGLT2 inhibitors reduce both systolic BP (~3-5 mm Hg) and diastolic BP (~2 mm Hg) in patients with type 2 diabetes. In addition, recent clinical and animal studies have revealed that SGLT2 inhibitors enable the change in BP circadian rhythm from a non-dipper to a dipper type, which is possibly associated with the improvement in CV outcomes in patients with type 2 diabetes. In this review, recent data on the effect of SGLT2 inhibitors on the circadian rhythm of BP will be summarized. The possible underlying mechanisms responsible for the SGLT2 inhibitor-induced improvement in the circadian rhythm of BP will also be discussed.

  2. Combined HQSAR, topomer CoMFA, homology modeling and docking studies on triazole derivatives as SGLT2 inhibitors.

    Science.gov (United States)

    Yu, Shuling; Yuan, Jintao; Zhang, Yi; Gao, Shufang; Gan, Ying; Han, Meng; Chen, Yuewen; Zhou, Qiaoqiao; Shi, Jiahua

    2017-06-01

    Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors. In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models. The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking. The models and docking provided important insights into the design of potent inhibitors for SGLT2.

  3. Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1.

    Science.gov (United States)

    Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian; Richter, Erik A; Jensen, Thomas E

    2015-02-01

    Rac1 regulates stretch-stimulated (i.e. mechanical stress) glucose transport in muscle. Actin depolymerization decreases stretch-induced glucose transport in skeletal muscle. Rac1 is a required part of the mechanical stress-component of the contraction-stimulus to glucose transport in skeletal muscle. An alternative to the canonical insulin signalling pathway for glucose transport is muscle contraction/exercise. Mechanical stress is an integrated part of the muscle contraction/relaxation cycle, and passive stretch stimulates muscle glucose transport. However, the signalling mechanism regulating stretch-stimulated glucose transport is not well understood. We recently reported that the actin cytoskeleton regulating GTPase, Rac1, was activated in mouse muscle in response to stretching. Rac1 is a regulator of contraction- and insulin-stimulated glucose transport, however, its role in stretch-stimulated glucose transport and signalling is unknown. We therefore investigated whether stretch-induced glucose transport in skeletal muscle required Rac1 and the actin cytoskeleton. We used muscle-specific inducible Rac1 knockout mice as well as pharmacological inhibitors of Rac1 and the actin cytoskeleton in isolated soleus and extensor digitorum longus muscles. In addition, the role of Rac1 in contraction-stimulated glucose transport during conditions without mechanical load on the muscles was evaluated in loosely hanging muscles and muscles in which cross-bridge formation was blocked by the myosin ATPase inhibitors BTS and Blebbistatin. Knockout as well as pharmacological inhibition of Rac1 reduced stretch-stimulated glucose transport by 30-50% in soleus and extensor digitorum longus muscle. The actin depolymerizing agent latrunculin B similarly decreased glucose transport in response to stretching by 40-50%. Rac1 inhibition reduced contraction-stimulated glucose transport by 30-40% in tension developing muscle but did not affect contraction-stimulated glucose transport in

  4. Simultaneous measurement of glucose transport and utilization in the human brain

    Science.gov (United States)

    Shestov, Alexander A.; Emir, Uzay E.; Kumar, Anjali; Henry, Pierre-Gilles; Seaquist, Elizabeth R.

    2011-01-01

    Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, KMt and Vmaxt, in humans have so far been obtained by measuring steady-state brain glucose levels by proton (1H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMRglc) obtained from other tracer studies, such as 13C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state 1H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ∼17 mmol/l for ∼2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMRglc, this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain. PMID:21791622

  5. Glucose Transporters in Diabetic Kidney Disease-Friends or Foes?

    Science.gov (United States)

    Wasik, Anita A; Lehtonen, Sanna

    2018-01-01

    Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin resistance correlates with the development of albuminuria in non-diabetic and diabetic patients. There is also accumulating evidence that glomerular epithelial cells or podocytes are insulin sensitive and that insulin signaling in podocytes is essential for maintaining normal kidney function. At the cellular level, the mechanisms leading to the development of insulin resistance include mutations in the insulin receptor gene, impairments in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, or perturbations in the trafficking of glucose transporters (GLUTs), which mediate the uptake of glucose into cells. Podocytes express several GLUTs, including GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. Of these, the most studied ones are GLUT1 and GLUT4, both shown to be insulin responsive in podocytes. In the basal state, GLUT4 is preferentially located in perinuclear and cytosolic vesicular structures and to a lesser extent at the plasma membrane. After insulin stimulation, GLUT4 is sorted into GLUT4-containing vesicles (GCVs) that translocate to the plasma membrane. GCV trafficking consists of several steps, including approaching of the GCVs to the plasma membrane, tethering, and docking, after which the lipid bilayers of the GCVs and the plasma membrane fuse, delivering GLUT4 to the cell surface for glucose uptake into the cell. Studies have revealed novel molecular regulators of the GLUT trafficking in podocytes and unraveled unexpected roles for GLUT1 and GLUT4 in the development of DKD, summarized in this review. These findings pave the way for better understanding of the mechanistic pathways associated with the development and progression of DKD and aid in the development of new treatments for this devastating disease.

  6. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations.

    Science.gov (United States)

    Scheen, André J

    2014-05-01

    Inhibitors of sodium-glucose cotransporters type 2 (SGLT2), which increase urinary glucose excretion independently of insulin, are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). An extensive literature search was performed to analyze the pharmacokinetic characteristics, toxicological issues and safety concerns of SGLT2 inhibitors in humans. This review focuses on three compounds (dapagliflozin, canagliflozin, empagliflozin) with results obtained in healthy volunteers (including drug-drug interactions), patients with T2DM (single dose and multiple doses) and special populations (those with renal or hepatic impairment). The three pharmacological agents share an excellent oral bioavailability, long half-life allowing once-daily administration, low accumulation index and renal clearance, the absence of active metabolites and a limited propensity to drug-drug interactions. No clinically relevant changes in pharmacokinetic parameters were observed in T2DM patients or in patients with mild/moderate renal or hepatic impairment. Adverse events are a slightly increased incidence of mycotic genital and rare benign urinary infections. SGLT2 inhibitors have the potential to reduce several cardiovascular risk factors, and cardiovascular outcome trials are currently ongoing. The best positioning of SGLT2 inhibitors in the armamentarium for treating T2DM is still a matter of debate.

  7. Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Leyna Leite Santos

    Full Text Available Summary Introduction: Diabetes mellitus is one of the most common chronic diseases in the world, with high morbidity and mortality rates, resulting in a greatly negative socioeconomic impact. Although there are several classes of oral antidiabetic agents, most of the patients are outside the therapeutic goal range. Objective: To review the use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus, focusing on their favorable and unfavorable effects, as well as on cardiovascular profile. Method: A literature search on Pubmed database was performed using the following keywords: "SGLT-2 inhibitors," "dapagliflozin," "empagliflozin," "canagliflozin." Results: SGLT-2 inhibitors are a class of oral antidiabetic drugs directed to the kidney. Their mechanism of action is to reduce blood glucose by inducing glycosuria. Extra-glycemic benefits have been described, such as weight loss, decline in blood pressure and levels of triglycerides and uric acid, and they can slow the progression of kidney disease. Genitourinary infections are the main side effects. There is a low risk of hypotension and hypoglycemia. Diabetic ketoacidosis is a serious adverse effect, although rare. Empagliflozin has already had its cardiovascular benefit demonstrated and studies with other drugs are currently being performed. Conclusion: SGLT-2 inhibitors are a new treatment option for type 2 diabetes mellitus, acting independently of insulin. They have potential benefits other than the reduction of blood glucose, but also carry a risk for adverse effects.

  8. Cellular and molecular cues of glucose sensing in the rat olfactory bulb

    Directory of Open Access Journals (Sweden)

    Dolly eAl Koborssy

    2014-10-01

    Full Text Available In the brain, glucose homeostasis of extracellular fluid is crucial to the point that systems specifically dedicated to glucose sensing are found in areas involved in energy regulation and feeding behavior. Olfaction is a major sensory modality regulating food consumption. Nutritional status in turn modulates olfactory detection. Recently it has been proposed that some olfactory bulb (OB neurons respond to glucose similarly to hypothalamic neurons. However, the precise molecular cues governing glucose sensing in the OB are largely unknown. To decrypt these molecular mechanisms, we first used immunostaining to demonstrate a strong expression of two neuronal markers of glucose-sensitivity, insulin-dependent glucose transporter type 4 (GLUT4, and sodium glucose co-transporter type 1 (SGLT1 in specific OB layers. We showed that expression and mapping of GLUT4 but not SGLT1 were feeding state-dependent. In order to investigate the impact of metabolic status on the delivery of blood-borne glucose to the OB, we measured extracellular fluid glucose concentration using glucose biosensors simultaneously in the OB and cortex of anesthetized rats. We showed that glucose concentration in the OB is higher than in the cortex, that metabolic steady-state glucose concentration is independent of feeding state in the two brain areas, and that acute changes in glycemic conditions affect bulbar glucose concentration alone. These data provide new evidence of a direct relationship between the OB and peripheral metabolism, and emphasize the importance of glucose for the OB network, providing strong arguments toward establishing the OB as a glucose-sensing organ.

  9. SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes introduction of SGLT2-inhibitors in clinical practice.

    Science.gov (United States)

    Cuypers, J; Mathieu, C; Benhalima, K

    2013-01-01

    Treatment of type 2 diabetes (T2DM) continues to present challenges, with significant proportion of patients failing to achieve and maintain glycemic targets. Despite the availability of many oral antidiabetic agents, therapeutic efficacy is offset by side effects such as weight gain and hypoglycemia. Therefore, the search for novel therapeutic agents with an improved benefit-risk profile continues. Recent research has focused on the kidney as a potential therapeutic target, especially because maximal renal glucose reabsorption is increased in T2DM. Under normal physiological conditions, nearly all filtered glucose is reabsorbed in the proximal tubule of the nephron, principally via the sodium-glucose cotransporter 2 (SGLT2). SGLT2-inhibitors are a new class of oral antidiabetics, which reduce hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. Clinical results are promising with significant lowering of HbA1c without increased risk of hypoglycemia, reduction of body weight and reduction of systolic blood pressure. Dapagliflozin is the first highly selective SGLT2-inhibitor approved by the European Medecine Agency. Canagliflozin and empagliflozin are undergoing phase III trials. Actual safety issues are an increased risk for genital- and urinary tract infections and a possible increased risk for bladder and breast cancer. This led to refusal of dapagliflozin by the Food and Drug Administration (FDA). A large randomized control trial is therefore warranted by the FDA. This review provides an overview of the current evidence available so far on the therapeutic potential of the SGLT2-inhibitors for the treatment of T2DM.

  10. Glucose transporter expression in human skeletal muscle fibers

    DEFF Research Database (Denmark)

    Gaster, M; Handberg, A; Beck-Nielsen, H

    2000-01-01

    , but its expression is markedly reduced around birth and is further reduced to undetectable levels within the first year of life; 2) GLUT-3 protein expression appears at 18 wk of gestation and disappears after birth; and 3) GLUT-4 protein is diffusely expressed in muscle cells throughout gestation, whereas...... after birth, the characteristic subcellular localization is as seen in adult muscle fibers. Our results show that GLUT-1, GLUT-3, and GLUT-4 seem to be of importance during muscle fiber growth and development. GLUT-5 protein was undetectable in fetal and adult skeletal muscle fibers. In adult muscle...... amplification (TSA) technique to detect the localization of glucose transporter expression in human skeletal muscle. We found expression of GLUT-1, GLUT-3, and GLUT-4 in developing human muscle fibers showing a distinct expression pattern. 1) GLUT-1 is expressed in human skeletal muscle cells during gestation...

  11. Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake.

    Science.gov (United States)

    Karim, Sumera; Liaskou, Evaggelia; Fear, Janine; Garg, Abhilok; Reynolds, Gary; Claridge, Lee; Adams, David H; Newsome, Philip N; Lalor, Patricia F

    2014-12-15

    Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease. Copyright © 2014 the American Physiological Society.

  12. The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes.

    Science.gov (United States)

    Katz, Pamela M; Leiter, Lawrence A

    2015-12-01

    Effective glycemic control reduces the risk for diabetes-related complications. However, the majority of patients with type 2 diabetes still do not achieve glycemic targets. Beyond metformin therapy, current practice guidelines for the management of type 2 diabetes recommend individualized treatment based on patient and agent characteristics. The sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a novel treatment strategy, independent of impaired beta-cell function and insulin resistance. SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion with subsequent reduction in plasma glucose levels and glycosylated hemoglobin concentrations. Current evidence suggests that they are effective as monotherapy or as add-ons to metformin either alone, or in combination with other oral glucose-lowering agents or insulin. They are generally well tolerated, though rates of lower urinary tract and genital mycotic infections are slightly increased. The advantages of this class include modest reductions in body weight and blood pressure, and low risk for hypoglycemia. Long-term safety data and results of ongoing cardiovascular outcome studies are awaited so we can fully understand the role that SGLT2 inhibitors will play in the comprehensive management of type 2 diabetes. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  13. Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery.

    Science.gov (United States)

    Patching, Simon G

    2017-03-01

    Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer's disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

  14. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    Directory of Open Access Journals (Sweden)

    Michela Riz

    2015-12-01

    Full Text Available Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1, peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT and ATP-sensitive K+-channels (K(ATP-channels to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

  15. Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study.

    Science.gov (United States)

    Katakami, Naoto; Mita, Tomoya; Yoshii, Hidenori; Shiraiwa, Toshihiko; Yasuda, Tetsuyuki; Okada, Yosuke; Umayahara, Yutaka; Kaneto, Hideaki; Osonoi, Takeshi; Yamamoto, Tsunehiko; Kuribayashi, Nobuichi; Maeda, Kazuhisa; Yokoyama, Hiroki; Kosugi, Keisuke; Ohtoshi, Kentaro; Hayashi, Isao; Sumitani, Satoru; Tsugawa, Mamiko; Ohashi, Makoto; Taki, Hideki; Nakamura, Tadashi; Kawashima, Satoshi; Sato, Yasunori; Watada, Hirotaka; Shimomura, Iichiro

    2017-10-01

    Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. Kowa Co., Ltd. UMIN000017607.

  16. Blood glucose level reconstruction as a function of transcapillary glucose transport.

    Science.gov (United States)

    Koutny, Tomas

    2014-10-01

    A diabetic patient occasionally undergoes a detailed monitoring of their glucose levels. Over the course of a few days, a monitoring system provides a detailed track of their interstitial fluid glucose levels measured in their subcutaneous tissue. A discrepancy in the blood and interstitial fluid glucose levels is unimportant because the blood glucose levels are not measured continuously. Approximately five blood glucose level samples are taken per day, and the interstitial fluid glucose level is usually measured every 5min. An increased frequency of blood glucose level sampling would cause discomfort for the patient; thus, there is a need for methods to estimate blood glucose levels from the glucose levels measured in subcutaneous tissue. The Steil-Rebrin model is widely used to describe the relationship between blood and interstitial fluid glucose dynamics. However, we measured glucose level patterns for which the Steil-Rebrin model does not hold. Therefore, we based our research on a different model that relates present blood and interstitial fluid glucose levels to future interstitial fluid glucose levels. Using this model, we derived an improved model for calculating blood glucose levels. In the experiments conducted, this model outperformed the Steil-Rebrin model while introducing no additional requirements for glucose sample collection. In subcutaneous tissue, 26.71% of the calculated blood glucose levels had absolute values of relative differences from smoothed measured blood glucose levels less than or equal to 5% using the Steil-Rebrin model. However, the same difference interval was encountered in 63.01% of the calculated blood glucose levels using the proposed model. In addition, 79.45% of the levels calculated with the Steil-Rebrin model compared with 95.21% of the levels calculated with the proposed model had 20% difference intervals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Diabetic Ketoacidosis in a Patient with Type 2 Diabetes After Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Treatment

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Bagger, Jonatan I; Knop, Filip K

    2016-01-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have...... been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT2i dapagliflozin. He was admitted with DKA 5 days after the initiation of treatment with the SGLT2i dapagliflozin...... 72 hr with insulin as the only glucose-lowering therapy. After 1 month, dapagliflozin was reintroduced as add-on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone...

  18. Influence of glucose and urea on 125I transport across an anion exchange paper membrane

    International Nuclear Information System (INIS)

    Inoue, Hiroyoshi

    2001-01-01

    In order to study the influence of glucose and urea on the 125 I transport across an anion exchange paper membrane, the transmembrane potential, the fluxes, and the concentrations of 125 I, glucose and urea within the membrane were measured in the Na 125 I concentration-cell system containing glucose or urea. Glucose and urea increased the membrane/solution distribution of the iodide ion, but scarcely affected the diffusion process of iodide ion within the membrane

  19. Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes

    International Nuclear Information System (INIS)

    Carter-Su, C.; Okamoto, K.

    1987-01-01

    The ability of glucocorticoids to modify the effect of insulin on glucose (L-1- 3 H(N)]glucose and D-[ 14 C-U]glucose) transport was investigated in both intact isolated rat adipocytes and in membranes isolated from hormone-treated adipocytes. In intact adipocytes, dexamethasone, a potent synthetic glucocorticoid, inhibited insulin-stimulated 3-O-methylglucose transport at all concentrations of insulin tested. Insulin sensitivity, as well as the maximal response to insulin, was decreased by dexamethasone in the absence of a change in 125 I insulin binding. The inhibition was observed regardless of which hormone acted first, was blocked by actinomycin D, and resulted from a decrease in V/sub max/ rather than an increase in K/sub t/ of transport. In plasma membranes isolated from insulin-treated adipocytes, glucose transport activity and the amount of glucose transporter covalently labeled with [ 3 H]cytochalasin B were increased in parallel in a dose-dependent fashion. The amount of labeled transporter in a low-density microsomal fraction (LDMF) was decreased in a reciprocal fashion. In contrast, addition of dexamethasone to insulin-stimulated cells caused decreases in both transport activity and amount of labeled transporter in the plasma membranes. This was accompanied by a small increase in the amount of [ 3 H]cytochalasin B incorporated into the glucose transporter in the LDMF. These results are consistent with both insulin and glucocorticoids altering the distribution of glucose transporters between the plasma membrane and LDMF, in opposite directions

  20. Glucose transporter-1 deficiency syndrome : the expanding clinical and genetic spectrum of a treatable disorder

    NARCIS (Netherlands)

    Leen, Wilhelmina G.; Klepper, Joerg; Verbeek, Marcel M.; Leferink, Maike; Hofste, Tom; van Engelen, Baziel G.; Wevers, Ron A.; Arthur, Todd; Bahi-Buisson, Nadia; Ballhausen, Diana; Bekhof, Jolita; van Bogaert, Patrick; Carrilho, Ines; Chabrol, Brigitte; Champion, Michael P.; Coldwell, James; Clayton, Peter; Donner, Elizabeth; Evangeliou, Athanasios; Ebinger, Friedrich; Farrell, Kevin; Forsyth, Rob J.; de Goede, Christian G. E. L.; Gross, Stephanie; Grunewald, Stephanie; Holthausen, Hans; Jayawant, Sandeep; Lachlan, Katherine; Laugel, Vincent; Leppig, Kathy; Lim, Ming J.; Mancini, Grazia; Della Marina, Adela; Martorell, Loreto; McMenamin, Joe; Meuwissen, Marije E. C.; Mundy, Helen; Nilsson, Nils O.; Panzer, Axel; Poll-The, Bwee T.; Rauscher, Christian; Rouselle, Christophe M. R.; Sandvig, Inger; Scheffner, Thomas; Sheridan, Eamonn; Simpson, Neil; Sykora, Parol; Tomlinson, Richard; Trounce, John; Webb, David; Weschke, Bernhard; Scheffer, Hans; Willemsen, Michel A.

    Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

  1. Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder

    NARCIS (Netherlands)

    W.G. Leen (Wilhelmina); J. Klepper (Joerg); M.M. Verbeek (Marcel); M. Leferink (Maike); T. Hofste (Tom); B.G.M. van Engelen (Baziel); R.A. Wevers (Ron); T. Arthur (Todd); N. Bahi-Buisson (Nadia); D. Ballhausen (Diana); J. Bekhof (Jolita); P. van Bogaert (Patrick); I. Carrilho (Inês); B. Chabrol (Brigitte); M.P. Champion (Michael); J. Coldwell (James); P. Clayton (Peter); E. Donner (Elizabeth); A. Evangeliou (Athanasios); F. Ebinger (Friedrich); K. Farrell (Kevin); R.J. Forsyth (Rob); C.G.E.L. de Goede (Christian); S. Gross (Stephanie); S. Grünewald (Sonja); H. Holthausen (Hans); S. Jayawant (Sandeep); K. Lachlan (Katherine); V. Laugel (Vincent); K. Leppig (Kathy); M.J. Lim (Ming); G.M.S. Mancini (Grazia); A.D. Marina; L. Martorell (Loreto); J. McMenamin (Joe); M.E.C. Meuwissen (Marije); H. Mundy (Helen); N.O. Nilsson (Nils); A. Panzer (Axel); B.T. Poll-The; C. Rauscher (Christian); C.M.R. Rouselle (Christophe); I. Sandvig (Inger); T. Scheffner (Thomas); E. Sheridan (Eamonn); N. Simpson (Neil); P. Sykora (Parol); R. Tomlinson (Richard); J. Trounce (John); D.W.M. Webb (David); B. Weschke (Bernhard); H. Scheffer (Hans); M.A. Willemsen (Michél)

    2010-01-01

    textabstractGlucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing

  2. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder

    NARCIS (Netherlands)

    Leen, Wilhelmina G.; Klepper, Joerg; Verbeek, Marcel M.; Leferink, Maike; Hofste, Tom; van Engelen, Baziel G.; Wevers, Ron A.; Arthur, Todd; Bahi-Buisson, Nadia; Ballhausen, Diana; Bekhof, Jolita; van Bogaert, Patrick; Carrilho, Inês; Chabrol, Brigitte; Champion, Michael P.; Coldwell, James; Clayton, Peter; Donner, Elizabeth; Evangeliou, Athanasios; Ebinger, Friedrich; Farrell, Kevin; Forsyth, Rob J.; de Goede, Christian G. E. L.; Gross, Stephanie; Grunewald, Stephanie; Holthausen, Hans; Jayawant, Sandeep; Lachlan, Katherine; Laugel, Vincent; Leppig, Kathy; Lim, Ming J.; Mancini, Grazia; Marina, Adela Della; Martorell, Loreto; McMenamin, Joe; Meuwissen, Marije E. C.; Mundy, Helen; Nilsson, Nils O.; Panzer, Axel; Poll-The, Bwee T.; Rauscher, Christian; Rouselle, Christophe M. R.; Sandvig, Inger; Scheffner, Thomas; Sheridan, Eamonn; Simpson, Neil; Sykora, Parol; Tomlinson, Richard; Trounce, John; Webb, David; Weschke, Bernhard; Scheffer, Hans; Willemsen, Michél A.

    2010-01-01

    Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

  3. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

    NARCIS (Netherlands)

    Leen, W.G.; Klepper, J.; Verbeek, M.M.; Leferink, M.; Hofste, T.; Engelen, B.G.M. van; Wevers, R.A.; Arthur, T.; Bahi-Buisson, N.; Ballhausen, D.; Bekhof, J.; Bogaert, P. van; Carrilho, I.; Chabrol, B.; Champion, M.P.; Coldwell, J.; Clayton, P.; Donner, E.; Evangeliou, A.; Ebinger, F.; Farrell, K.; Forsyth, R.J.; Goede, C.G. de; Gross, S.; Grunewald, S.; Holthausen, H.; Jayawant, S.; Lachlan, K.; Laugel, V.; Leppig, K.; Lim, M.J.; Mancini, G.; Marina, A.D.; Martorell, L.; McMenamin, J.; Meuwissen, M.E.; Mundy, H.; Nilsson, N.O.; Panzer, A.; Poll-The, B.T.; Rauscher, C.; Rouselle, C.M.; Sandvig, I.; Scheffner, T.; Sheridan, E.; Simpson, N.; Sykora, P.; Tomlinson, R.; Trounce, J.; Webb, D.; Weschke, B.; Scheffer, H.; Willemsen, M.A.A.P.

    2010-01-01

    Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex

  4. Stretch-stimulated glucose transport in skeletal muscle is regulated by Rac1

    DEFF Research Database (Denmark)

    Sylow, Lykke; Møller, Lisbeth L V; Kleinert, Maximilian

    2015-01-01

    -stimulated glucose transport and signaling is unknown. We therefore investigated whether stretch-induced glucose transport in skeletal muscle required Rac1 and the actin cytoskeleton. We used muscle specific inducible Rac1 knockout mice as well as pharmacological inhibitors of Rac1 and the actin cytoskeleton...

  5. SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies.

    Science.gov (United States)

    Hayashi, Akinori; Takano, Koji; Kawai, Sayuki; Shichiri, Masayoshi

    2016-01-01

    Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.

  6. High Glucose Concentration Stimulates NHE-1 Activity in Distal Nephron Cells: the Role of the Mek/Erk1/2/p90RSK and p38MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Juliana Martins da Costa-Pessoa

    2014-02-01

    Full Text Available Aims: In models of diabetes, distal nephron cells contribute to glucose uptake and oxidation. How these cells contribute to the use of glucose for the regulation of H+ extrusion remains unknown. We used Madin-Darby Canine Kidney (MDCK cells to investigate the effect of acute or chronic high glucose concentration on the abundance and activity of the Na+/H+ exchanger (NHE-1. Methods: Using RT-PCR, we also evaluated the mRNA expression for sodium glucose co-transporters SGLT1 and SGLT2. Protein abundance was analyzed using immunoblotting, and intracellular pH (pHi recovery was evaluated using microscopy in conjunction with the fluorescent probe BCECF/AM. The Na+-dependent pHi recovery rate was monitored with HOE-694 (50 µM and/or S3226 (10 µM, specific NHE-1 and NHE-3 inhibitors. Results: MDCK cells did not express the mRNA for SGLT1 or SGLT2 but did express the GLUT2, NHE-1 and NHE-3 proteins. Under control conditions, we observed a greater contribution of NHE-1 to pHi recovery relative to the other H+ transporters. Acute high glucose treatment increased the HOE-694-sensitive pHi recovery rate and p-Erk1/2 and p90RSK abundance. These parameters were reduced by PD-98059, a Mek inhibitor (1 µM. Chronic high glucose treatment also increased the HOE-694-sensitive pHi recovery rate and p-p38MAPK abundance. Both parameters were reduced by SB-203580, a p38MAPK inhibitor (10 µM. Conclusion: These results suggested that extracellular high glucose stimulated NHE-1 acutely and chronically through Mek/Erk1/2/p90RSK and p38MAPK pathways, respectively.

  7. Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

    Science.gov (United States)

    Fidler, Trevor P; Middleton, Elizabeth A; Rowley, Jesse W; Boudreau, Luc H; Campbell, Robert A; Souvenir, Rhonda; Funari, Trevor; Tessandier, Nicolas; Boilard, Eric; Weyrich, Andrew S; Abel, E Dale

    2017-09-01

    On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets. Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on α-granule membranes and under basal conditions facilitates glucose uptake into α-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased α-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis. GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes α-granule release, platelet activation, and postactivation functions. © 2017 American Heart Association, Inc.

  8. AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

    Science.gov (United States)

    de Laat, M A; Robinson, M A; Gruntmeir, K J; Liu, Y; Soma, L R; Lacombe, V A

    2015-09-01

    Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P managing IR requires investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors.

    Science.gov (United States)

    Cangoz, S; Chang, Y-Y; Chempakaseril, S J; Guduru, R C; Huynh, L M; John, J S; John, S T; Joseph, M E; Judge, R; Kimmey, R; Kudratov, K; Lee, P J; Madhani, I C; Shim, P J; Singh, S; Singh, S; Ruchalski, C; Raffa, R B

    2013-10-01

    A novel class of antidiabetic drugs - SGLT2 (Na(+) /glucose cotransporter type 2) inhibitors - target renal reabsorption of glucose and promote normal glucose levels, independent of insulin production or its action at receptors. We review this new mechanistic approach and the reported efficacy and safety of clinical testing of lead compounds. Information was obtained from various bibliographic sources, including PubMed and others, on the basic science and the clinical trials of SGLT2 inhibitors. The information was then summarized and evaluated from the perspective of contribution to a fuller understanding of the potential and current status of the lead clinical candidates. Diabetes mellitus is a spectrum of disorders that involves inadequate insulin function resulting in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses either insulin production at the pancreatic β-cells or insulin action at insulin receptors. These drugs have less than full clinical effectiveness and sometimes therapy-limiting adverse effects. The third major component of glucose balance, namely elimination, has not been a significant therapeutic target to date. SGLT2 inhibitors are a novel approach. A sufficient number of clinical trials have been conducted on sufficiently chemically diverse SGLT2 inhibitors to reasonably conclude that they have efficacy (HbA1c reductions of 0·4-1%), and thus far, the majority of adverse effects have been mild and transitory or treatable, with the caveat of possible association with increased risk of breast cancer in women and bladder cancer in men. © 2013 John Wiley & Sons Ltd.

  10. The biphasic effect of extracellular glucose concentration on carbachol-induced fluid secretion from mouse submandibular glands.

    Science.gov (United States)

    Terachi, Momomi; Hirono, Chikara; Kitagawa, Michinori; Sugita, Makoto

    2018-06-01

    Cholinergic agonists evoke elevations of the cytoplasmic free-calcium concentration ([Ca 2+ ] i ) to stimulate fluid secretion in salivary glands. Salivary flow rates are significantly reduced in diabetic patients. However, it remains elusive how salivary secretion is impaired in diabetes. Here, we used an ex vivo submandibular gland perfusion technique to characterize the dependency of salivary flow rates on extracellular glucose concentration and activities of glucose transporters expressed in the glands. The cholinergic agonist carbachol (CCh) induced sustained fluid secretion, the rates of which were modulated by the extracellular glucose concentration in a biphasic manner. Both lowering the extracellular glucose concentration to less than 2.5 mM and elevating it to higher than 5 mM resulted in decreased CCh-induced fluid secretion. The CCh-induced salivary flow was suppressed by phlorizin, an inhibitor of the sodium-glucose cotransporter 1 (SGLT1) located basolaterally in submandibular acinar cells, which is altered at the protein expression level in diabetic animal models. Our data suggest that SGLT1-mediated glucose uptake in acinar cells is required to maintain the fluid secretion by sustaining Cl - secretion in real-time. High extracellular glucose levels may suppress the CCh-induced secretion of salivary fluid by altering the activities of ion channels and transporters downstream of [Ca 2+ ] i signals. © 2018 Eur J Oral Sci.

  11. Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin, an SGLT2 Inhibitor.

    Directory of Open Access Journals (Sweden)

    Masato Furuhashi

    Full Text Available Fatty acid-binding protein 4 (FABP4/A-FABP/aP2 is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP. Sodium-glucose cotransporter 2 (SGLT2 inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level.Canagliflozin (100 mg/day was administered to type 2 diabetic patients (n = 39 for 12 weeks. Serum FABP4 level was measured before and after treatment.At baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 ± 1.0 vs. 19.8 ± 1.2 ng/ml, P = 0.008, though elevation of FABP4 level after treatment was observed in 26 (66.7% out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044, HbA1c (r = 0.329, P = 0.044 and noradrenaline (r = 0.329, P = 0.041 but was not significantly correlated with change in adiposity or other variables.Canagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2.UMIN-CTR Clinical Trial UMIN000018151.

  12. Glucose transporter of the human brain and blood-brain barrier

    International Nuclear Information System (INIS)

    Kalaria, R.N.; Gravina, S.A.; Schmidley, J.W.; Perry, G.; Harik, S.I.

    1988-01-01

    We identified and characterized the glucose transporter in the human cerebral cortex, cerebral microvessels, and choroid plexus by specific D-glucose-displaceable [3H]cytochalasin B binding. The binding was saturable, with a dissociation constant less than 1 microM. Maximal binding capacity was approximately 7 pmol/mg protein in the cerebral cortex, approximately 42 pmol/mg protein in brain microvessels, and approximately 27 pmol/mg protein in the choroid plexus. Several hexoses displaced specific [3H]cytochalasin B binding to microvessels in a rank-order that correlated well with their known ability to cross the blood-brain barrier; the only exception was 2-deoxy-D-glucose, which had much higher affinity for the glucose transporter than the natural substrate, D-glucose. Irreversible photoaffinity labeling of the glucose transporter of microvessels with [3H]cytochalasin B, followed by solubilization and polyacrylamide gel electrophoresis, labeled a protein band with an average molecular weight of approximately 55,000. Monoclonal and polyclonal antibodies specific to the human erythrocyte glucose transporter immunocytochemically stained brain blood vessels and the few trapped erythrocytes in situ, with minimal staining of the neuropil. In the choroid plexus, blood vessels did not stain, but the epithelium reacted positively. We conclude that human brain microvessels are richly endowed with a glucose transport moiety similar in molecular weight and antigenic characteristics to that of human erythrocytes and brain microvessels of other mammalian species

  13. Differentiation of the insulin-sensitive glucose transporter in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Frost, S.C.; Baly, D.L.; Cushman, S.W.; Lane, M.D.; Simpson, I.A.

    1986-01-01

    3T3-L1 fibroblasts differentiate in culture to resemble adipocytes both morphologically and biochemically. Insulin-sensitive glucose transport, as measured by 2-deoxy-[1- 14 C]- glucose uptake in the undifferentiated cell is small (2X). In contrast, the rate of glucose transport in fully differentiated cells is elevated 15-fold over basal in the presence of insulin. To determine if this is due to an increase in the number of transporters/cell or accessibility to the transporters, the number of transporters was measured in subcellular fractions over differentiation using a 3 H-cytochalasin B binding assay. The increase in the rate of insulin-sensitive glucose transport directly parallels an increase in the number of transporters which reside in an insulin-responsive intracellular compartment. This observation was confirmed by identifying the transporters by immunoblotting using an antibody generated against the human erythrocyte transporter. The molecular weight of this transporter increases over differentiation from a single band of 40kDa to a heterogeneous triplet of 40, 44 and 48kDa. These data suggest that the transporter undergoes differential processing and that the functional, insulin-responsive transporter may be different from the insulin-insensitive (basal) transporter

  14. Glucose uptake and growth of glucose-limited chemostat cultures of Aspergillus niger and a disruptant lacking MstA, a high-affinity glucose transporter

    DEFF Research Database (Denmark)

    Jørgensen, Thomas R; vanKuyk, Patricia A; Poulsen, Bjarne R

    2007-01-01

    This is a study of high-affinity glucose uptake in Aspergillus niger and the effect of disruption of a high-affinity monosaccharide-transporter gene, mstA. The substrate saturation constant (K(s)) of a reference strain was about 15 microM in glucose-limited chemostat culture. Disruption of mst......-affinity uptake system of A. niger. The mstA disruptant and a reference strain were cultivated in glucose-limited chemostat cultures at low, intermediate and high dilution rate (D=0.07 h(-1), 0.14 h(-1) and 0.20 h(-1)). Mycelium harvested from steady-state cultures was subjected to glucose uptake assays...

  15. Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice.

    Science.gov (United States)

    Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

    2017-08-15

    In this study, we investigated and compared the effects of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan on diabetes-related diseases and complications in type 2 diabetic mice. Following 4-week repeated administration to diabetic mice, all SGLT2 inhibitors showed significant improvement in diabetes-related diseases and complications, including obesity; abnormal lipid metabolism; steatohepatitis; inflammation; endothelial dysfunction; and nephropathy. While all SGLT2 inhibitors exerted comparable effects in reducing hyperglycemia, improvement of these diabetes-related diseases and complications was more potent with the two long-acting drugs (ipragliflozin and dapagliflozin) than with the four intermediate-acting four drugs (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin), albeit without statistical significance. These findings demonstrate that SGLT2 inhibitors alleviate various diabetic pathological conditions in type 2 diabetic mice, and suggest that SGLT2 inhibitors, particularly long-acting drugs, might be useful not only for hyperglycemia but also in diabetes-related diseases and complications, including nephropathy in type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle.

    Science.gov (United States)

    Cervone, Daniel T; Dyck, David J

    2017-07-01

    Emerging evidence implicates ghrelin, a gut-derived, orexigenic hormone, as a potential mediator of insulin-responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin-stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin-stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser 473 AKT or Thr 172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin-dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle. © 2017 The

  17. Inhibition by nucleosides of glucose-transport activity in human erythrocytes.

    OpenAIRE

    Jarvis, S M

    1988-01-01

    The interaction of nucleosides with the glucose carrier of human erythrocytes was examined by studying the effect of nucleosides on reversible cytochalasin B-binding activity and glucose transport. Adenosine, inosine and thymidine were more potent inhibitors of cytochalasin B binding to human erythrocyte membranes than was D-glucose [IC50 (concentration causing 50% inhibition) values of 10, 24, 28 and 38 mM respectively]. Moreover, low concentrations of thymidine and adenosine inhibited D-glu...

  18. Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA

    International Nuclear Information System (INIS)

    Permutt, M.A.; Koranyi, L.; Keller, K.; Lacy, P.E.; Scharp, D.W.; Mueckler, M.

    1989-01-01

    Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-K m , low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. The authors isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus

  19. Intracellular ascorbic acid inhibits transport of glucose by neurons, but not by astrocytes.

    Science.gov (United States)

    Castro, Maite A; Pozo, Miguel; Cortés, Christian; García, María de Los Angeles; Concha, Ilona I; Nualart, Francisco

    2007-08-01

    It has been demonstrated that glutamatergic activity induces ascorbic acid (AA) depletion in astrocytes. Additionally, different data indicate that AA may inhibit glucose accumulation in primary cultures of rat hippocampal neurons. Thus, our hypothesis postulates that AA released from the astrocytes during glutamatergic synaptic activity may inhibit glucose uptake by neurons. We observed that cultured neurons express the sodium-vitamin C cotransporter 2 and the facilitative glucose transporters (GLUT) 1 and 3, however, in hippocampal brain slices GLUT3 was the main transporter detected. Functional activity of GLUTs was confirmed by means of kinetic analysis using 2-deoxy-d-glucose. Therefore, we showed that AA, once accumulated inside the cell, inhibits glucose transport in both cortical and hippocampal neurons in culture. Additionally, we showed that astrocytes are not affected by AA. Using hippocampal slices, we observed that upon blockade of monocarboxylate utilization by alpha-cyano-4-hydroxycinnamate and after glucose deprivation, glucose could rescue neuronal response to electrical stimulation only if AA uptake is prevented. Finally, using a transwell system of separated neuronal and astrocytic cultures, we observed that glutamate can reduce glucose transport in neurons only in presence of AA-loaded astrocytes, suggesting the essential role of astrocyte-released AA in this effect.

  20. A Hexose Transporter Homologue Controls Glucose Repression in the Methylotrophic Yeast Hansenula polymorpha

    NARCIS (Netherlands)

    Stasyk, Oleh V.; Stasyk, Olena G.; Komduur, Janet; Veenhuis, Marten; Cregg, James M.; Sibirny, Andrei A.

    2004-01-01

    Peroxisome biogenesis and synthesis of peroxisomal enzymes in the methylotrophic yeast Hansenula polymorpha are under the strict control of glucose repression. We identified an H. polymorpha glucose catabolite repression gene (HpGCR1) that encodes a hexose transporter homologue. Deficiency in GCR1

  1. Role of beta-adrenoceptors in memory consolidation: beta3-adrenoceptors act on glucose uptake and beta2-adrenoceptors on glycogenolysis.

    Science.gov (United States)

    Gibbs, Marie E; Hutchinson, Dana S; Summers, Roger J

    2008-09-01

    Noradrenaline, acting via beta(2)- and beta(3)-adrenoceptors (AR), enhances memory formation in single trial-discriminated avoidance learning in day-old chicks by mechanisms involving changes in metabolism of glucose and/or glycogen. Earlier studies of memory consolidation in chicks implicated beta(3)- rather than beta(2)-ARs in enhancement of memory consolidation by glucose, but did not elucidate whether stimulation of glucose uptake or of glycolysis was responsible. This study examines the role of glucose transport in memory formation using central injection of the nonselective facilitative glucose transporter (GLUT) inhibitor cytochalasin B, the endothelial/astrocytic GLUT-1 inhibitor phloretin and the Na(+)/energy-dependent endothelial glucose transporter (SGLT) inhibitor phlorizin. Cytochalasin B inhibited memory when injected into the mesopallium (avian cortex) either close to or between 25 and 45 min after training, whereas phloretin and phlorizin only inhibited memory at 30 min. This suggested that astrocytic/endothelial (GLUT-1) transport is critical at the time of consolidation, whereas a different transporter, probably the neuronal glucose transporter (GLUT-3), is important at the time of training. Inhibition of glucose transport by cytochalasin B, phloretin, or phlorizin also interfered with beta(3)-AR-mediated memory enhancement 20 min posttraining, whereas inhibition of glycogenolysis interfered with beta(2)-AR agonist enhancement of memory. We conclude that in astrocytes (1) activities of both GLUT-1 and SGLT are essential for memory consolidation 30 min posttraining; (2) neuronal GLUT-3 is essential at the time of training; and (3) beta(2)- and beta(3)-ARs consolidate memory by different mechanisms; beta(3)-ARs stimulate central glucose transport, whereas beta(2)-ARs stimulate central glycogenolysis.

  2. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

    Science.gov (United States)

    Lee, Tsung-Ming; Chang, Nen-Chung; Lin, Shinn-Zong

    2017-03-01

    During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during

  3. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials.

    Science.gov (United States)

    Tang, Huilin; Zhang, Xi; Zhang, Jingjing; Li, Yufeng; Del Gobbo, Liana C; Zhai, Suodi; Song, Yiqing

    2016-12-01

    By analysing available evidence from randomised controlled trials (RCTs), we aimed to examine whether and to what extent sodium-glucose cotransporter 2 (SGLT2) inhibitors affect serum electrolyte levels in type 2 diabetes patients. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov up to 24 May 2016 for published RCTs of SGLT2 inhibitors that reported changes in serum electrolyte levels. Weighted mean differences (WMD) between each SGLT2 inhibitor and placebo were calculated using a random-effects model. Dose-dependent relationships for each SGLT2 inhibitor were evaluated using meta-regression analysis. Eighteen eligible RCTs, including 15,309 patients and four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated. In patients without chronic kidney disease, each SGLT2 inhibitor significantly increased serum magnesium levels compared with placebo (canagliflozin: WMD 0.06 mmol/l for 100 mg and 0.09 mmol/l for 300 mg; dapagliflozin: WMD 0.1 mmol/l for 10 mg; empagliflozin: WMD 0.04 mmol/l for 10 mg and 0.07 mmol/l for 25 mg; and ipragliflozin: WMD 0.05 mmol/l for 50 mg). Canagliflozin increased serum magnesium in a linear dose-dependent manner (p = 0.10). Serum phosphate was significantly increased by dapagliflozin. Serum sodium appeared to significantly differ by SGLT2 inhibitor type. No significant changes in serum calcium and potassium were observed. Findings were robust after including trials involving patients with chronic kidney disease. SGLT2 inhibitors marginally increased serum magnesium levels in type 2 diabetes patients indicating a drug class effect. Further investigations are required to examine the clinical significance of elevated magnesium levels in individuals with type 2 diabetes.

  4. The small intestinal epithelia of beef steers differentially express sugar transporter messenger ribonucleic acid in response to abomasal versus ruminal infusion of starch hydrolysate.

    Science.gov (United States)

    Liao, S F; Harmon, D L; Vanzant, E S; McLeod, K R; Boling, J A; Matthews, J C

    2010-01-01

    In mammals, the absorption of monosaccharides from small intestinal lumen involves at least 3 sugar transporters (SugT): sodium-dependent glucose transporter 1 (SGLT1; gene SLC5A1) transports glucose and galactose, whereas glucose transporter (GLUT) 5 (GLUT5; gene SLC2A5) transports fructose, across the apical membrane of enterocytes. In contrast, GLUT2 (gene SLC2A2) transports all of these sugars across basolateral and apical membranes. To compare the distribution patterns and sensitivity with nutritional regulation of these 3 SugT mRNA in beef cattle small intestinal tissue, 18 ruminally and abomasally catheterized Angus steers (BW approximately 260 kg) were assigned to water (control), ruminal cornstarch (partially hydrolyzed by alpha-amylase; SH), or abomasal SH infusion treatments (n = 6) and fed an alfalfa-cube-based diet at 1.3 x NE(m) requirement. The SH infusions amounted to 20% of ME intake. After 14- or 16-d of infusion, steers were killed; duodenal, jejunal, and ileal epithelia harvested; and total RNA extracted. The relative amount of SugT mRNA in epithelia was determined using real-time reverse transcription-PCR quantification methods. Basal expression of GLUT2 and SGLT1 mRNA was greater (P content of GLUT5 mRNA was greater (P content of GLUT5 mRNA in small intestinal epithelia was not affected (P > or = 0.16) by either SH infusion treatment. In contrast, GLUT2 and SGLT1 mRNA content in the ileal epithelium was increased (P content also was increased (P = 0.07) by 64% after ruminal SH infusion. These results demonstrate that the ileum of beef cattle small intestine adapts to an increased luminal supply of glucose by increasing SGLT1 and GLUT2 mRNA content, whereas increased ruminal SH supply results in duodenal upregulation of SGLT1 mRNA content. These adaptive responses of GLUT2 and SGLT1 mRNA to abomasal or ruminal SH infusion suggest that beef cattle can adapt to increase their carbohydrate assimilation through small intestinal epithelia, assuming

  5. Brain Transport Profiles of Ginsenoside Rb1 by Glucose Transporter 1: In Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Yu-Zhu Wang

    2018-04-01

    Full Text Available Ginsenoside Rb1 (Rb1 has been demonstrated its protection for central nervous system and is apparently highly distributed to the brain. The objective of this study was to characterize Rb1 transport at the blood–brain barrier (BBB using primary cultured rat brain microvascular endothelial cells (rBMEC, an in vitro BBB model. The initial uptake velocity of Rb1 in rBMEC was temperature- and concentration-dependent, and was significantly reduced by phloretin, an inhibitor of GLUT1 transporter, but was independent of metabolic inhibitor. Furthermore, the transport of Rb1 into rBMEC was significantly diminished in the presence of natural substrate α-D-glucose, suggesting a facilitated transport of Rb1 via GLUT1 transporter. The impact of GLUT1 on the distribution of Rb1 between brain and plasma was studied experimentally in rats. Administration of phloretin (5 mg/kg, i.v. to normal rats for consecutive 1 week before Rb1 (10 mg/kg, i.v. at 0.5, 2, and 6 h did not alter Rb1 concentrations in plasma, but resulted in significant decreased brain concentrations of Rb1 compared to in the phloretin-untreated normal rats (489.6 ± 58.3 versus 105.1 ± 15.1 ng/g, 193.8 ± 11.1 versus 84.8 ± 4.1 ng/g, and 114.2 ± 24.0 versus 39.9 ± 4.9 ng/g, respectively. The expression of GLUT1 in the phloretin-treated group by western blotting analysis in vitro and in vivo experiments was significantly decreased, indicating that the decreased transport of Rb1 in brain was well related to the down-regulated function and level of GLUT1. Therefore, our in vitro and in vivo results indicate that the transport of Rb1 at the BBB is at least partly mediated by GLUT1 transporter.

  6. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH.

    Science.gov (United States)

    Shiba, Kumiko; Tsuchiya, Kyoichiro; Komiya, Chikara; Miyachi, Yasutaka; Mori, Kentaro; Shimazu, Noriko; Yamaguchi, Shinobu; Ogasawara, Naomi; Katoh, Makoto; Itoh, Michiko; Suganami, Takayoshi; Ogawa, Yoshihiro

    2018-02-05

    Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes. CANA treatment for 20 weeks inhibited the development of hepatic fibrosis in WD-fed MC4R-KO mice. After one year of CANA treatment, the number of liver tumors was significantly reduced in WD-fed MC4R-KO mice. In adipose tissue, CANA suppressed the ratio of oxidative to reduced forms of glutathiones (GSSG/GSH) in WD-fed MC4R-KO mice. Treatment with GSH significantly attenuated the H 2 O 2 -induced upregulation of genes related to NADPH oxidase in 3T3-L1 adipocytes, and that of Il6, Tgfb, and Pdgfb in RAW264.7 cells. This study provides evidence that SGLT2 inhibitors represent the unique class of drugs that can attenuate or delay the onset of NASH and eventually hepatocellular carcinoma, at least partly, through "healthy adipose expansion".

  7. Glucose transporter expression differs between bovine monocyte and macrophage subsets and is influenced by milk production.

    Science.gov (United States)

    Eger, M; Hussen, J; Koy, M; Dänicke, S; Schuberth, H-J; Breves, G

    2016-03-01

    The peripartal period of dairy cows is characterized by negative energy balance and higher incidences of infectious diseases such as mastitis or metritis. With the onset of lactation, milk production is prioritized and large amounts of glucose are transported into the mammary gland. Decreased overall energy availability might impair the function of monocytes acting as key innate immune cells, which give rise to macrophages and dendritic cells and link innate and adaptive immunity. Information on glucose requirements of bovine immune cells is rare. Therefore, this study aims to evaluate glucose transporter expression of the 3 bovine monocyte subsets (classical, intermediate, and nonclassical monocytes) and monocyte-derived macrophages and to identify influences of the peripartal period. Blood samples were either collected from nonpregnant healthy cows or from 16 peripartal German Holstein cows at d -14, +7, and +21 relative to parturition. Quantitative real-time PCR was applied to determine mRNA expression of glucose transporters (GLUT) 1, GLUT3, and GLUT4 in monocyte subsets and monocyte-derived macrophages. The low GLUT1 and GLUT3 expression in nonclassical monocytes was unaltered during differentiation into macrophages, whereas in classical and intermediate monocytes GLUT expression was downregulated. Alternatively activated M2 macrophages consumed more glucose compared with classically activated M1 macrophages. The GLUT4 mRNA was only detectable in unstimulated macrophages. Neither monocytes nor macrophages were insulin responsive. In the peripartum period, monocyte GLUT1 and GLUT3 expression and the GLUT3/GLUT1 ratio were negatively correlated with lactose production. The high-affinity GLUT3 transporter appears to be the predominant glucose transporter on bovine monocytes and macrophages, especially in the peripartal period when blood glucose levels decline. Glucose transporter expression in monocytes is downregulated as a function of lactose production, which

  8. Promising cardiovascular and blood pressure effects of the SGLT2 inhibitors: a new class of antidiabetic drugs.

    Science.gov (United States)

    Chrysant, S G

    2017-03-01

    Patients with type 2 diabetes mellitus (T2DM) exhibit an increased risk of cardiovascular (CV) events. Treatment of these patients with traditional as well as newer glucose-lowering drugs has not demonstrated superiority in CV outcomes compared to placebo, despite effective control of diabetes. However, the recently FDA-approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of T2DM have demonstrated promising CV-protecting and blood pressure-lowering effects in addition to their effectiveness in glucose lowering, making them a novel class of drugs for the treatment of T2DM. So far, there are three SGLT2 inhibitors approved by the FDA and EMA for the treatment of T2DM: canagliflozin, dapagliflozin and empagliflozin. They exert their antihyperglycemic effect through inhibition of SGLT2 in the kidney and significantly reduce glucose reabsorption from the proximal renal tubule. By blocking glucose reabsorption, they lead to loss of calories, weight, abdominal and total body fat, blood pressure and CV complications. One CV outcomes randomized trial and several short-term studies have shown reductions in CV events and blood pressure in patients with T2DM. It is the hope that large ongoing long-term outcome studies will provide further much-needed information, when they are completed. Copyright 2017 Clarivate Analytics.

  9. Effects of Thyroidectomy and Thyroxine on Glucose Transport ...

    African Journals Online (AJOL)

    10mg/kg b/w Ketamine was administered intraperitoneally as anesthesia before the surgeries. On the thirty-fifth day post-surgery all the animals were sacrificed and their small intestines were harvested. 10cm length of jejunum and ileum respectively were used to make everted sacs for the in vitro study. Mucosa glucose ...

  10. Glucose, epithelium, and enteric nervous system: dialogue in the dark.

    Science.gov (United States)

    Pfannkuche, H; Gäbel, G

    2009-06-01

    The gastrointestinal epithelium is in close contact with the various components of the chymus, including nutrients, bacteria and toxins. The epithelial barrier has to decide which components are effectively absorbed and which components are extruded. In the small intestine, a nutrient like glucose is mainly absorbed by the sodium linked glucose cotransporter 1 (SGLT1) and the glucose transporter 2 (GLUT2). The expression and activity of both transport proteins is directly linked to the amount of intraluminal glucose. Besides the direct interaction between glucose and the enterocytes, glucose also stimulates different sensory mechanisms within the intestinal wall. The most important types of cells involved in the sensing of intraluminal contents are enteroendocrine cells and neurones of the enteric nervous system. Regarding glucosensing, a distinct type of enteroendocrine cells, the enterochromaffine (EC) cells are involved. Excitation of EC cells by intraluminal glucose results in the release of serotonin (5-HT), which modulates epithelial functions and activates enteric secretomotorneurones. Enteric neurones are not only activated by 5-HT, but also directly by glucose. The activation of different cell types and the subsequent crosstalk between these cells may trigger appropriate absorptive and secretory processes within the intestine.

  11. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Eiichi [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Hosokawa, Masaya [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Faculty of Human Sciences, Tezukayama Gakuin University, Osaka (Japan); Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Tsukiyama, Katsushi; Yamada, Yuichiro [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Department of Internal Medicine, Division of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, Akita (Japan); Seino, Yutaka [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); Kansai Electric Power Hospital, Osaka (Japan); Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp [Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University (Japan); CREST of Japan Science and Technology Cooperation (JST), Kyoto (Japan)

    2011-01-07

    Research highlights: {yields} Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. {yields} Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. {yields} The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic {beta} cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [{sup 14}C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [{sup 14}C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin

  12. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice

    International Nuclear Information System (INIS)

    Ogawa, Eiichi; Hosokawa, Masaya; Harada, Norio; Yamane, Shunsuke; Hamasaki, Akihiro; Toyoda, Kentaro; Fujimoto, Shimpei; Fujita, Yoshihito; Fukuda, Kazuhito; Tsukiyama, Katsushi; Yamada, Yuichiro; Seino, Yutaka; Inagaki, Nobuya

    2011-01-01

    Research highlights: → Exogenous GIP inhibits intestinal motility through a somatostatin-mediated pathway. → Exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility. → The GIP-receptor-mediated action in intestine does not involve in GLP-1-mediated pathway. -- Abstract: Gastric inhibitory polypeptide (GIP) is released from the small intestine upon meal ingestion and increases insulin secretion from pancreatic β cells. Although the GIP receptor is known to be expressed in small intestine, the effects of GIP in small intestine are not fully understood. This study was designed to clarify the effect of GIP on intestinal glucose absorption and intestinal motility. Intestinal glucose absorption in vivo was measured by single-pass perfusion method. Incorporation of [ 14 C]-glucose into everted jejunal rings in vitro was used to evaluate the effect of GIP on sodium-glucose co-transporter (SGLT). Motility of small intestine was measured by intestinal transit after oral administration of a non-absorbed marker. Intraperitoneal administration of GIP inhibited glucose absorption in wild-type mice in a concentration-dependent manner, showing maximum decrease at the dosage of 50 nmol/kg body weight. In glucagon-like-peptide-1 (GLP-1) receptor-deficient mice, GIP inhibited glucose absorption as in wild-type mice. In vitro examination of [ 14 C]-glucose uptake revealed that 100 nM GIP did not change SGLT-dependent glucose uptake in wild-type mice. After intraperitoneal administration of GIP (50 nmol/kg body weight), small intestinal transit was inhibited to 40% in both wild-type and GLP-1 receptor-deficient mice. Furthermore, a somatostatin receptor antagonist, cyclosomatostatin, reduced the inhibitory effect of GIP on both intestinal transit and glucose absorption in wild-type mice. These results demonstrate that exogenous GIP inhibits intestinal glucose absorption by reducing intestinal motility through a somatostatin-mediated pathway rather

  13. Glucose metabolism transporters and epilepsy: only GLUT1 has an established role.

    Science.gov (United States)

    Hildebrand, Michael S; Damiano, John A; Mullen, Saul A; Bellows, Susannah T; Oliver, Karen L; Dahl, Hans-Henrik M; Scheffer, Ingrid E; Berkovic, Samuel F

    2014-02-01

    The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

  14. Two Cases of Mistaken Polyuria and Nephrocalcinosis in Infants with Glucose-Galactose Malabsorption: A Possible Role of 1,25(OH)2D3
.

    Science.gov (United States)

    Fiscaletti, Melissa; Lebel, Marie-Jeanne; Alos, Nathalie; Benoit, Geneviève; Jantchou, Prévost

    2017-01-01

    Glucose-galactose malabsorption (GGM) is a rare and potentially fatal disorder. The autosomal recessive mutation of the SGLT1 gene interferes with the active glucose transport in the gut resulting in osmotic diarrhea and failure to thrive (FTT). Two nonrelated infants with GGM are presented as well as a novel mutation in SGLT1. The first case consulted for FTT and presented with hypercalcemia and hypercalciuria. His mother had self-medicated with high doses of vitamin D. The second case consulted for macroscopic hematuria, and presented with dehydration and secondary acute kidney injury. In both cases, the profuse diarrhea, initially mistaken for polyuria, promptly resolved after the introduction of glucose-galactose-free milk. Investigations showed bilateral nephrocalcinosis and high levels of 1,25(OH)2D3 in both patients. We hypothesize that the upregulation of epithelial calcium channels (TRPV6) and 1,25(OH)2D3 are possible factors involved in the pathophysiology of nephrocalcinosis sometimes seen in GGM. Furthermore, a novel intronic SGLT1 mutation (c.207+2dup) is described. These 2 cases demonstrate that a malabsorption disorder such as GGM can present with nephrocalcinosis and/or hypercalcemia, with increased 1,25(OH)2D3 levels in infants. Prompt recognition of GGM is sometimes difficult but crucial.
. © 2017 S. Karger AG, Basel.

  15. Role of vitamin D on the expression of glucose transporters in L6 myotubes

    Directory of Open Access Journals (Sweden)

    Bubblu Tamilselvan

    2013-01-01

    Full Text Available Altered expression of glucose transporters is a major characteristic of diabetes. Vitamin D has evolved widespread interest in the pathogenesis and prevention of diabetes. The present study was designed to investigate the effect of vitamin D in the overall regulation of muscle cell glucose transporter expression. L6 cells were exposed to type 1 and type 2 diabetic conditions and the effect of calcitriol (1,25, dihydroxy cholicalciferol on the expression of glucose transporters was studied by real time polymerase chain reaction (RT-PCR. There was a significant decrease in glucose transporter type 1 (GLUT1, GLUT4, vitamin D receptor (VDR, and IR expression in type 1 and 2 diabetic model compared to control group. Treatment of myoblasts with 10-7 M calcitriol for 24 h showed a significant increase in GLUT1, GLUT4, VDR, and insulin receptor (IR expression. The results indicate a potential antidiabetic function of vitamin D on GLUT1, GLUT4, VDR, and IR by improving receptor gene expression suggesting a role for vitamin D in regulation of expression of the glucose transporters in muscle cells.

  16. Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis.

    Science.gov (United States)

    Min, Se Hee; Yoon, Jeong-Hwa; Hahn, Seokyung; Cho, Young Min

    2017-01-01

    Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors. We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through June 2015. Randomized controlled trials published in English that compare SGLT2 inhibitor plus insulin (SGLT2i/INS) with placebo plus insulin or DPP4 inhibitor plus insulin (DPP4i/INS) with placebo plus insulin in patients with T2DM were selected. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between SGLT2i/INS and DPP4i/INS indirectly with covariates adjustment. Risk of potential bias was assessed. Fourteen eligible randomized controlled trials comprising 6980 patients were included (five SGLT2 inhibitor studies and nine DPP4 inhibitor studies). Covariate-adjusted indirect comparison using meta-regression analyses revealed that SGLT2i/INS achieved greater reduction in HbA 1c [weighted mean difference (WMD) -0.24%, 95% confidence interval (CI) -0.43 to -0.05%], fasting plasma glucose (WMD -18.0 mg/dL, 95% CI -28.5 to -7.6 mg/dL) and body weight (WMD -2.38 kg, 95% CI -3.18 to -1.58 kg) from baseline than DPP4i/INS without increasing the risk of hypoglycaemia (relative risks 1.19, 95% CI 0.78 to 1.82). Sodium glucose cotransporter 2 inhibitors achieved better glycaemic control and greater weight reduction than DPP4 inhibitors without increasing the risk of hypoglycaemia in patients with T2DM that is inadequately controlled with insulin. There has been no direct comparison of SGLT2 inhibitors and DPP4 inhibitors in patients with T2DM inadequately controlled with insulin therapy. In this study, we performed indirect meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors added to insulin

  17. Genome, secretome and glucose transport highlight unique features of the protein production host Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Mattanovich Diethard

    2009-06-01

    Full Text Available Abstract Background Pichia pastoris is widely used as a production platform for heterologous proteins and model organism for organelle proliferation. Without a published genome sequence available, strain and process development relied mainly on analogies to other, well studied yeasts like Saccharomyces cerevisiae. Results To investigate specific features of growth and protein secretion, we have sequenced the 9.4 Mb genome of the type strain DSMZ 70382 and analyzed the secretome and the sugar transporters. The computationally predicted secretome consists of 88 ORFs. When grown on glucose, only 20 proteins were actually secreted at detectable levels. These data highlight one major feature of P. pastoris, namely the low contamination of heterologous proteins with host cell protein, when applying glucose based expression systems. Putative sugar transporters were identified and compared to those of related yeast species. The genome comprises 2 homologs to S. cerevisiae low affinity transporters and 2 to high affinity transporters of other Crabtree negative yeasts. Contrary to other yeasts, P. pastoris possesses 4 H+/glycerol transporters. Conclusion This work highlights significant advantages of using the P. pastoris system with glucose based expression and fermentation strategies. As only few proteins and no proteases are actually secreted on glucose, it becomes evident that cell lysis is the relevant cause of proteolytic degradation of secreted proteins. The endowment with hexose transporters, dominantly of the high affinity type, limits glucose uptake rates and thus overflow metabolism as observed in S. cerevisiae. The presence of 4 genes for glycerol transporters explains the high specific growth rates on this substrate and underlines the suitability of a glycerol/glucose based fermentation strategy. Furthermore, we present an open access web based genome browser http://www.pichiagenome.org.

  18. A Glimpse of Membrane Transport through Structures-Advances in the Structural Biology of the GLUT Glucose Transporters.

    Science.gov (United States)

    Yan, Nieng

    2017-08-18

    The cellular uptake of glucose is an essential physiological process, and movement of glucose across biological membranes requires specialized transporters. The major facilitator superfamily glucose transporters GLUTs, encoded by the SLC2A genes, have been a paradigm for functional, mechanistic, and structural understanding of solute transport in the past century. This review starts with a glimpse into the structural biology of membrane proteins and particularly membrane transport proteins, enumerating the landmark structures in the past 25years. The recent breakthrough in the structural elucidation of GLUTs is then elaborated following a brief overview of the research history of these archetypal transporters, their functional specificity, and physiological and pathophysiological significances. Structures of GLUT1, GLUT3, and GLUT5 in distinct transport and/or ligand-binding states reveal detailed mechanisms of the alternating access transport cycle and substrate recognition, and thus illuminate a path by which structure-based drug design may be applied to help discover novel therapeutics against several debilitating human diseases associated with GLUT malfunction and/or misregulation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    Science.gov (United States)

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Pnootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Pnootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

  20. Activation of glycolysis and inhibition of glucose transport into leaves by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Lustinec, J; Pokorna, V; Ruzicka, J

    1962-01-01

    During stimulation of wheat leaf respiration by fluoride at 100 to 200 ppM fluorine in dry tissue the ratio of radioactivities of /sup 14/CO/sub 2/ released from glucose-6-/sup 14/C and that released from glucose-1-/sup 14/C (C/sub 6//C/sub 1/) increases due especially to an increased output of 6-/sup 14/CO/sub 2/ which suggests an activation of glycolysis. The absolute values of radioactivity of /sup 14/CO/sub 2/, however, are decreased by the action of fluoride due to its inhibition of the transport of glucose into leaves. 15 references, 2 figures, 2 tables.

  1. Effect of diet on insulin binding and glucose transport in rat sarcolemmal vesicles

    International Nuclear Information System (INIS)

    Grimditch, G.K.; Barnard, R.J.; Sternlicht, E.; Whitson, R.H.; Kaplan, S.A.

    1987-01-01

    The purpose of this study was to compare the effects of a high-fat, high-sucrose diet (HFS) and a low-fat, high-complex carbohydrate diet (LFC) on glucose tolerance, insulin binding, and glucose transport in rat skeletal muscle. During the intravenous glucose tolerance test, peak glucose values at 5 min were significantly higher in the HFS group; 0-, 20-, and 60-min values were similar. Insulin values were significantly higher in the HFS group at all time points (except 60 min), indicating whole-body insulin resistance. Skeletal muscle was responsible, in part, for this insulin resistance, because specific D-glucose transport in isolated sarcolemmal (SL) vesicles under basal conditions was similar between LFC and HFS rats, despite the higher plasma insulin levels. Scatchard analyses of insulin binding curves to sarcolemmal vesicles revealed that the K/sub a/ of the high-affinity binding sites was significantly reduced by the HFS diet; no other binding changes were noted. Specific D-glucose transport in SL vesicles after maximum insulin stimulation (1 U/kg) was significantly depressed in the HFS group, indicating that HFS feeding also caused a postbinding defect. These results indicate that the insulin resistance in skeletal muscle associated with a HFS diet is due to both a decrease in the K/sub a/ of the high-affinity insulin receptors and a postbinding defect

  2. Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus.

    Science.gov (United States)

    Stanirowski, Paweł Jan; Szukiewicz, Dariusz; Pazura-Turowska, Monika; Sawicki, Włodzimierz; Cendrowski, Krzysztof

    2018-04-01

    Gestational diabetes mellitus and pregestational diabetes mellitus constitute carbohydrate metabolism disorders, which, if not diagnosed and adequately treated, lead to serious and often life-threatening pregnancy complications. According to a recently formulated hypothesis, some diabetes-related complications, such as fetal macrosomia, may be the result of disturbances in the transplacental transport of nutrients-in particular, excessive maternal-fetal glucose transfer. Throughout pregnancy, glucose flux across the placenta is mediated by the group of facilitative glucose transporters (GLUT), the expression of which in different placental compartments is the precondition for effective glucose uptake from maternal blood and its subsequent transfer to the fetal circulation. In diabetes-complicated pregnancies, the location, expression and activity of glucose transporters are modified to an extent that results in alterations in the maternal-fetal glucose exchange, potentially leading to an excessive supply of energy substrates to the fetus. This paper reviews the literature on the expression and activity of glucose transporter proteins-GLUT-1, GLUT-3, GLUT-4, GLUT-8, GLUT-9 and GLUT-12-in the human placenta, with a special focus on diabetes-complicated pregnancy. The characteristics of transporters in conditions of maternal normoglycemia and modifications occurring in the diabetic placenta are summarized, and the factors responsible for the regulation of the expression of selected isoforms are described. Finally, the impact of alterations in the placental expression of the aforementioned members of the GLUT family on intrauterine fetal development in pregnancies complicated by diabetes mellitus is discussed. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  3. Effect of selective blockade of oxygen consumption, glucose transport, and Ca2+ influx on thyroxine action in human mononuclear cells

    DEFF Research Database (Denmark)

    Kvetny, J; Matzen, L E

    1990-01-01

    The effect of selective blockade of cellular glucose transporters, Ca2+ influx, and mitochondrial oxygen consumption on thyroxine (T4)-stimulated oxygen consumption and glucose uptake was examined in human mononuclear blood cells. Blockade of glucose transporters by cytochalasin B (1 x 10(-5) mol....../L) and of Ca2+ influx by alprenolol (1 x 10(-5) mol/L) and verapamil (4 x 10(-4) mol/L) inhibited T4-activated glucose uptaken and reduced T4-stimulated oxygen consumption by 20%. Uncoupling of mitochondrial oxygen consumption by azide (1 x 10(-3) mol/L) inhibited T4-stimulated oxygen consumption, but had...... no effect on glucose uptake. We conclude that T4-stimulated glucose uptake in human mononuclear blood cells is dependent on intact glucose transporters and Ca2+ influx, but not on mitochondrial oxygen consumption. However, oxygen consumption is, in part, dependent on intact glucose uptake....

  4. Wortmannin inhibits both insulin- and contraction-stimulated glucose uptake and transport in rat skeletal muscle

    DEFF Research Database (Denmark)

    Wojtaszewski, Jørgen; Hansen, B F; Ursø, Birgitte

    1996-01-01

    The role of phosphatidylinositol (PI) 3-kinase for insulin- and contraction-stimulated muscle glucose transport was investigated in rat skeletal muscle perfused with a cell-free perfusate. The insulin receptor substrate-1-associated PI 3-kinase activity was increased sixfold upon insulin...... stimulation but was unaffected by contractions. In addition, the insulin-stimulated PI 3-kinase activity and muscle glucose uptake and transport in individual muscles were dose-dependently inhibited by wortmannin with one-half maximal inhibition values of approximately 10 nM and total inhibition at 1 micro......M. This concentration of wortmannin also decreased the contraction-stimulated glucose transport and uptake by approximately 30-70% without confounding effects on contractility or on muscle ATP and phosphocreatine concentrations. At higher concentrations (3 and 10 microM), wortmannin completely blocked the contraction...

  5. Is contraction-stimulated glucose transport feedforward regulated by Ca2+?

    DEFF Research Database (Denmark)

    Jensen, Thomas Elbenhardt; Angin, Yeliz; Sylow, Lykke

    2014-01-01

    cell types. The literature is contrasted against our recent findings suggesting that SR Ca(2+) release is neither essential nor adequate to stimulate glucose transport in muscle. Instead, feedback signals through AMPK and mechanical stress are likely to account for most of contraction......In many cell types, Ca(2+) signals to increase the movement and surface membrane insertion of vesicles. In skeletal muscle, Ca(2+) is predominantly released from the sarcoplasmic reticulum (SR) to initiate contraction. Sarcoplasmic reticulum Ca(2+) release is widely believed to be a direct......-stimulated glucose transport. A revised working model is proposed, in which muscle glucose transport during contraction is not directly regulated by SR Ca(2+) release but rather responds exclusively to feedback signals activated secondary to cross-bridge cycling and tension development....

  6. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Directory of Open Access Journals (Sweden)

    Reed JW

    2016-10-01

    Full Text Available James W Reed Morehouse School of Medicine, Atlanta, GA, USA Abstract: SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM. These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose

  7. Validation of 123I-6-deoxy-6-iodo-D-glucose (6-DIC) as tracer for the in-vivo glucose transport

    International Nuclear Information System (INIS)

    Perret, P.; Ghezzi, C.; Mathieu, J.P.; Morin, C.; Vidal, M.; Comet, M.; Fagret, D.

    1997-01-01

    The evaluation of the glucose transport is very important clinically because alterations of this transport were described in numerous pathologies, in neurology, oncology and endocrinology. A new analog of the 123 I-labelled has been synthesized: 123 I-6-deoxy-6-iodo-D-glucose (6-DIG). Its in-vitro biological behaviour is similar to that of 3-O-methyl-D-glucose (3-OMG), the reference tracer of glucose transport. The aim of the study was to determine if it is possible to make evident by 6-DIG a variations of in-vivo glucose transport. The studies were effected on a model of homozygote mice (db/db), genetically diabetic (NIDDM), presenting a severe insulin-resistance, characterized by deficient glucose transport in response to insulin. The studies of 6-DIG biodistribution (5 nmol/mouse) with (1.5 UI/Kg) or without exogenous insulin, were conducted in diabetic mice (db/db) and in non-diabetic (db/+) control mice. The results show that the capture of 6-DIG, as well as that of glucose, increases (by 30%) in response to insulin in most of insulin-sensitive tissues in control mice. In the insulin-resistant and hyperglycemic db/db mouse, the capture of 6-DIG is not modified, no matter whether the exogenous insulin is present. In conclusion, the 6-DIG is able to make evident a lack of glucose transport in heart, diaphragm and skeletal muscle in diabetic mouse and a physiological variation of this transport in response to insulin, in the control mouse. This result should be stressed because for the first time it is possible to evidence in-vivo variations into glucose transport with a iodated molecule

  8. Herbivory-induced glucose transporter gene expression in the brown planthopper, Nilaparvata lugens.

    Science.gov (United States)

    Kikuta, Shingo; Nakamura, Yuki; Hattori, Makoto; Sato, Ryoichi; Kikawada, Takahiro; Noda, Hiroaki

    2015-09-01

    Nilaparvata lugens, the brown planthopper (BPH) feeds on rice phloem sap, containing high amounts of sucrose as a carbon source. Nutrients such as sugars in the digestive tract are incorporated into the body cavity via transporters with substrate selectivity. Eighteen sugar transporter genes of BPH (Nlst) were reported and three transporters have been functionally characterized. However, individual characteristics of NlST members associated with sugar transport remain poorly understood. Comparative gene expression analyses using oligo-microarray and quantitative RT-PCR revealed that the sugar transporter gene Nlst16 was markedly up-regulated during BPH feeding. Expression of Nlst16 was induced 2 h after BPH feeding on rice plants. Nlst16, mainly expressed in the midgut, appears to be involved in carbohydrate incorporation from the gut cavity into the hemolymph. Nlst1 (NlHT1), the most highly expressed sugar transporter gene in the midgut was not up-regulated during BPH feeding. The biochemical function of NlST16 was shown as facilitative glucose transport along gradients. Glucose uptake activity by NlST16 was higher than that of NlST1 in the Xenopus oocyte expression system. At least two NlST members are responsible for glucose uptake in the BPH midgut, suggesting that the midgut of BPH is equipped with various types of transporters having diversified manner for sugar uptake. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Evolutionary ancestry and novel functions of the mammalian glucose transporter (GLUT) family.

    Science.gov (United States)

    Wilson-O'Brien, Amy L; Patron, Nicola; Rogers, Suzanne

    2010-05-21

    In general, sugar porters function by proton-coupled symport or facilitative transport modes. Symporters, coupled to electrochemical energy, transport nutrients against a substrate gradient. Facilitative carriers transport sugars along a concentration gradient, thus transport is dependent upon extracellular nutrient levels. Across bacteria, fungi, unicellular non-vertebrates and plants, proton-coupled hexose symport is a crucial process supplying energy under conditions of nutrient flux. In mammals it has been assumed that evolution of whole body regulatory mechanisms would eliminate this need. To determine whether any isoforms bearing this function might be conserved in mammals, we investigated the relationship between the transporters of animals and the proton-coupled hexose symporters found in other species. We took a comparative genomic approach and have performed the first comprehensive and statistically supported phylogenetic analysis of all mammalian glucose transporter (GLUT) isoforms. Our data reveals the mammalian GLUT proteins segregate into five distinct classes. This evolutionary ancestry gives insight to structure, function and transport mechanisms within the groups. Combined with biological assays, we present novel evidence that, in response to changing nutrient availability and environmental pH, proton-coupled, active glucose symport function is maintained in mammalian cells. The analyses show the ancestry, evolutionary conservation and biological importance of the GLUT classes. These findings significantly extend our understanding of the evolution of mammalian glucose transport systems. They also reveal that mammals may have conserved an adaptive response to nutrient demand that would have important physiological implications to cell survival and growth.

  10. Aspergillus niger membrane-associated proteome analysis for the identification of glucose transporters.

    Science.gov (United States)

    Sloothaak, J; Odoni, D I; de Graaff, L H; Martins Dos Santos, V A P; Schaap, P J; Tamayo-Ramos, J A

    2015-01-01

    The development of biological processes that replace the existing petrochemical-based industry is one of the biggest challenges in biotechnology. Aspergillus niger is one of the main industrial producers of lignocellulolytic enzymes, which are used in the conversion of lignocellulosic feedstocks into fermentable sugars. Both the hydrolytic enzymes responsible for lignocellulose depolymerisation and the molecular mechanisms controlling their expression have been well described, but little is known about the transport systems for sugar uptake in A. niger. Understanding the transportome of A. niger is essential to achieve further improvements at strain and process design level. Therefore, this study aims to identify and classify A. niger sugar transporters, using newly developed tools for in silico and in vivo analysis of its membrane-associated proteome. In the present research work, a hidden Markov model (HMM), that shows a good performance in the identification and segmentation of functionally validated glucose transporters, was constructed. The model (HMMgluT) was used to analyse the A. niger membrane-associated proteome response to high and low glucose concentrations at a low pH. By combining the abundance patterns of the proteins found in the A. niger plasmalemma proteome with their HMMgluT scores, two new putative high-affinity glucose transporters, denoted MstG and MstH, were identified. MstG and MstH were functionally validated and biochemically characterised by heterologous expression in a S. cerevisiae glucose transport null mutant. They were shown to be a high-affinity glucose transporter (K m = 0.5 ± 0.04 mM) and a very high-affinity glucose transporter (K m = 0.06 ± 0.005 mM), respectively. This study, focusing for the first time on the membrane-associated proteome of the industrially relevant organism A. niger, shows the global response of the transportome to the availability of different glucose concentrations. Analysis of the A. niger

  11. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

    Directory of Open Access Journals (Sweden)

    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  12. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

    Science.gov (United States)

    Besson, Marie Thérèse; Alegría, Karin; Garrido-Gerter, Pamela; Barros, Luis Felipe; Liévens, Jean-Charles

    2015-01-01

    Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93). We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP) impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK) which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to mediate the hGluT3

  13. Enhanced neuronal glucose transporter expression reveals metabolic choice in a HD Drosophila model.

    Directory of Open Access Journals (Sweden)

    Marie Thérèse Besson

    Full Text Available Huntington's disease is a neurodegenerative disorder caused by toxic insertions of polyglutamine residues in the Huntingtin protein and characterized by progressive deterioration of cognitive and motor functions. Altered brain glucose metabolism has long been suggested and a possible link has been proposed in HD. However, the precise function of glucose transporters was not yet determined. Here, we report the effects of the specifically-neuronal human glucose transporter expression in neurons of a Drosophila model carrying the exon 1 of the human huntingtin gene with 93 glutamine repeats (HQ93. We demonstrated that overexpression of the human glucose transporter in neurons ameliorated significantly the status of HD flies by increasing their lifespan, reducing their locomotor deficits and rescuing eye neurodegeneration. Then, we investigated whether increasing the major pathways of glucose catabolism, glycolysis and pentose-phosphate pathway (PPP impacts HD. To mimic increased glycolytic flux, we overexpressed phosphofructokinase (PFK which catalyzes an irreversible step in glycolysis. Overexpression of PFK did not affect HQ93 fly survival, but protected from photoreceptor loss. Overexpression of glucose-6-phosphate dehydrogenase (G6PD, the key enzyme of the PPP, extended significantly the lifespan of HD flies and rescued eye neurodegeneration. Since G6PD is able to synthesize NADPH involved in cell survival by maintenance of the redox state, we showed that tolerance to experimental oxidative stress was enhanced in flies co-expressing HQ93 and G6PD. Additionally overexpressions of hGluT3, G6PD or PFK were able to circumvent mitochondrial deficits induced by specific silencing of genes necessary for mitochondrial homeostasis. Our study confirms the involvement of bioenergetic deficits in HD course; they can be rescued by specific expression of a glucose transporter in neurons. Finally, the PPP and, to a lesser extent, the glycolysis seem to

  14. Caveolin-1 and glucose transporter 4 involved in the regulation of glucose-deprivation stress in PC12 cells.

    Science.gov (United States)

    Zhang, Qi-Qi; Huang, Liang; Han, Chao; Guan, Xin; Wang, Ya-Jun; Liu, Jing; Wan, Jing-Hua; Zou, Wei

    2015-08-25

    Recent evidence suggests that caveolin-1 (Cav-1), the major protein constituent of caveolae, plays a prominent role in neuronal nutritional availability with cellular fate regulation besides in several cellular processes such as cholesterol homeostasis, regulation of signal transduction, integrin signaling and cell growth. Here, we aimed to investigate the function of Cav-1 and glucose transporter 4 (GLUT4) upon glucose deprivation (GD) in PC12 cells. The results demonstrated firstly that both Cav-1 and GLUT4 were up-regulated by glucose withdrawal in PC12 cells by using Western blot and laser confocal technology. Also, we found that the cell death rate, mitochondrial membrane potential (MMP) and intracellular free Ca(2+) concentration ([Ca(2+)]i) were also respectively changed followed the GD stress tested by CCK8 and flow cytometry. After knocking down of Cav-1 in the cells by siRNA, the level of [Ca(2+)]i was increased, and MMP was reduced further in GD-treated PC12 cells. Knockdown of Cav-1 or methylated-β-Cyclodextrin (M-β-CD) treatment inhibited the expression of GLUT4 protein upon GD. Additionally, we found that GLUT4 could translocate from cytoplasm to cell membrane upon GD. These findings might suggest a neuroprotective role for Cav-1, through coordination of GLUT4 in GD.

  15. Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Tang, Huilin; Cui, Wei; Li, Dandan; Wang, Tiansheng; Zhang, Jingjing; Zhai, Suodi; Song, Yiqing

    2017-01-01

    Given inconsistent trial results of sodium-glucose cotransporter 2 (SGLT2) inhibitors in addition to insulin therapy for treating type 2 diabetes mellitus (T2DM), a meta-analysis was performed to evaluate the efficacy and safety of this combination for T2DM by searching available randomized trials from PubMed, Embase, CENTRAL and ClinicalTrials.gov. Our meta-analysis included seven eligible placebo-controlled trials involving 4235 patients. Compared with placebo, SGLT2 inhibitor treatment was significantly associated with a mean reduction in HbA1c of -0.56%, fasting plasma glucose of -0.95 mmol/L, body weight of -2.63 kg and insulin dose of -8.79 IU, but an increased risk of drug-related adverse events by 36%, urinary tract infections by 29% and genital infections by 357%. No significant increase was observed in risk of overall adverse events [risk ratio (RR), 1.00], serious adverse events (RR, 0.90), adverse events leading to discontinuation (RR, 1.16), hypoglycaemia events (RR, 1.07) and severe hypoglycaemia events (RR, 1.24). No diabetic ketoacidosis events were reported. Further studies are needed to establish optimal combination type and dose. © 2016 John Wiley & Sons Ltd.

  16. SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

    Directory of Open Access Journals (Sweden)

    Seufert J

    2015-11-01

    Full Text Available Jochen SeufertDepartment of Endocrinology and Diabetology, Clinic for Internal Medicine II, Freiburg University Hospital, Freiburg, GermanyAbstract: Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2 inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand

  17. Reduced Expression of the Liver/Beta-Cell Glucose Transporter Isoform in Glucose-Insensitive Pancreatic Beta Cells of Diabetic Rats

    Science.gov (United States)

    Thorens, Bernard; Weir, Gordon C.; Leahy, John L.; Lodish, Harvey F.; Bonner-Weir, Susan

    1990-09-01

    Rats injected with a single dose of streptozocin at 2 days of age develop non-insulin-dependent diabetes 6 weeks later. The pancreatic beta islet cells of these diabetic rats display a loss of glucose-induced insulin secretion while maintaining sensitivity to other secretagogues such as arginine. We analyzed the level of expression of the liver/beta-cell glucose transporter isoform in diabetic islets by immunofluorescence staining of pancreas sections and by Western blotting of islet lysates. Islets from diabetic animals have a reduced expression of this beta-cell-specific glucose transporter isoform and the extent of reduction is correlated with the severity of hyperglycemia. In contrast, expression of this transporter isoform in liver is minimally modified by the diabetes. Thus a decreased expression of the liver/beta-cell glucose transporter isoform in beta cells is associated with the impaired glucose sensing characteristic of diabetic islets; our data suggest that this glucose transporter may be part of the beta-cell glucose sensor.

  18. Crystal structure of a bacterial homologue of glucose transporters GLUT1-4.

    Science.gov (United States)

    Sun, Linfeng; Zeng, Xin; Yan, Chuangye; Sun, Xiuyun; Gong, Xinqi; Rao, Yu; Yan, Nieng

    2012-10-18

    Glucose transporters are essential for metabolism of glucose in cells of diverse organisms from microbes to humans, exemplified by the disease-related human proteins GLUT1, 2, 3 and 4. Despite rigorous efforts, the structural information for GLUT1-4 or their homologues remains largely unknown. Here we report three related crystal structures of XylE, an Escherichia coli homologue of GLUT1-4, in complex with d-xylose, d-glucose and 6-bromo-6-deoxy-D-glucose, at resolutions of 2.8, 2.9 and 2.6 Å, respectively. The structure consists of a typical major facilitator superfamily fold of 12 transmembrane segments and a unique intracellular four-helix domain. XylE was captured in an outward-facing, partly occluded conformation. Most of the important amino acids responsible for recognition of D-xylose or d-glucose are invariant in GLUT1-4, suggesting functional and mechanistic conservations. Structure-based modelling of GLUT1-4 allows mapping and interpretation of disease-related mutations. The structural and biochemical information reported here constitutes an important framework for mechanistic understanding of glucose transporters and sugar porters in general.

  19. Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices.

    Science.gov (United States)

    Jakoby, Patrick; Schmidt, Elke; Ruminot, Iván; Gutiérrez, Robin; Barros, L Felipe; Deitmer, Joachim W

    2014-01-01

    Glucose is the most important energy substrate for the brain, and its cellular distribution is a subject of great current interest. We have employed fluorescent glucose probes, the 2-deoxy-D-glucose derivates 6- and 2-([N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose) (2-NBDG), to measure transport and metabolism of glucose in acute slices of mouse hippocampus and cerebellum. In the hippocampus, 6-NBDG, which is not metabolized and hence indicates glucose transport, was taken up faster in astrocyte-rich layers (Stratum radiatum [S.r.], Stratum oriens [S.o.]) than in pyramidal cells. Metabolizable 2-NBDG showed larger signals in S.r. and S.o. than in Stratum pyramidale, suggesting faster glucose utilization rate in the astrocyte versus the neuronal compartment. Similarly, we found higher uptake and temperature-sensitive metabolism of 2-NBDG in Bergmann glia when compared with adjacent Purkinje neurons of cerebellar slices. A comparison between 6-NBDG transport and glucose transport in cultured cells using a fluorescence resonance energy transfer nanosensor showed that relative to glucose, 6-NBDG is transported better by neurons than by astrocytes. These results indicate that the preferential transport and metabolism of glucose by glial cells versus neurons proposed for the hippocampus and cerebellum by ourselves (in vitro) and for the barrel cortex by Chuquet et al. (in vivo) is more pronounced than anticipated.

  20. Glucose uptake and transport in contracting, perfused rat muscle with different pre-contraction glycogen concentrations

    DEFF Research Database (Denmark)

    Hespel, P; Richter, Erik

    1990-01-01

    1. Glucose uptake and transport, muscle glycogen, free glucose and glucose-6-phosphate concentrations were studied in perfused resting and contracting rat skeletal muscle with different pre-contraction glycogen concentrations. Rats were pre-conditioned by a combination of swimming exercise and diet......, resulting in either low (glycogen-depleted rats), normal (control rats) or high (supercompensated rats) muscle glycogen concentrations at the time their hindlimbs were perfused. 2. Compared with control rats, pre-contraction muscle glycogen concentration was approximately 40% lower in glycogen-depleted rats......, whereas it was 40% higher in supercompensated rats. Muscle glycogen break-down correlated positively (r = 0.76; P less than 0.001) with pre-contraction muscle glycogen concentration. 3. Glucose uptake during contractions was approximately 50% higher in glycogen-depleted hindquarters than in control...

  1. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Science.gov (United States)

    Reed, James W

    2016-01-01

    SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP) lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin) on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose control. PMID:27822054

  2. Adipose tissue insulin receptor and glucose transporter 4 expression, and blood glucose and insulin responses during glucose tolerance tests in transition Holstein cows with different body condition.

    Science.gov (United States)

    Jaakson, H; Karis, P; Ling, K; Ilves-Luht, A; Samarütel, J; Henno, M; Jõudu, I; Waldmann, A; Reimann, E; Pärn, P; Bruckmaier, R M; Gross, J J; Kaart, T; Kass, M; Ots, M

    2018-01-01

    Glucose uptake in tissues is mediated by insulin receptor (INSR) and glucose transporter 4 (GLUT4). The aim of this study was to examine the effect of body condition during the dry period on adipose tissue mRNA and protein expression of INSR and GLUT4, and on the dynamics of glucose and insulin following the i.v. glucose tolerance test in Holstein cows 21 d before (d -21) and after (d 21) calving. Cows were grouped as body condition score (BCS) ≤3.0 (thin, T; n = 14), BCS = 3.25 to 3.5 (optimal, O; n = 14), and BCS ≥3.75 (overconditioned, OC; n = 14). Blood was analyzed for glucose, insulin, fatty acids, and β-hydroxybutyrate concentrations. Adipose tissue was analyzed for INSR and GLUT4 mRNA and protein concentrations. During the glucose tolerance test 0.15 g/kg of body weight glucose was infused; blood was collected at -5, 5, 10, 20, 30, 40, 50, and 60 min, and analyzed for glucose and insulin. On d -21 the area under the curve (AUC) of glucose was smallest in group T (1,512 ± 33.9 mg/dL × min) and largest in group OC (1,783 ± 33.9 mg/dL × min), and different between all groups. Basal insulin on d -21 was lowest in group T (13.9 ± 2.32 µU/mL), which was different from group OC (24.9 ± 2.32 µU/mL. On d -21 the smallest AUC 5-60 of insulin in group T (5,308 ± 1,214 µU/mL × min) differed from the largest AUC in group OC (10,867 ± 1,215 µU/mL × min). Time to reach basal concentration of insulin in group OC (113 ± 14.1 min) was longer compared with group T (45 ± 14.1). The INSR mRNA abundance on d 21 was higher compared with d -21 in groups T (d -21: 3.3 ± 0.44; d 21: 5.9 ± 0.44) and O (d -21: 3.7 ± 0.45; d 21: 4.7 ± 0.45). The extent of INSR protein expression on d -21 was highest in group T (7.3 ± 0.74 ng/mL), differing from group O (4.6 ± 0.73 ng/mL), which had the lowest expression. The amount of GLUT4 protein on d -21 was lowest in group OC (1.2 ± 0.14 ng/mL), different from group O (1.8 ± 0.14 ng/mL), which had the highest amount

  3. Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders.

    Science.gov (United States)

    Zhao, Y; Fung, C; Shin, D; Shin, B-C; Thamotharan, S; Sankar, R; Ehninger, D; Silva, A; Devaskar, S U

    2010-03-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristics of autism spectrum disorders. This clinical presentation occurred despite metabolic adaptations consisting of an increase in microvascular/glial GLUT1, neuronal GLUT8 and monocarboxylate transporter isoform 2 concentrations, with minimal to no change in brain glucose uptake but an increase in lactate uptake. Neuron-specific glucose deficiency has a negative impact on neurodevelopment interfering with functional competence. This is the first description of GLUT3 deficiency that forms a possible novel genetic mechanism for pervasive developmental disorders, such as the neuropsychiatric autism spectrum disorders, requiring further investigation in humans.

  4. Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I.

    Directory of Open Access Journals (Sweden)

    Marc U Baumann

    Full Text Available Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

  5. Effects of insulin and epinephrine on Na+-K+ and glucose transport in soleus muscle

    International Nuclear Information System (INIS)

    Clausen, T.; Flatman, J.A.

    1987-01-01

    To identify possible cause-effect relationships between changes in active Na + -K + transport, resting membrane potential, and glucose transport, the effects of insulin and epinephrine were compared in rat soleus muscle. Epinephrine, which produced twice as large a hyperpolarization as insulin, induced only a modest increase in 14 C-labeled sugar transport. Ouabain, at a concentration (10 -3 M) sufficient to block active Na + -K + transport and the hyperpolarization induced by the two hormones, did not interfere with sugar transport stimulation. After Na + loading in K + -free buffer, the return to K + -containing standard buffer caused marked stimulation of active 22 Na + - 42 K + transport, twice the hyperpolarization produced by insulin but no change in sugar transport. The insulin-induced activation of the 22 Na + - 42 K + pump leads to decreased intracellular 22 Na + concentration and hyperpolarization, but none of these events can account for the concomitant activation of the glucose transport system. The stimulating effect of insulin on active Na + -K + transport was not suppressed by amiloride, indicating that in intact skeletal muscle it is not elicited by a primary increase in Na + influx via the Na + /H + -exchange system

  6. Neuronal Glucose Transporter Isoform 3 Deficient Mice Demonstrate Features of Autism Spectrum Disorders

    OpenAIRE

    Zhao, Yuanzi; Fung, Camille; Shin, Don; Shin, Bo-Chul; Thamotharan, Shanthie; Sankar, Raman; Ehninger, Dan; Silva, Alcino; Devaskar, Sherin U.

    2009-01-01

    Neuronal glucose transporter (GLUT) isoform 3 deficiency in null heterozygous mice led to abnormal spatial learning and working memory but normal acquisition and retrieval during contextual conditioning, abnormal cognitive flexibility with intact gross motor ability, electroencephalographic seizures, perturbed social behavior with reduced vocalization and stereotypies at low frequency. This phenotypic expression is unique as it combines the neurobehavioral with the epileptiform characteristic...

  7. Fast evolutionary rates associated with functional loss in class I glucose transporters of Schistosoma mansoni

    Czech Academy of Sciences Publication Activity Database

    Cabezas-Cruz, A.; Valdés, James J.; Lancelot, J.; Pierce, R.J.

    2015-01-01

    Roč. 16, NOV 19 2015 (2015), s. 980 ISSN 1471-2164 R&D Projects: GA MŠk(CZ) EE2.3.30.0032 Institutional support: RVO:60077344 Keywords : Schistosoma mansoni * glucose transporters * transcriptional regulation * phylogen * biophysics Subject RIV: EI - Biotechnology ; Bionics Impact factor: 3.867, year: 2015

  8. Transport of the Glucosamine-Derived Browning Product Fructosazine (Polyhydroxyalkylpyrazine) Across the Human Intestinal Caco-2 Cell Monolayer: Role of the Hexose Transporters.

    Science.gov (United States)

    Bhattacherjee, Abhishek; Hrynets, Yuliya; Betti, Mirko

    2017-06-14

    The transport mechanism of fructosazine, a glucosamine self-condensation product, was investigated using a Caco-2 cell model. Fructosazine transport was assessed by measuring the bidirectional permeability coefficient across Caco-2 cells. The mechanism of transport was evaluated using phlorizin, an inhibitor of sodium-dependent glucose cotransporters (SGLT) 1 and 2, phloretin and quercetin, inhibitors of glucose transporters (GLUT) 1 and 2, transcytosis inhibitor wortmannin, and gap junction disruptor cytochalasin D. The role of hexose transporters was further studied using downregulated or overexpressed cell lines. The apparent permeability (P a,b ) of fructosazine was 1.30 ± 0.02 × 10 -6 cm/s. No significant (p > 0.05) effect was observed in fructosazine transport by adding wortmannin and cytochalasin D. The presence of phlorizin, phloretin, and quercetin decreased fructosazine transport. The downregulated GLUT cells line was unable to transport fructosazine. In human intestinal epithelial Caco-2 cells, GLUT1 or GLUT2 and SGLT are mainly responsible for fructosazine transport.

  9. The Structure of a Sugar Transporter of the Glucose EIIC Superfamily Provides Insight into the Elevator Mechanism of Membrane Transport.

    Science.gov (United States)

    McCoy, Jason G; Ren, Zhenning; Stanevich, Vitali; Lee, Jumin; Mitra, Sharmistha; Levin, Elena J; Poget, Sebastien; Quick, Matthias; Im, Wonpil; Zhou, Ming

    2016-06-07

    The phosphoenolpyruvate:carbohydrate phosphotransferase systems are found in bacteria, where they play central roles in sugar uptake and regulation of cellular uptake processes. Little is known about how the membrane-embedded components (EIICs) selectively mediate the passage of carbohydrates across the membrane. Here we report the functional characterization and 2.55-Å resolution structure of a maltose transporter, bcMalT, belonging to the glucose superfamily of EIIC transporters. bcMalT crystallized in an outward-facing occluded conformation, in contrast to the structure of another glucose superfamily EIIC, bcChbC, which crystallized in an inward-facing occluded conformation. The structures differ in the position of a structurally conserved substrate-binding domain that is suggested to play a central role in sugar transport. In addition, molecular dynamics simulations suggest a potential pathway for substrate entry from the periplasm into the bcMalT substrate-binding site. These results provide a mechanistic framework for understanding substrate recognition and translocation for the glucose superfamily EIIC transporters. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. IGF-II receptors and IGF-II-stimulated glucose transport in human fat cells

    International Nuclear Information System (INIS)

    Sinha, M.K.; Buchanan, C.; Raineri-Maldonado, C.; Khazanie, P.; Atkinson, S.; DiMarchi, R.; Caro, J.F.

    1990-01-01

    Insulin-like growth factor II (IGF-II) receptors have been described in rat but not in human adipocytes. In both species, IGF-II has been reported to stimulate glucose transport by interacting with the insulin receptor. In this study, we have unequivocally demonstrated the presence of IGF-II receptors in human adipocytes. 125I-labeled IGF-II specifically binds to intact adipocytes, membranes, and lectin-purified detergent solubilized extracts. Through the use of 0.5 mM disuccinimidyl suberate, 125I-IGF-II is cross-linked to a 260-kDa protein that is identified as the IGF-II receptor by displacement experiments with unlabeled IGF-II, IGF-I, and insulin and either by immunoprecipitation or by Western blot analysis with mannose 6-phosphate receptor antibodies. The concentrations of IGF-II required for half-maximal and maximal stimulation of glucose transport in human adipocytes are 35 and 100 times more than that of insulin. The possibility of IGF-II stimulating glucose transport by interacting predominantly with the insulin receptor is suggested by the following: (1) the concentration of IGF-II that inhibits half of insulin binding is only 20 times more than that of insulin; (2) the lack of an additive effect of IGF-II and insulin for maximal stimulation of glucose transport; (3) the ability of monoclonal insulin receptor antibodies to decrease glucose transport stimulated by submaximal concentrations of both IGF-II and insulin; and (4) the ability of IGF-II to stimulate insulin receptor autophosphorylation albeit at a reduced potency when compared with insulin

  11. Renal glucose handling in diabetes and sodium glucose cotransporter 2 inhibition

    Directory of Open Access Journals (Sweden)

    Resham Raj Poudel

    2013-01-01

    Full Text Available The kidneys play a major role in glucose homeostasis through its utilization, gluconeogenesis, and reabsorption via sodium glucose cotransporters (SGLTs. The defective renal glucose handling from upregulation of SGLTs, mainly the SGLT2, plays a fundamental role in the pathogenesis of type 2 diabetes mellitus. Genetic mutations in a SGLT2 isoform that results in benign renal glycosuria, as well as clinical studies with SGLT2 inhibitors in type 2 diabetes support the potential of this approach. These studies indicate that inducing glycosuria by suppressing SGLT2 can reduce plasma glucose and A1c levels, as well as decrease weight, resulting in improved β-cell function and enhanced insulin sensitivity in liver and muscle. Because the mechanism of SGLT2 inhibition is independent of insulin secretion and sensitivity, these agents can be combined with other antidiabetic agents, including exogenous insulin. This class represents a novel therapeutic approach with potential for the treatment of both type 2 and type 1 diabetes.

  12. Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect.

    Science.gov (United States)

    Kalra, Sanjay; Jain, Arpit; Ved, Jignesh; Unnikrishnan, A G

    2016-01-01

    This review discusses two distinct, yet related, mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibition: Calorie restriction mimicry (CRM) and pro-ketogenic effect, which may explain their cardiovascular benefits. We term these adaptive CRM and pro-ketogenic effects of SGLT2 inhibition, the Robin Hood hypothesis. In English history, Robin Hood was a "good person," who stole from the rich and helped the poor. He supported redistribution of resources as he deemed fit for the common good. In a similar fashion, SGLT2 inhibition provides respite to the overloaded glucose metabolism while utilizing lipid stores for energy production.

  13. Sodium-glucose cotransporter 2 inhibition and health benefits: The Robin Hood effect

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2016-01-01

    Full Text Available This review discusses two distinct, yet related, mechanisms of sodium-glucose cotransporter 2 (SGLT2 inhibition: Calorie restriction mimicry (CRM and pro-ketogenic effect, which may explain their cardiovascular benefits. We term these adaptive CRM and pro-ketogenic effects of SGLT2 inhibition, the Robin Hood hypothesis. In English history, Robin Hood was a "good person," who stole from the rich and helped the poor. He supported redistribution of resources as he deemed fit for the common good. In a similar fashion, SGLT2 inhibition provides respite to the overloaded glucose metabolism while utilizing lipid stores for energy production.

  14. The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Sugiyama, Seigo; Jinnouchi, Hideaki; Kurinami, Noboru; Hieshima, Kunio; Yoshida, Akira; Jinnouchi, Katsunori; Nishimura, Hiroyuki; Suzuki, Tomoko; Miyamoto, Fumio; Kajiwara, Keizo; Jinnouchi, Tomio

    2018-03-30

    Objective Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled (hemoglobin A1c [HbA1c] >7.0%) T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

  15. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

    Science.gov (United States)

    Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

    2018-02-15

    The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways.

    Science.gov (United States)

    Ducroc, Robert; Voisin, Thierry; El Firar, Aadil; Laburthe, Marc

    2007-10-01

    Orexins are neuropeptides involved in energy homeostasis. We investigated the effect of orexin A (OxA) and orexin B (OxB) on intestinal glucose transport in the rat. Injection of orexins led to a decrease in the blood glucose level in oral glucose tolerance tests (OGTTs). Effects of orexins on glucose entry were analyzed in Ussing chambers using the Na(+)-dependent increase in short-circuit current (Isc) to quantify jejunal glucose transport. The rapid and marked increase in Isc induced by luminal glucose was inhibited by 10 nmol/l OxA or OxB (53 and 59%, respectively). Response curves to OxA and OxB were not significantly different with half-maximal inhibitory concentrations at 0.9 and 0.4 nmol/l, respectively. On the one hand, OxA-induced inhibition of Isc was reduced by the neuronal blocker tetrodotoxin (TTX) and by a cholecystokinin (CCK) 2R antagonist, indicating involvement of neuronal and endocrine CCK-releasing cells. The OX(1)R antagonist SB334867 had no effect on OxA-induced inhibition, which is likely to occur via a neuronal and/or endocrine OX(2)R. On the other hand, SB334867 induced a significant right shift of the concentration-effect curve for OxB. This OxB-preferring OX(1)R pathway was not sensitive to TTX or to CCKR antagonists, suggesting that OxB may act directly on enterocytic OX(1)R. These distinct effects of OxA and OxB are consistent with the expression of OX(1)R and OX(2)R mRNA in the epithelial and nonepithelial tissues, respectively. Our data delineate a new function for orexins as inhibitors of intestinal glucose absorption and provide a new basis for orexin-induced short-term control of energy homeostasis.

  17. Glucose transporters GLUT4 and GLUT8 are upregulated after facial nerve axotomy in adult mice.

    Science.gov (United States)

    Gómez, Olga; Ballester-Lurbe, Begoña; Mesonero, José E; Terrado, José

    2011-10-01

    Peripheral nerve axotomy in adult mice elicits a complex response that includes increased glucose uptake in regenerating nerve cells. This work analyses the expression of the neuronal glucose transporters GLUT3, GLUT4 and GLUT8 in the facial nucleus of adult mice during the first days after facial nerve axotomy. Our results show that whereas GLUT3 levels do not vary, GLUT4 and GLUT8 immunoreactivity increases in the cell body of the injured motoneurons after the lesion. A sharp increase in GLUT4 immunoreactivity was detected 3 days after the nerve injury and levels remained high on Day 8, but to a lesser extent. GLUT8 also increased the levels but later than GLUT4, as they only rose on Day 8 post-lesion. These results indicate that glucose transport is activated in regenerating motoneurons and that GLUT4 plays a main role in this function. These results also suggest that metabolic defects involving impairment of glucose transporters may be principal components of the neurotoxic mechanisms leading to motoneuron death. © 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.

  18. Insights from the Fungus Fusarium oxysporum Point to High Affinity Glucose Transporters as Targets for Enhancing Ethanol Production from Lignocellulose

    Science.gov (United States)

    Ali, Shahin S.; Nugent, Brian; Mullins, Ewen; Doohan, Fiona M.

    2013-01-01

    Ethanol is the most-widely used biofuel in the world today. Lignocellulosic plant biomass derived from agricultural residue can be converted to ethanol via microbial bioprocessing. Fungi such as Fusarium oxysporum can simultaneously saccharify straw to sugars and ferment sugars to ethanol. But there are many bottlenecks that need to be overcome to increase the efficacy of microbial production of ethanol from straw, not least enhancement of the rate of fermentation of both hexose and pentose sugars. This research tested the hypothesis that the rate of sugar uptake by F. oxysporum would enhance the ethanol yields from lignocellulosic straw and that high affinity glucose transporters can enhance ethanol yields from this substrate. We characterized a novel hexose transporter (Hxt) from this fungus. The F. oxysporum Hxt represents a novel transporter with homology to yeast glucose signaling/transporter proteins Rgt2 and Snf3, but it lacks their C-terminal domain which is necessary for glucose signalling. Its expression level decreased with increasing glucose concentration in the medium and in a glucose uptake study the Km(glucose) was 0.9 mM, which indicated that the protein is a high affinity glucose transporter. Post-translational gene silencing or over expression of the Hxt in F. oxysporum directly affected the glucose and xylose transport capacity and ethanol yielded by F. oxysporum from straw, glucose and xylose. Thus we conclude that this Hxt has the capacity to transport both C5 and C6 sugars and to enhance ethanol yields from lignocellulosic material. This study has confirmed that high affinity glucose transporters are ideal candidates for improving ethanol yields from lignocellulose because their activity and level of expression is high in low glucose concentrations, which is very common during the process of consolidated processing. PMID:23382943

  19. Insights from the fungus Fusarium oxysporum point to high affinity glucose transporters as targets for enhancing ethanol production from lignocellulose.

    Directory of Open Access Journals (Sweden)

    Shahin S Ali

    Full Text Available Ethanol is the most-widely used biofuel in the world today. Lignocellulosic plant biomass derived from agricultural residue can be converted to ethanol via microbial bioprocessing. Fungi such as Fusarium oxysporum can simultaneously saccharify straw to sugars and ferment sugars to ethanol. But there are many bottlenecks that need to be overcome to increase the efficacy of microbial production of ethanol from straw, not least enhancement of the rate of fermentation of both hexose and pentose sugars. This research tested the hypothesis that the rate of sugar uptake by F. oxysporum would enhance the ethanol yields from lignocellulosic straw and that high affinity glucose transporters can enhance ethanol yields from this substrate. We characterized a novel hexose transporter (Hxt from this fungus. The F. oxysporum Hxt represents a novel transporter with homology to yeast glucose signaling/transporter proteins Rgt2 and Snf3, but it lacks their C-terminal domain which is necessary for glucose signalling. Its expression level decreased with increasing glucose concentration in the medium and in a glucose uptake study the Km((glucose was 0.9 mM, which indicated that the protein is a high affinity glucose transporter. Post-translational gene silencing or over expression of the Hxt in F. oxysporum directly affected the glucose and xylose transport capacity and ethanol yielded by F. oxysporum from straw, glucose and xylose. Thus we conclude that this Hxt has the capacity to transport both C5 and C6 sugars and to enhance ethanol yields from lignocellulosic material. This study has confirmed that high affinity glucose transporters are ideal candidates for improving ethanol yields from lignocellulose because their activity and level of expression is high in low glucose concentrations, which is very common during the process of consolidated processing.

  20. Herpes simplex virus vectors overexpressing the glucose transporter gene protect against seizure-induced neuron loss.

    OpenAIRE

    Lawrence, M S; Ho, D Y; Dash, R; Sapolsky, R M

    1995-01-01

    We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypo...

  1. Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

    Energy Technology Data Exchange (ETDEWEB)

    Tomioka, Shigemasa, E-mail: tomioka@dent.tokushima-u.ac.jp [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Kaneko, Miyuki [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Satomura, Kazuhito [First Department of Oral and Maxillofacial Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Mikyu, Tomiko; Nakajo, Nobuyoshi [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan)

    2009-10-09

    We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2-{sup 3}H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 {mu}M) significantly increased V{sub max} but not K{sub m} of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

  2. Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

    International Nuclear Information System (INIS)

    Tomioka, Shigemasa; Kaneko, Miyuki; Satomura, Kazuhito; Mikyu, Tomiko; Nakajo, Nobuyoshi

    2009-01-01

    We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2- 3 H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 μM) significantly increased V max but not K m of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

  3. Evolutionary ancestry and novel functions of the mammalian glucose transporter (GLUT family

    Directory of Open Access Journals (Sweden)

    Patron Nicola

    2010-05-01

    Full Text Available Abstract Background In general, sugar porters function by proton-coupled symport or facilitative transport modes. Symporters, coupled to electrochemical energy, transport nutrients against a substrate gradient. Facilitative carriers transport sugars along a concentration gradient, thus transport is dependent upon extracellular nutrient levels. Across bacteria, fungi, unicellular non-vertebrates and plants, proton-coupled hexose symport is a crucial process supplying energy under conditions of nutrient flux. In mammals it has been assumed that evolution of whole body regulatory mechanisms would eliminate this need. To determine whether any isoforms bearing this function might be conserved in mammals, we investigated the relationship between the transporters of animals and the proton-coupled hexose symporters found in other species. Results We took a comparative genomic approach and have performed the first comprehensive and statistically supported phylogenetic analysis of all mammalian glucose transporter (GLUT isoforms. Our data reveals the mammalian GLUT proteins segregate into five distinct classes. This evolutionary ancestry gives insight to structure, function and transport mechanisms within the groups. Combined with biological assays, we present novel evidence that, in response to changing nutrient availability and environmental pH, proton-coupled, active glucose symport function is maintained in mammalian cells. Conclusions The analyses show the ancestry, evolutionary conservation and biological importance of the GLUT classes. These findings significantly extend our understanding of the evolution of mammalian glucose transport systems. They also reveal that mammals may have conserved an adaptive response to nutrient demand that would have important physiological implications to cell survival and growth.

  4. A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes.

    Science.gov (United States)

    Cha, Seon-Ah; Park, Yong-Moon; Yun, Jae-Seung; Lim, Tae-Seok; Song, Ki-Ho; Yoo, Ki-Dong; Ahn, Yu-Bae; Ko, Seung-Hyun

    2017-04-13

    Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes. From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA). A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, -0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, -14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, -5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor. The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study. This study was conducted by retrospective medical record review.

  5. Lack of SLC2A1 (glucose transporter 1) mutations in 30 Italian patients with alternating hemiplegia of childhood.

    Science.gov (United States)

    De Grandis, Elisa; Stagnaro, Michela; Biancheri, Roberta; Giannotta, Melania; Gobbi, Giuseppe; Traverso, Monica; Veneselli, Edvige; Zara, Federico

    2013-07-01

    Alternating hemiplegia of childhood is a rare, predominantly sporadic disorder. Diagnosis is clinical, and little is known about genetics. Glucose transporter 1 deficiency syndrome shares with alternating hemiplegia of childhood paroxysmal and nonparoxysmal symptoms. The aim of the study was to investigate glucose transporter 1 mutations in 30 Italian patients. Genetic material was analyzed by DNA amplification and glucose transporter 1 region sequencing. Mutational analysis findings of the SLC2A1 gene were negative in all patients. The pattern of movement disorders was reviewed. Interictal dystonia and multiple paroxysmal events were typical of alternating hemiplegia of childhood. In conclusion, alternating hemiplegia of childhood is a heterogeneous clinical condition, and although glucose transporter 1 deficiency can represent an undiagnosed cause of this disorder, mutational analysis is not routinely recommended. Alternatively, a careful clinical analysis and the 3-O-methyl-D-glucose uptake test can allow prompt identification of a subgroup of patients with alternating hemiplegia of childhood treatable with a ketogenic diet.

  6. Drugs affecting the incretin system and renal glucose transport: do they meet the expectations of modern therapy of type 2 diabetes?

    Directory of Open Access Journals (Sweden)

    Anna Gumieniczek

    2016-05-01

    Full Text Available Agents introduced into therapy of type 2 diabetes in the last few years are still the subject of numerous clinical and experimental studies. Although many studies have been completed, we still do not know all aspects of these drugs’ action, especially the long-term effects of their use. Most questionable is their impact on the processes of cell proliferation, on the cardiovascular and immune systems, on lipids and uric acid metabolism. A summary of the most important observations on the use of three groups of new drugs – analogs of glucagon-like peptide 1 (GLP-1, inhibitors of dipeptidyl peptidase IV (DPPIV and inhibitors of sodium glucose cotransporters (SGLT1 and SGLT2 – has been made, based on a review of the literature over the past five years (2010-2014. The information included in the present review concerns the structure and activity relationship, therapeutic efficacy, side effects and the observed additional therapeutic effects, which can determine new standards in therapy of diabetes and also facilitate the development of better antidiabetic drugs.

  7. Expression of glucocorticoid receptor and glucose transporter-1 during placental development in the diabetic rat

    Directory of Open Access Journals (Sweden)

    Ramazan Demir

    2011-07-01

    Full Text Available In various tissues, glucocorticoids (GCs are known to downregulate glucose transport systems; however, their effects on glucose transporters (GLUTs in the placenta of a diabetic rat are unknown. Glucocorticoid hormone action within the cell is regulated by the glucocorticoid receptor (GR. Thus, this study was designed to investigate the relationship between GR and glucose transporter expression in the placenta of the diabetic rat. Our immunohistochemical results indicated that GR and glucose transporter protein 1 (GLUT 1 are expressed ubiquitously in the trophoblast and endothelial cells of the labyrinthine zone, where maternal fetal transport takes place in the rat placenta. Expression of GR in the junctional zone of the rat placenta was detected in giant cells, and in some spongiotrophoblast cells, but not in the glycogen cells. GLUT 1 was present, especially in glycogen cells during early pregnancy, and in the spongiotrophoblast cells of the junctional zone during late pregnancy. Amounts of GR and GLUT 1 protein were increased towards the end of gestation both in the control and the diabetic placenta. However, at days 17 and 19 of gestation, only the placental GR protein was significantly increased in the streptozotocin-induced diabetic rats compared to control rats. Diabetes led to a significant decrease in placental weight at gestation day 15. In contrast, at gestational days 17 and 21, the weights of the diabetic placenta were significantly increased as compared with the controls. Moreover, diabetes induced fetus intrauterine growth retardation at gestational days 13, 17 and 21. In conclusion, the localization pattern of GR and GLUT 1 proteins in the same cell types led us to believe that there might be a relationship between GR and GLUT 1 expressions at the cellular level. GLUT 1 does not play a pivotal role in diabetic pregnancies. However, placental growth abnormalities during diabetic pregnancy may be related to the amount of GR

  8. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects

    Directory of Open Access Journals (Sweden)

    Atsuo Tahara

    2016-03-01

    Full Text Available The sodium-glucose cotransporter (SGLT 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes.

  9. Insulin-sensitive phospholipid signaling systems and glucose transport. Update II.

    Science.gov (United States)

    Farese, R V

    2001-04-01

    Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidylcholine with subsequent increases in phosphatidic acid (PA) and diacylglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.

  10. Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

    Science.gov (United States)

    Akman, Cigdem I; Engelstad, Kristin; Hinton, Veronica J; Ullner, Paivi; Koenigsberger, Dorcas; Leary, Linda; Wang, Dong; De Vivo, Darryl C

    2010-01-01

    Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

  11. N-Methyl-D aspartate receptor-mediated effect on glucose transporter-3 levels of high glucose exposed-SH-SY5Y dopaminergic neurons.

    Science.gov (United States)

    Engin, Ayse Basak; Engin, Evren Doruk; Karakus, Resul; Aral, Arzu; Gulbahar, Ozlem; Engin, Atilla

    2017-11-01

    High glucose and insulin lead to neuronal insulin resistance. Glucose transport into the neurons is achieved by regulatory induction of surface glucose transporter-3 (GLUT3) instead of the insulin. N-methyl-D aspartate (NMDA) receptor activity increases GLUT3 expression. This study explored whether an endogenous NMDA receptor antagonist, kynurenic acid (KynA) affects the neuronal cell viability at high glucose concentrations. SH-SY5Y neuroblastoma cells were exposed to 150-250 mg/dL glucose and 40 μU/mL insulin. In KynA and N-nitro-l-arginine methyl ester (L-NAME) supplemented cultures, oxidative stress, mitochondrial metabolic activity (MTT), nitric oxide as nitrite+nitrate (NOx) and GLUT3 were determined at the end of 24 and 48-h incubation periods. Viable cells were counted by trypan blue dye. High glucose-exposed SH-SY5Y cells showed two-times more GLUT3 expression at second 24-h period. While GLUT3-stimulated glucose transport and oxidative stress was increased, total mitochondrial metabolic activity was significantly reduced. Insulin supplementation to high glucose decreased NOx synthesis and GLUT3 levels, in contrast oxidative stress increased three-fold. KynA significantly reduced oxidative stress, and increased MTT by regulating NOx production and GLUT3 expression. KynA is a noteworthy compound, as an endogenous, specific NMDA receptor antagonist; it significantly reduces oxidative stress, while increasing cell viability at high glucose and insulin concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Radiation inactivation target size of rat adipocyte glucose transporters in the plasma membrane and intracellular pools

    International Nuclear Information System (INIS)

    Jacobs, D.B.; Berenski, C.J.; Spangler, R.A.; Jung, C.Y.

    1987-01-01

    The in situ assembly states of the glucose transport carrier protein in the plasma membrane and in the intracellular (microsomal) storage pool of rat adipocytes were assessed by studying radiation-induced inactivation of the D-glucose-sensitive cytochalasin B binding activities. High energy radiation inactivated the glucose-sensitive cytochalasin B binding of each of these membrane preparations by reducing the total number of the binding sites without affecting the dissociation constant. The reduction in total number of binding sites was analyzed as a function of radiation dose based on target theory, from which a radiation-sensitive mass (target size) was calculated. When the plasma membranes of insulin-treated adipocytes were used, a target size of approximately 58,000 daltons was obtained. For adipocyte microsomal membranes, we obtained target sizes of approximately 112,000 and 109,000 daltons prior to and after insulin treatment, respectively. In the case of microsomal membranes, however, inactivation data showed anomalously low radiation sensitivities at low radiation doses, which may be interpreted as indicating the presence of a radiation-sensitive inhibitor. These results suggest that the adipocyte glucose transporter occurs as a monomer in the plasma membrane while existing in the intracellular reserve pool either as a homodimer or as a stoichiometric complex with a protein of an approximately equal size

  13. Brain glucose transport and phosphorylation under acute insulin-induced hypoglycemia in mice: an 18F-FDG PET study.

    Science.gov (United States)

    Alf, Malte F; Duarte, João M N; Schibli, Roger; Gruetter, Rolf; Krämer, Stefanie D

    2013-12-01

    We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. Quantitative (18)F-FDG PET combined with the acquisition of real-time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue-compartment model for (18)F-FDG, and the results were evaluated with Michaelis-Menten saturation kinetics. Glucose clearance from plasma to brain (K1,glc) and the phosphorylation rate constant increased with decreasing plasma glucose (Gp), in particular at a Gp of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a Gp of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a Gp of less than 2-3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function.

  14. Solutes transport characteristics in peritoneal dialysis: variations in glucose and insulin serum levels.

    Science.gov (United States)

    da Silva, Dirceu R; Figueiredo, Ana E; Antonello, Ivan C; Poli de Figueiredo, Carlos E; d'Avila, Domingos O

    2008-01-01

    Differences in small solutes transport rate (SSTR) during peritoneal dialysis (PD) may affect water and solutes removal. Patients with high SSTR must rely on shorter dwell times and increased dialysate glucose concentrations to keep fluid balance. Glucose absorption during peritoneal dialysis (PD), besides affecting glucose and insulin metabolism, may induce weight gain. The study aimed at examining acute glucose and insulin serum level changes and other potential relationships in PD patients with diverse SSTR. This cross-sectional study used a modified peritoneal equilibration test (PET) that enrolled 34 prevalent PD patients. Zero, 15, 30, 60, 120, 180, and 240-minute glucose and insulin serum levels were measured. Insulin resistance index was assessed by the homeostasis model assessment (HOMA-IR) formula. SSTR categories were classified by quartiles of the four-hour dialysate/serum creatinine ratio (D(4)/P(Cr)). Demographic and clinical variables were evaluated, and the body mass index (BMI) was estimated. Correlations among variables of interest and categories of SSTR were explored. Glucose serum levels were significantly different at 15, 30, and 60 minutes between high and low SSTR categories (p = 0.014, 0.009, and 0.022). Increased BMI (25.5 +/- 5.1) and insulin resistance [HOMA-IR = 2.60 (1.40-4.23)] were evidenced overall. Very strong to moderate correlations between insulin levels along the PET and HOMA-IR (r = 0.973, 0.834, 0.766, 0.728, 0.843, 0.857, 0.882) and BMI (r = 0.562, 0.459, 0.417, 0.370, 0.508, 0.514, 0.483) were disclosed. CONCLUSIONS; Early glucose serum levels were associated with SSTR during a PET. Overweight or obesity and insulin resistance were prevalent. An association between insulin serum levels and BMI was demonstrated.

  15. Action of Phytochemicals on Insulin Signaling Pathways Accelerating Glucose Transporter (GLUT4 Protein Translocation

    Directory of Open Access Journals (Sweden)

    Abu Sadat Md Sayem

    2018-01-01

    Full Text Available Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro- and macro-complications like heart disease, stroke, dementia, cancer, kidney failure and blindness. All these complications rise primarily due to consistent high blood glucose levels. Insulin and glucagon help to maintain the homeostasis of glucose and lipids through signaling cascades. Pancreatic hormones stimulate translocation of the glucose transporter isoform 4 (GLUT4 from an intracellular location to the cell surface and facilitate the rapid insulin-dependent storage of glucose in muscle and fat cells. Malfunction in glucose uptake mechanisms, primarily contribute to insulin resistance in type 2 diabetes. Plant secondary metabolites, commonly known as phytochemicals, are reported to have great benefits in the management of type 2 diabetes. The role of phytochemicals and their action on insulin signaling pathways through stimulation of GLUT4 translocation is crucial to understand the pathogenesis of this disease in the management process. This review will summarize the effects of phytochemicals and their action on insulin signaling pathways accelerating GLUT4 translocation based on the current literature.

  16. Water transport by the Na+/glucose cotransporter under isotonic conditions

    DEFF Research Database (Denmark)

    Zeuthen, T; Meinild, A K; Klaerke, D A

    1997-01-01

    Solute cotransport in the Na+/glucose cotransporter is directly coupled to significant water fluxes. The water fluxes are energized by the downhill fluxes of the other substrates by a mechanism within the protein itself. In the present paper we investigate the Na+/glucose cotransporter expressed ...... of water molecules and the number of Na+ ions transported, equivalent to 390 water molecules per glucose molecule. Unstirred layer effects are ruled out on the basis of experiments on native oocytes incubated with the ionophores gramicidin D or nystatin.......Solute cotransport in the Na+/glucose cotransporter is directly coupled to significant water fluxes. The water fluxes are energized by the downhill fluxes of the other substrates by a mechanism within the protein itself. In the present paper we investigate the Na+/glucose cotransporter expressed...... in Xenopus oocytes. We present a method which allows short-term exposures to sugar under voltage clamp conditions. We demonstrate that water is cotransported with the solutes despite no osmotic differences between the external and intracellular solutions. There is a fixed ratio of 195:1 between the number...

  17. Insulin binding and glucose transport in adipocytes of acarbose-treated Zucker lean and obese rats.

    Science.gov (United States)

    Vasselli, J R; Flory, T; Fried, S K

    1987-01-01

    The intestinal glucosidase inhibitor acarbose was administered as a dietary admix (30 mg/100 g chow diet) to male Zucker obese and lean rats. After 15 weeks, epidiymal fat pads were removed and adipocytes isolated by collagenase digestion. Equilibrium binding of A-14 tyrosine 125I-insulin, and transport of U-14C-glucose was determined was adipocytes incubated for 50 min at 37 degrees C in 0-16000 pM insulin. Insulin binding/cell was enhanced two-fold in lean (P less than 0.01) and obese (n.s.) drug groups. In drug-treated leans, increased sensitivity of glucose transport to submaximally stimulating concentrations of insulin was observed (P less than 0.02). For both genotypes, acarbose mildly decreased insulin levels and body weight gain, although adipocyte size was unaffected. Results indicate that enhanced insulin binding accompanies metabolic improvements induced by acarbose in lean Zucker rats.

  18. Expression and Purification of Rat Glucose Transporter 1 in Pichia pastoris.

    Science.gov (United States)

    Venskutonytė, Raminta; Elbing, Karin; Lindkvist-Petersson, Karin

    2018-01-01

    Large amounts of pure and homogenous protein are a prerequisite for several biochemical and biophysical analyses, and in particular if aiming at resolving the three-dimensional protein structure. Here we describe the production of the rat glucose transporter 1 (GLUT1), a membrane protein facilitating the transport of glucose in cells. The protein is recombinantly expressed in the yeast Pichia pastoris. It is easily maintained and large-scale protein production in shaker flasks, as commonly performed in academic research laboratories, results in relatively high yields of membrane protein. The purification protocol describes all steps needed to obtain a pure and homogenous GLUT1 protein solution, including cell growth, membrane isolation, and chromatographic purification methods.

  19. The human Na+-glucose cotransporter is a molecular water pump

    DEFF Research Database (Denmark)

    Meinild, A; Klaerke, D A; Loo, D D

    1998-01-01

    1. The human Na+-glucose cotransporter (hSGLT1) was expressed in Xenopus laevis oocytes. The transport activity, given by the Na+ current, was monitored as a clamp current and the concomitant flux of water followed optically as the change in oocyte volume. 2. When glucose was added to the bathing...... solution there was an abrupt increase in clamp current and an immediate swelling of the oocyte. The transmembrane transport of two Na+ ions and one sugar molecule was coupled, within the protein itself, to the influx of 210 water molecules. 3. This stoichiometry was constant and independent of the external...... parameters: Na+ concentrations, sugar concentrations, transmembrane voltages, temperature and osmotic gradients. 4. The cotransport of water occurred in the presence of adverse osmotic gradients. In accordance with the Gibbs equation, energy was transferred within the protein from the downhill fluxes of Na...

  20. Effect of vanadate on glucose transporter (GLUT4) intrinsic activity in skeletal muscle plasma membrane giant vesicles

    DEFF Research Database (Denmark)

    Kristiansen, S; Youn, J; Richter, Erik

    1996-01-01

    of vanadate (NaVO3) on glucose transporter (GLUT4) intrinsic activity (V(max) = intrinsic activity x [GLUT4 protein]) was studied in muscle plasma membrane giant vesicles. Giant vesicles (average diameter 7.6 microns) were produced by collagenase treatment of rat skeletal muscle. The vesicles were incubated......) 55% and 60%, respectively, compared with control. The plasma membrane GLUT4 protein content was not changed in response to vanadate. It is concluded that vanadate decreased glucose transport per GLUT4 (intrinsic activity). This finding suggests that regulation of glucose transport in skeletal muscle...

  1. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  2. Apoptosis and changes in glucose transport early after treatment of Morris hepatoma with gemcitabine

    International Nuclear Information System (INIS)

    Haberkorn, U.; Bellemann, M.E.; Brix, G.; Kamencic, H.; Traut, U.; Kinscherf, R.; Doll, J.; Blatter, J.

    2001-01-01

    Apoptosis has been described as an energy-consuming process. This combined in vivo/in vitro study investigated the effects of the antineoplastic agent gemcitabine on tumour metabolism and on the induction of apoptosis. Dynamic positron emission tomography (PET) measurements of fluorine-18 fluorodeoxyglucose (FDG) uptake were done in rats bearing Morris hepatoma prior to and after therapy with 90 mg gemcitabine/kg b.w. Furthermore, thymidine (TdR) incorporation into the DNA of these tumours was determined. In vitro measurements of FDG and TdR uptake were performed immediately and 24 h after the end of gemcitabine treatment, and the amount of apoptotic cells was determined using the TUNEL reaction. In vivo an increase in FDG transport and phosphorylation occurred early after gemcitabine treatment, although TdR incorporation into the DNA of the tumours declined. In vitro, an enhanced glucose transport, an increase in TdR uptake in the cytoplasm and a decrease in TdR incorporation in the nucleic acid fraction early after treatment occurred. Inhibition of glucose transport caused an increase in the amount of apoptotic cells. The increase in glucose uptake and TdR metabolism early after therapy is interpreted as a stress reaction of the tumour cells, protecting the cells from apoptosis during this early period after exposure to cytotoxic drugs like gemcitabine. (orig.)

  3. Apoptosis and changes in glucose transport early after treatment of Morris hepatoma with gemcitabine

    Energy Technology Data Exchange (ETDEWEB)

    Haberkorn, U. [Heidelberg Univ. (Germany). Abt. fuer Klinische Nuklearmedizin; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Bellemann, M.E. [Department of Biomedical Engineering, University of Applied Sciences, Jena (Germany); Brix, G. [Department of Medical Radiation Hygiene, Federal Office for Radiation Protection, Neuherberg (Germany); Kamencic, H.; Traut, U.; Kinscherf, R. [Heidelberg Univ. (Germany). Inst. fuer Anatomie und Zellbiologie; Morr, I.; Altmann, A. [Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg (Germany); Doll, J. [Dept. of Medical Physics, German Cancer Research Center, Heidelberg (Germany); Blatter, J. [Lilly GmbH Germany, Bad Homburg (Germany)

    2001-04-01

    Apoptosis has been described as an energy-consuming process. This combined in vivo/in vitro study investigated the effects of the antineoplastic agent gemcitabine on tumour metabolism and on the induction of apoptosis. Dynamic positron emission tomography (PET) measurements of fluorine-18 fluorodeoxyglucose (FDG) uptake were done in rats bearing Morris hepatoma prior to and after therapy with 90 mg gemcitabine/kg b.w. Furthermore, thymidine (TdR) incorporation into the DNA of these tumours was determined. In vitro measurements of FDG and TdR uptake were performed immediately and 24 h after the end of gemcitabine treatment, and the amount of apoptotic cells was determined using the TUNEL reaction. In vivo an increase in FDG transport and phosphorylation occurred early after gemcitabine treatment, although TdR incorporation into the DNA of the tumours declined. In vitro, an enhanced glucose transport, an increase in TdR uptake in the cytoplasm and a decrease in TdR incorporation in the nucleic acid fraction early after treatment occurred. Inhibition of glucose transport caused an increase in the amount of apoptotic cells. The increase in glucose uptake and TdR metabolism early after therapy is interpreted as a stress reaction of the tumour cells, protecting the cells from apoptosis during this early period after exposure to cytotoxic drugs like gemcitabine. (orig.)

  4. Dissociation of in vitro sensitivities of glucose transport and antilipolysis to insulin in NIDDM

    International Nuclear Information System (INIS)

    Yki-Jaervinen, H.; Kubo, K.; Zawadzki, J.; Lillioja, S.; Young, A.; Abbott, W.; Foley, J.E.

    1987-01-01

    It is unclear from previous studies whether qualitative or only quantitative differences exist in insulin action in adipocytes obtained from obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) when compared with equally obese nondiabetic subjects. In addition, the role of changes in insulin binding as a cause of insulin resistance in NIDDM is still controversial. The authors compared the sensitivities of [ 14 C]-glucose transport and antilipolysis to insulin and measured [ 125 I]-insulin binding in abdominal adipocytes obtained from 45 obese nondiabetic, obese diabetic, and 15 nonobese female southwestern American Indians. Compared with the nonobese group, the sensitivities of glucose transport antilipolysis were reduced in both the obese nondiabetic and obese diabetic groups. Compared with the obese nondiabetic subjects, the ED 50 for stimulation of glucose transport was higher in the obese patients with NIDDM. In contrast, the ED 50 S for antilipolysis were similar in obese diabetic patients and obese nondiabetic subjects. No differences was found in insulin binding in patients with NIDDM when compared with the equally obese nondiabetic subjects. These data indicate 1) the mechanism of insulin resistance differs in NIDDM and obesity, and 2) the selective loss of insulin sensitivity in NIDDM precludes changes in insulin binding as a cause of insulin resistance in this disorder

  5. GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, M.; Brock, B.; Egefjord, L.

    2017-01-01

    transport capacity (Tmax) with [18F]FDG (FDG) (ClinicalTrials.gov NCT01469351). Results: In both groups, the Tmax estimates declined in proportion to the duration of AD. The GLP-1 analog treatment very significantly (P cerebral cortex as a whole compared...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

  6. Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid

    Directory of Open Access Journals (Sweden)

    Hongbin Tu

    2015-11-01

    Full Text Available Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA, a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.

  7. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    OpenAIRE

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide...

  8. Urotensin II inhibits skeletal muscle glucose transport signaling pathways via the NADPH oxidase pathway.

    Directory of Open Access Journals (Sweden)

    Hong-Xia Wang

    Full Text Available Our previous studies have demonstrated that the urotensin (UII and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM, but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.

  9. Metabolic and hemodynamic effects of sodium-dependent glucose cotransporter 2 inhibitors on cardio-renal protection in the treatment of patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Kashiwagi, Atsunori; Maegawa, Hiroshi

    2017-07-01

    The specific sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) inhibit glucose reabsorption in proximal renal tubular cells, and both fasting and postprandial glucose significantly decrease because of urinary glucose loss. As a result, pancreatic β-cell function and peripheral insulin action significantly improve with relief from glucose toxicity. Furthermore, whole-body energy metabolism changes to relative glucose deficiency and triggers increased lipolysis in fat cells, and fatty acid oxidation and then ketone body production in the liver during treatment with SGLT2 inhibitors. In addition, SGLT2 inhibitors have profound hemodynamic effects including diuresis, dehydration, weight loss and lowering blood pressure. The most recent findings on SGLT2 inhibitors come from results of the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes trial. SGLT2 inhibitors exert extremely unique and cardio-renal protection through metabolic and hemodynamic effects, with long-term durability on the reduction of blood glucose, bodyweight and blood pressure. Although a site of action of SGLT2 inhibitors is highly specific to inhibit renal glucose reabsorption, whole-body energy metabolism, and hemodynamic and renal functions are profoundly modulated during the treatment of SGLT2 inhibitors. Previous studies suggest multifactorial clinical benefits and safety concerns of SGLT2 inhibitors. Although ambivalent clinical results of this drug are still under active discussion, the present review summarizes promising recent evidence on the cardio-renal and metabolic benefits of SGLT2 inhibitors in the treatment of type 2 diabetes. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  10. In vivo measurements of brain glucose transport using the reversible michaelis-menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia

    OpenAIRE

    Choi, I.-Y.; Lee, S.-P.; Kim, S.-G.; Gruetter, R.

    2001-01-01

    Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in α-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma ...

  11. Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.

    Science.gov (United States)

    Tanegashima, Kosuke; Sato-Miyata, Yukiko; Funakoshi, Masabumi; Nishito, Yasumasa; Aigaki, Toshiro; Hara, Takahiko

    2017-01-01

    We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon β-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9-mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that β-OHB is a HDAC inhibitor and show that β-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  12. Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

    Science.gov (United States)

    Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

    Science.gov (United States)

    Masuda, Takahiro; Watanabe, Yuko; Fukuda, Keiko; Watanabe, Minami; Onishi, Akira; Ohara, Ken; Imai, Toshimi; Koepsell, Hermann; Muto, Shigeaki; Vallon, Volker; Nagata, Daisuke

    2018-05-23

    The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood, because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 weeks) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a non-obese type 2 diabetic model, and non-diabetic Sprague-Dawley rats. In non-diabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these 4 parameters, but Ipra had no further effect; probably due to its antihyperglycemic effect, such that glucosuria and as a consequence food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the 4 groups. To study the impact of food and fluid intake, non-diabetic rats were treated for 7 days with Veh, Ipra or Ipra+pair-feeding+pair-drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, while Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize body fluid volume, including compensatory increases in fluid and food intake.

  14. Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle

    OpenAIRE

    Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu; Jung, Michelle M.; Rathod, Amee; Middelbeek, R. Jan-Willem; Lessard, Sarah J.; Treebak, Jonas T.; Tsuchihara, Katsuya; Esumi, Hiroyasu; Richter, Erik A.; Wojtaszewski, Jørgen F. P.; Hirshman, Michael F.; Goodyear, Laurie J.

    2010-01-01

    The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKα2 activity showing no effect on contraction-stimulated...

  15. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs

    DEFF Research Database (Denmark)

    Kosiborod, Mikhail; Cavender, Matthew A.; Fu, Alex Z.

    2017-01-01

    and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. METHODS: Data were collected via medical claims, primary care/hospital records, and national registries from...... for Germany. RESULTS: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i...... class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334...

  16. Na(+)-D-glucose cotransporter in the kidney of Squalus acanthias: molecular identification and intrarenal distribution.

    Science.gov (United States)

    Althoff, Thorsten; Hentschel, Hartmut; Luig, Jutta; Schütz, Hendrike; Kasch, Myriam; Kinne, Rolf K-H

    2006-04-01

    Using primers against conserved regions of mammalian Na(+)-d-glucose cotransporters (SGLT), a cDNA was cloned from the kidney of spiny dogfish shark (Squalus acanthias). On the basis of comparison of amino acid sequence, membrane topology, and putative glycosylation and phosphorylation sites, the cDNA could be shown to belong to the family of sglt genes. Indeed, Na(+)-dependent d-glucose uptake could be demonstrated after expression of the gene in Xenopus laevis oocytes. In a dendrogram, the SGLT from shark kidney has a high homology to the mammalian SGLT2. Computer analysis revealed that the elasmobranch protein is most similar to the mammalian proteins in the transmembrane regions and contains already all the amino acids identified to be functionally important, suggesting early conservation during evolution. Extramembraneous loops show larger variations. This holds especially for loop 13, which has been implied as a phlorizin-binding domain. Antibodies were generated and the intrarenal distribution of the SGLT was studied in cryosections. In parallel, the nephron segments were identified by lectins. Positive immunoreactions were found in the proximal tubule in the early parts PIa and PIb and the late segment PIIb. The large PIIa segment of the proximal tubule showed no reaction. In contrast to the mammalian kidney also the late distal tubule, the collecting tubule, and the collecting duct showed immunoreactivity. The molecular information confirms previous vesicle studies in which a low affinity SGLT with a low stoichiometry has been observed and supports the notion of a similarity of the shark kidney SGLT to the mammalian SGLT2. Despite its presence in the late parts of the nephron, the absence of SGLT in the major part of the proximal tubule, the relatively low affinity, and in particular the low stoichiometry might explain the lack of a T(m) for d-glucose in the shark kidney.

  17. Inhibition of protein kinase CbetaII increases glucose uptake in 3T3-L1 adipocytes through elevated expression of glucose transporter 1 at the plasma membrane

    NARCIS (Netherlands)

    Bosch, Remko R.; Bazuine, Merlijn; Wake, Michelle M.; Span, Paul N.; Olthaar, André J.; Schürmann, Annette; Maassen, J. Antonie; Hermus, Ad R. M. M.; Willems, Peter H. G. M.; Sweep, C. G. J.

    2003-01-01

    The mechanism via which diacylglycerol-sensitive protein kinase Cs (PKCs) stimulate glucose transport in insulin-sensitive tissues is poorly defined. Phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), are potent activators of conventional and novel PKCs. Addition of PMA increases the

  18. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4.

    Science.gov (United States)

    Kraft, Thomas E; Hresko, Richard C; Hruz, Paul W

    2015-12-01

    The insulin-responsive facilitative glucose transporter GLUT4 is of fundamental importance for maintenance of glucose homeostasis. Despite intensive effort, the ability to express and purify sufficient quantities of structurally and functionally intact protein for biophysical analysis has previously been exceedingly difficult. We report here the development of novel methods to express, purify, and functionally reconstitute GLUT4 into detergent micelles and proteoliposomes. Rat GLUT4 containing FLAG and His tags at the amino and carboxy termini, respectively, was engineered and stably transfected into HEK-293 cells. Overexpression in suspension culture yielded over 1.5 mg of protein per liter of culture. Systematic screening of detergent solubilized GLUT4-GFP fusion protein via fluorescent-detection size exclusion chromatography identified lauryl maltose neopentyl glycol (LMNG) as highly effective for isolating monomeric GLUT4 micelles. Preservation of structural integrity and ligand binding was demonstrated via quenching of tryptophan fluorescence and competition of ATB-BMPA photolabeling by cytochalasin B. GLUT4 was reconstituted into lipid nanodiscs and proper folding was confirmed. Reconstitution of purified GLUT4 with amphipol A8-35 stabilized the transporter at elevated temperatures for extended periods of time. Functional activity of purified GLUT4 was confirmed by reconstitution of LMNG-purified GLUT4 into proteoliposomes and measurement of saturable uptake of D-glucose over L-glucose. Taken together, these data validate the development of an efficient means to generate milligram quantities of stable and functionally intact GLUT4 that is suitable for a wide array of biochemical and biophysical analyses. © 2015 The Protein Society.

  19. Analysis of metabolism of 6FDG: a PET glucose transport tracer

    Energy Technology Data Exchange (ETDEWEB)

    Muzic, Raymond F., E-mail: raymond.muzic@case.edu [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106 (United States); Chandramouli, Visvanathan [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Huang, Hsuan-Ming [Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106 (United States); Wu Chunying; Wang Yanming [Department of Radiology, Case Western Reserve University, Cleveland, OH 44106 (United States); Ismail-Beigi, Faramarz [Department of Medicine, Case Western Reserve University, Cleveland, OH 44106 (United States)

    2011-07-15

    Introduction: We are developing {sup 18}F-labeled 6-fluoro-6-deoxy-D-glucose ([{sup 18}F]6FDG) as a tracer of glucose transport. As part of this process it is important to characterize and quantify putative metabolites. In contrast to the ubiquitous positron emission tomography (PET) tracer {sup 18}F-labeled 2-fluoro-2-deoxy-D-glucose ([{sup 18}F]2FDG) which is phosphorylated and trapped intracellularly, the substitution of fluorine for a hydroxyl group at carbon-6 in [{sup 18}F]6FDG should prevent its phosphorylation. Consequently, [{sup 18}F]6FDG has the potential to trace the transport step of glucose metabolism without the confounding effects of phosphorylation and subsequent steps of metabolism. Herein the focus is to determine whether, and the degree to which, [{sup 18}F]6FDG remains unchanged following intravenous injection. Methods: Biodistribution studies were performed using 6FDG labeled with {sup 18}F or with the longer-lived radionuclides {sup 3}H and {sup 14}C. Tissues were harvested at 1, 6, and 24 h following intravenous administration and radioactivity was extracted from the tissues and analyzed using a combination of ion exchange columns, high-performance liquid chromatography, and chemical reactivity. Results: At the 1 h time-point, the vast majority of radioactivity in the liver, brain, heart, skeletal muscle, and blood was identified as 6FDG. At the 6-h and 24-h time points, there was evidence of a minor amount of radioactive material that appeared to be 6-fluoro-6-deoxy-D-sorbitol and possibly 6-fluoro-6-deoxy-D-gluconic acid. Conclusion: On the time scale typical of PET imaging studies radioactive metabolites of [{sup 18}F]6FDG are negligible.

  20. Sodium-glucose cotransporter 2 inhibitor use: A pharmaco-ergonomic qualification tool

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2017-01-01

    Full Text Available Pharmaco-ergonomics implies tailoring the drug therapy to an individual patient's requirement(s. The development of sodium-glucose cotransporter 2 inhibitor (SGLT2-i agents has impelled multiple clinical considerations, in the management of type-2 diabetes. This paper attempts to summarize the pharmaco-ergonomic considerations for these agents, in the form of an SGLT2-i qualification tool, based on a clinical score. This tool may serve as a simple and inexpensive practical guide, to optimize the risk-benefit considerations for SGLT2-i agents.

  1. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Kim Y

    2012-08-01

    Full Text Available Yoojin Kim, Ambika R BabuDivision of Endocrinology, John Stroger Jr Hospital of Cook County and Rush University, Chicago, IL, USABackground: The kidney plays an important role in glucose metabolism, and has been considered a target for therapeutic intervention. The sodium-glucose cotransporter type 2 (SGLT2 mediates most of the glucose reabsorption from the proximal renal tubule. Inhibition of SGLT2 leads to glucosuria and provides a unique mechanism to lower elevated blood glucose levels in diabetes. The purpose of this review is to explore the physiology of SGLT2 and discuss several SGLT2 inhibitors which have clinical data in patients with type 2 diabetes.Methods: We performed a PubMed search using the terms "SGLT2" and "SGLT2 inhibitor" through April 10, 2012. Published articles, press releases, and abstracts presented at national and international meetings were considered.Results: SGLT2 inhibitors correct a novel pathophysiological defect, have an insulin-independent action, are efficacious with glycosylated hemoglobin reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used at any stage of diabetes. They are generally well tolerated. However, due to side effects, such as repeated urinary tract and genital infections, increased hematocrit, and decreased blood pressure, appropriate patient selection for drug initiation and close monitoring after initiation will be important. Results of ongoing clinical studies of the effect of SGLT2 inhibitors on diabetic complications and cardiovascular safety are crucial to determine the risk-benefit ratio. A recent decision by the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including

  2. Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome.

    Science.gov (United States)

    Tepavčević, Snežana; Vojnović Milutinović, Danijela; Macut, Djuro; Žakula, Zorica; Nikolić, Marina; Božić-Antić, Ivana; Romić, Snježana; Bjekić-Macut, Jelica; Matić, Gordana; Korićanac, Goran

    2014-05-01

    It is supposed that women with polycystic ovary syndrome (PCOS) are prone to develop cardiovascular disease as a consequence of multiple risk factors that are mostly related to the state of insulin resistance and consequent hyperinsulinemia. In the present study, we evaluated insulin signaling and glucose transporters (GLUT) in cardiac cells of dihydrotestosterone (DHT) treated female rats as an animal model of PCOS. Expression of proteins involved in cardiac insulin signaling pathways and glucose transporters, as well as their phosphorylation or intracellular localization were studied by Western blot analysis in DHT-treated and control rats. Treatment with DHT resulted in increased body mass, absolute mass of the heart, elevated plasma insulin concentration, dyslipidemia and insulin resistance. At the molecular level, DHT treatment did not change protein expression of cardiac insulin receptor and insulin receptor substrate 1, while phosphorylation of the substrate at serine 307 was increased. Unexpectedly, although expression of downstream Akt kinase and its phosphorylation at threonine 308 were not altered, phosphorylation of Akt at serine 473 was increased in the heart of DHT-treated rats. In contrast, expression and phosphorylation of extracellular signal regulated kinases 1/2 were decreased. Plasma membrane contents of GLUT1 and GLUT4 were decreased, as well as the expression of GLUT4 in cardiac cells at the end of androgen treatment. The obtained results provide evidence for alterations in expression and especially in functional characteristics of insulin signaling molecules and glucose transporters in the heart of DHT-treated rats with PCOS, indicating impaired cardiac insulin action. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Glucose transporter expression in an avian nectarivore: the ruby-throated hummingbird (Archilochus colubris.

    Directory of Open Access Journals (Sweden)

    Kenneth C Welch

    Full Text Available Glucose transporter (GLUT proteins play a key role in the transport of monosaccharides across cellular membranes, and thus, blood sugar regulation and tissue metabolism. Patterns of GLUT expression, including the insulin-responsive GLUT4, have been well characterized in mammals. However, relatively little is known about patterns of GLUT expression in birds with existing data limited to the granivorous or herbivorous chicken, duck and sparrow. The smallest avian taxa, hummingbirds, exhibit some of the highest fasted and fed blood glucose levels and display an unusual ability to switch rapidly and completely between endogenous fat and exogenous sugar to fuel energetically expensive hovering flight. Despite this, nothing is known about the GLUT transporters that enable observed rapid rates of carbohydrate flux. We examined GLUT (GLUT1, 2, 3, & 4 expression in pectoralis, leg muscle, heart, liver, kidney, intestine and brain from both zebra finches (Taeniopygia guttata and ruby-throated hummingbirds (Archilochus colubris. mRNA expression of all four transporters was probed using reverse-transcription PCR (RT-PCR. In addition, GLUT1 and 4 protein expression were assayed by western blot and immunostaining. Patterns of RNA and protein expression of GLUT1-3 in both species agree closely with published reports from other birds and mammals. As in other birds, and unlike in mammals, we did not detect GLUT4. A lack of GLUT4 correlates with hyperglycemia and an uncoupling of exercise intensity and relative oxidation of carbohydrates in hummingbirds. The function of GLUTs present in hummingbird muscle tissue (e.g. GLUT1 and 3 remain undescribed. Thus, further work is necessary to determine if high capillary density, and thus surface area across which cellular-mediated transport of sugars into active tissues (e.g. muscle occurs, rather than taxon-specific differences in GLUT density or kinetics, can account for observed rapid rates of sugar flux into these

  4. Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory.

    Science.gov (United States)

    Pearson-Leary, Jiah; McNay, Ewan C

    2016-11-23

    The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues. The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long

  5. The Small Protein SgrT Controls Transport Activity of the Glucose-Specific Phosphotransferase System.

    Science.gov (United States)

    Lloyd, Chelsea R; Park, Seongjin; Fei, Jingyi; Vanderpool, Carin K

    2017-06-01

    The bacterial small RNA (sRNA) SgrS has been a fruitful model for discovery of novel RNA-based regulatory mechanisms and new facets of bacterial physiology and metabolism. SgrS is one of only a few characterized dual-function sRNAs. SgrS can control gene expression posttranscriptionally via sRNA-mRNA base-pairing interactions. Its second function is coding for the small protein SgrT. Previous work demonstrated that both functions contribute to relief of growth inhibition caused by glucose-phosphate stress, a condition characterized by disrupted glycolytic flux and accumulation of sugar phosphates. The base-pairing activity of SgrS has been the subject of numerous studies, but the activity of SgrT is less well characterized. Here, we provide evidence that SgrT acts to specifically inhibit the transport activity of the major glucose permease PtsG. Superresolution microscopy demonstrated that SgrT localizes to the cell membrane in a PtsG-dependent manner. Mutational analysis determined that residues in the N-terminal domain of PtsG are important for conferring sensitivity to SgrT-mediated inhibition of transport activity. Growth assays support a model in which SgrT-mediated inhibition of PtsG transport activity reduces accumulation of nonmetabolizable sugar phosphates and promotes utilization of alternative carbon sources by modulating carbon catabolite repression. The results of this study expand our understanding of a basic and well-studied biological problem, namely, how cells coordinate carbohydrate transport and metabolism. Further, this work highlights the complex activities that can be carried out by sRNAs and small proteins in bacteria. IMPORTANCE Sequencing, annotation and investigation of hundreds of bacterial genomes have identified vast numbers of small RNAs and small proteins, the majority of which have no known function. In this study, we explore the function of a small protein that acts in tandem with a well-characterized small RNA during metabolic

  6. Assessment of glucose homeostasis in crossbred steer progeny sired by Brahman bulls that experienced prenatal transportation stress

    Science.gov (United States)

    The objective of this experiment was to assess glucose homeostasis of crossbred male progeny whose Brahman sires experienced prenatal transportation stress (PS) in utero. Sixteen steers (PNS group) sired by 3 PS bulls gestating dams were transported for 2 h at 60, 80, 100, 120, and 140 ± 5 d of gest...

  7. Effect of in vivo injection of cholera and pertussis toxin on glucose transport in rat skeletal muscle

    DEFF Research Database (Denmark)

    Ploug, Thorkil; Han, X; Petersen, L N

    1997-01-01

    Cholera toxin (CTX) and pertussis toxin (PTX) were examined for their ability to inhibit glucose transport in perfused skeletal muscle. Twenty-five hours after an intravenous injection of CTX, basal transport was decreased approximately 30%, and insulin- and contraction-stimulated transport...... in GLUT-1 protein content was found. In contrast, GLUT-4 mRNA was unchanged, but transcripts for GLUT-1 were increased > or = 150% in all three muscles from CTX-treated rats. The findings suggest that CTX via increased cAMP impairs basal as well as insulin- and contraction-stimulated muscle glucose...

  8. The Regulation of Insulin-Stimulated Cardiac Glucose Transport via Protein Acetylation

    Directory of Open Access Journals (Sweden)

    Edith Renguet

    2018-06-01

    Full Text Available Cellular catabolism is the cell capacity to generate energy from various substrates to sustain its function. To optimize this energy production, cells are able to switch between various metabolic pathways in accordance to substrate availability via a modulation of several regulatory enzymes. This metabolic flexibility is essential for the healthy heart, an organ requiring large quantities of ATP to sustain its contractile function. In type 2 diabetes, excess of non-glucidic nutrients such as fatty acids, branched-chain amino-acids, or ketones bodies, induces cardiac metabolic inflexibility. It is characterized by a preferential use of these alternative substrates to the detriment of glucose, this participating in cardiomyocytes dysfunction and development of diabetic cardiomyopathy. Identification of the molecular mechanisms leading to this metabolic inflexibility have been scrutinized during last decades. In 1963, Randle demonstrated that accumulation of some metabolites from fatty acid metabolism are able to allosterically inhibit regulatory steps of glucose metabolism leading to a preferential use of fatty acids by the heart. Nevertheless, this model does not fully recapitulate observations made in diabetic patients, calling for a more complex model. A new piece of the puzzle emerges from recent evidences gathered from different laboratories showing that metabolism of the non-glucidic substrates induces an increase in acetylation levels of proteins which is concomitant to the perturbation of glucose transport. The purpose of the present review is to gather, in a synthetic model, the different evidences that demonstrate the role of acetylation in the inhibition of the insulin-stimulated glucose uptake in cardiac muscle.

  9. An evaluation of US patent 2015065565 (A1) for a new class of SGLT2 inhibitors for treatment 1 of type II diabetes mellitus.

    Science.gov (United States)

    Jiang, Meiyan; Steyger, Peter S

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a growing and serious global health problem. Pharmacological inhibition of the sodium-glucose cotransporter-2 (SGLT2; SLC5A2) increases urinary glucose excretion, decreasing plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 have recently become available for clinical therapy of T2DM. The patent claims a new class of SGLT2 inhibitors: derivatives of dioxa-bicyclo[3.2.1]octane-2,3,4-triol (including ertugliflozin; PF-04971729). The invention describes the design, synthesis and pharmacological tests related to ertugliflozin, which could ultimately lead to efficacious therapy for T2DM alone or in combination with other anti-diabetic agents. Ertugliflozin is likely to be of great clinical significance in the near future. Continued analysis of ertugliflozin derivatives to now validate safe and efficacious treatment of T2DM in a larger number of clinical subjects over an extended period is needed to further support clinical utility. Identification, and discussion, of likely contra-indications is also needed.

  10. SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice

    Directory of Open Access Journals (Sweden)

    Liang Xu

    2017-06-01

    Full Text Available Sodium-glucose cotransporter (SGLT 2 inhibitors increase urinary glucose excretion (UGE, leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO mice. C57BL/6J mice were pair-fed a high-fat diet (HFD or a HFD with empagliflozin for 16 weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT. Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.

  11. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

    Directory of Open Access Journals (Sweden)

    Santos Cavaiola T

    2018-04-01

    Full Text Available Tricia Santos Cavaiola, Jeremy Pettus Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA Abstract: As the first cardiovascular (CV outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM, the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME® trial, which investigated the sodium glucose cotransporter 2 (SGLT2 inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL, which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. Keywords: canagliflozin, cardiovascular outcomes, dapagliflozin, empagliflozin, mechanisms, sodium glucose cotransporter 2 inhibitors

  12. Immunohistochemical Evaluation of Glucose Transporter Type 1 in Epithelial Dysplasia and Oral Squamous Cell Carcinoma.

    Science.gov (United States)

    Pereira, Karuza Maria Alves; Feitosa, Sthefane Gomes; Lima, Ana Thayssa Tomaz; Luna, Ealber Carvalho Macedo; Cavalcante, Roberta Barroso; de Lima, Kenio Costa; Chaves, Filipe Nobre; Costa, Fábio Wildson Gurgel

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and some of these have been documented in association or preceded by oral epithelial dysplasia (OED). Aggressive cancers with fast growth have demonstrated overexpression of some glucose transporters (GLUTs). Thus, the aim of this study was to analyze the immunohistochemical expression of the glucose transporter, GLUT-1, in OEDs and OSCCs, seeking to better elucidate the biological behavior of neoplasias. Fifteen cases were selected this research of both lesions. Five areas were analyzed from each case by counting the percentage of positive cells at 400x magnification. Immunoreactivity of GLUT-1 was observed in 100% of the samples ranging from 54.2% to 86.2% for the OSCC and 73.9% to 97.4% for the OED. Statistical test revealed that there was greater overexpression of GLUT-1 in OED than the OSCC (p=0.01). It is believed the high expression of GLUT-1 may reflect the involvement of GLUT-1 in early stages of oral carcinogenesis.

  13. Glucose transporter type 1 deficiency syndrome with carbohydrate-responsive symptoms but without epilepsy.

    Science.gov (United States)

    Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan

    2011-12-01

    Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female child (3 y 4 mo) who presented with delayed psychomotor development and frequent episodes of staggering, impaired vigilance, and vomiting that resolved promptly after food intake. Electroencephalography was normal. The cerebrospinal fluid-blood glucose ratio was 0.42 (normal ≥ 0.45). GLUT1-DS was confirmed by molecular genetic testing, which showed a novel de novo heterozygous mutation in the SLC2A1 gene (c.497_499delTCG, p.VAL166del). Before starting a ketogenic diet, the child's cognitive development was tested using the Snijders-Oomen Non-Verbal Intelligence Test, which revealed a heterogeneous intelligence profile with deficits in her visuomotor skills and spatial awareness. Her motor development was delayed. Three months after introducing a ketogenic diet, she showed marked improvement in speech and motor development, as tested by the Movement Assessment Battery for Children (manual dexterity 16th centile, ball skills 1st centile, static and dynamic balance 5th centile). This case demonstrates that GLUT1-DS should be investigated in individuals with unexplained developmental delay. Epilepsy is not a mandatory symptom. The ketogenic diet is also beneficial for non-epileptic symptoms in GLUT1-DS. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

  14. Comparative study of expression and activity of glucose transporters between stem cell-derived brain microvascular endothelial cells and hCMEC/D3 cells.

    Science.gov (United States)

    Al-Ahmad, Abraham J

    2017-10-01

    Glucose constitutes a major source of energy of mammalian brains. Glucose uptake at the blood-brain barrier (BBB) occurs through a facilitated glucose transport, through glucose transporter 1 (GLUT1), although other isoforms have been described at the BBB. Mutations in GLUT1 are associated with the GLUT1 deficiency syndrome, yet none of the current in vitro models of the human BBB maybe suited for modeling such a disorder. In this study, we investigated the expression of glucose transporters and glucose diffusion across brain microvascular endothelial cells (BMECs) derived from healthy patient-derived induced pluripotent stem cells (iPSCs). We investigated the expression of different glucose transporters at the BBB using immunocytochemistry and flow cytometry and measured glucose uptake and diffusion across BMEC monolayers obtained from two iPSC lines and from hCMEC/D3 cells. BMEC monolayers showed expression of several glucose transporters, in particular GLUT1, GLUT3, and GLUT4. Diffusion of glucose across the monolayers was mediated via a saturable transcellular mechanism and partially inhibited by pharmacological inhibitors. Taken together, our study suggests the presence of several glucose transporters isoforms at the human BBB and demonstrates the feasibility of modeling glucose across the BBB using patient-derived stem cells. Copyright © 2017 the American Physiological Society.

  15. Sodium-glucose co-transporter type 2 inhibitors reduce evening home blood pressure in type 2 diabetes with nephropathy.

    Science.gov (United States)

    Takenaka, Tsuneo; Kishimoto, Miyako; Ohta, Mari; Tomonaga, Osamu; Suzuki, Hiromichi

    2017-05-01

    The effects of sodium-glucose co-transporter type 2 inhibitors on home blood pressure were examined in type 2 diabetes with nephropathy. The patients with diabetic nephropathy were screened from medical records in our hospitals. Among them, 52 patients who measured home blood pressure and started to take sodium-glucose co-transporter type 2 inhibitors were selected. Clinical parameters including estimated glomerular filtration rate, albuminuria and home blood pressure for 6 months were analysed. Sodium-glucose co-transporter type 2 inhibitors (luseogliflozin 5 mg/day or canagliflozin 100 mg/day) reduced body weight, HbA1c, albuminuria, estimated glomerular filtration rate and office blood pressure. Although sodium-glucose co-transporter type 2 inhibitors did not alter morning blood pressure, it reduced evening systolic blood pressure. Regression analyses revealed that decreases in evening blood pressure predicted decrements in albuminuria. The present data suggest that sodium-glucose co-transporter type 2 inhibitors suppress sodium overload during daytime to reduce evening blood pressure and albuminuria.

  16. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium–glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents

    Directory of Open Access Journals (Sweden)

    Takahiro Oguma

    2016-12-01

    Full Text Available We investigated whether structurally different sodium–glucose cotransporter (SGLT 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4 inhibitors, could enhance glucagon-like peptide-1 (GLP-1 secretion during oral glucose tolerance tests (OGTTs in rodents. Three different SGLT inhibitors—1-(β-d-Glucopyranosyl-4-chloro-3-[5-(6-fluoro-2-pyridyl-2-thienylmethyl]benzene (GTB, TA-1887, and canagliflozin—were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1 elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus.

  17. Glucose transportation in the brain and its impairment in Huntington disease: one more shade of the energetic metabolism failure?

    Science.gov (United States)

    Morea, Veronica; Bidollari, Eris; Colotti, Gianni; Fiorillo, Annarita; Rosati, Jessica; De Filippis, Lidia; Squitieri, Ferdinando; Ilari, Andrea

    2017-07-01

    Huntington's disease (HD) or Huntington's chorea is the most common inherited, dominantly transmitted, neurodegenerative disorder. It is caused by increased CAG repeats number in the gene coding for huntingtin (Htt) and characterized by motor, behaviour and psychiatric symptoms, ultimately leading to death. HD patients also exhibit alterations in glucose and energetic metabolism, which result in pronounced weight loss despite sustained calorie intake. Glucose metabolism decreases in the striatum of all the subjects with mutated Htt, but affects symptom presentation only when it drops below a specific threshold. Recent evidence points at defects in glucose uptake by the brain, and especially by neurons, as a relevant component of central glucose hypometabolism in HD patients. Here we review the main features of glucose metabolism and transport in the brain in physiological conditions and how these processes are impaired in HD, and discuss the potential ability of strategies aimed at increasing intracellular energy levels to counteract neurological and motor degeneration in HD patients.

  18. Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    International Nuclear Information System (INIS)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine; Halimi, Serge; Demongeot, Jacques

    2007-01-01

    Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using 125 I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

  19. Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    Science.gov (United States)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

    2007-01-01

    Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state and it has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats with 125I-6-Deoxy-6-Iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood were assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady-state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p<0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) and whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. PMID:17171359

  20. Assessment of insulin resistance in fructose-fed rats with {sup 125}I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    Energy Technology Data Exchange (ETDEWEB)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine [INSERM, E340, 38000 Grenoble, (France); Univ Grenoble, 38000 Grenoble, (France); Halimi, Serge [CHRU Grenoble, Hopital Michallon, Service de Diabetologie, 38000 Grenoble, (France); Demongeot, Jacques [Univ Grenoble, 38000 Grenoble, (France); CNRS, UMR 5525, 38000 Grenoble, (France)

    2007-05-15

    Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using {sup 125}I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

  1. Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca2+ release

    Directory of Open Access Journals (Sweden)

    Thomas E. Jensen

    2014-10-01

    Full Text Available Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca2+ as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca2+ release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca2+ centric paradigm.

  2.  The role of glucose transporter 1 (GLUT1 in the diagnosis and therapy of tumors

    Directory of Open Access Journals (Sweden)

    Paweł Jóźwiak

    2012-03-01

    Full Text Available  Malignant cells are known to enhance glucose metabolism, to increase glucose uptake and to inhibit the process of oxidative phosphorylation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells that allow them to compensate the inefficient extraction of energy from glucose in order to continue their uncontrolled growth and proliferation. Upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins named GLUT. Overexpression of GLUTs, especially the hypoxia-responsive GLUT1, has been frequently observed in various human carcinomas. Many studies have reported a correlation between GLUT1 expression level and the grade of tumor aggressiveness, which suggests that GLUT1 expression may be of prognostic significance. Therefore, GLUT1 is a key rate-limiting factor in the transport and glucose metabolism in cancer cells. This paper presents the current state of knowledge on GLUT1 regulation as well as its utility in the diagnosis and therapy of cancers.

  3. Triiodothyronine Acutely Stimulates Glucose Transport into L6 Muscle Cells Without Increasing Surface GLUT4, GLUT1, or GLUT3

    Science.gov (United States)

    Teixeira, Silvania Silva; Tamrakar, Akhilesh K.; Goulart-Silva, Francemilson; Serrano-Nascimento, Caroline; Klip, Amira

    2012-01-01

    Background Thyroid hormones (THs) act genomically to stimulate glucose transport by elevating glucose transporter (Slc2a) expression and glucose utilization by cells. However, nongenomic effects of THs are now emerging. Here, we assess how triiodothyronine (T3) acutely affects glucose transport and the content of GLUT4, GLUT1, and GLUT3 at the surface of muscle cells, and possible interactions between T3 and insulin action. Methods Differentiated L6 myotubes transfected with myc-tagged Slc2a4 (L6-GLUT4myc) or Slc2a1 (L6-GLUT1myc) and wild-type L6 myotubes were studied in the following conditions: control, hypothyroid (Tx), Tx plus T3, Tx plus insulin, and Tx plus insulin and T3. Results Glucose uptake and GLUT4 content at the cell surface decreased in the Tx group relative to controls. T3 treatment for 30 minutes increased glucose transport into L6-GLUT4myc cells without altering surface GLUT4 content, which increased only thereafter. The total amount of GLUT4 protein remained unchanged among the groups studied. The surface GLUT1 content of L6-GLUT1myc cells also remained unaltered after T3 treatment; however, in these cells glucose transport was not stimulated by T3. In wild-type L6 cells, although T3 treatment increased the total amount of GLUT3, it did not change the surface GLUT3 content. Moreover, within 30 minutes, T3 stimulation of glucose uptake was additive to that of insulin in L6-GLUT4myc cells. As expected, insulin elevated surface GLUT4 content and glucose uptake. However, interestingly, surface GLUT4 content remained unchanged or even dropped with T3 plus insulin. Conclusions These data reveal that T3 rapidly increases glucose uptake in L6-GLUT4myc cells, which, at least for 30 minutes, did not depend on an increment in GLUT4 at the cell surface yet potentiates insulin action. We propose that this rapid T3 effect involves activation of GLUT4 transporters at the cell surface, but cannot discount the involvement of an unknown GLUT. PMID:22663547

  4. Role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Solini, Anna

    2016-12-01

    In the last ten years, knowledge on pathophysiology of type 2 diabetes (T2DM) has significantly increased, with multiple failures (decreased incretin effect, increased lipolysis, increased glucagon secretion, neurotransmitters dysfunction) recognized as important contributors, together with decreased insulin secretion and reduced peripheral glucose uptake. As a consequence, the pharmacologic therapy of T2DM has been progressively enriched by several novel classes of drugs, trying to overcome these defects. The last, intriguing compounds come into the market are SGLT2 inhibitors, framing the kidney in a different scenario, not as site of a harmful disease complication, but rather as the means to correct hyperglycemia and fight the disease. This review aims to offer a short, updated overview of the role of these compounds in the treatment of T2DM, focusing on efficacy, ancillary albeit relevant clinical effects, safety, potential cardiovascular protection, positioning in common therapeutic algorithms.

  5. ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease.

    Science.gov (United States)

    Perico, Norberto; Ruggenenti, Piero; Remuzzi, Giuseppe

    2017-04-01

    Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases. For those individuals in which nephroprotection by RAS blockade is only partial, sodium-glucose linked cotransporter-2 (SGLT2) inhibitors could be a promising new class of drugs to provide further renoprotective benefit when added on to RAS blockers. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin

    Directory of Open Access Journals (Sweden)

    Sandra Bowles

    2017-03-01

    Full Text Available Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer tested at 1–150 µM had an apparent rate of permeability (Papp typical of poorly absorbed compounds (1.73 × 10−6 cm/s. Major glucose transporters, sodium glucose linked transporter 1 (SGLT1 and glucose transporter 2 (GLUT2, and efflux protein (P-glycoprotein, PgP (1.84 × 10−6 cm/s; efflux ratio: 1.1 were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM, which decreased the Papp value to 2.9 × 10−7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.

  7. Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin.

    Science.gov (United States)

    Bowles, Sandra; Joubert, Elizabeth; de Beer, Dalene; Louw, Johan; Brunschwig, Christel; Njoroge, Mathew; Lawrence, Nina; Wiesner, Lubbe; Chibale, Kelly; Muller, Christo

    2017-03-30

    Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (P app ) typical of poorly absorbed compounds (1.73 × 10 -6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10 -6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the P app of aspalathin was not affected by the presence of specific inhibitors. The P app of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the P app value to 2.9 × 10 -7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.

  8. Contraction-stimulated glucose transport in muscle is controlled by AMPK and mechanical stress but not sarcoplasmatic reticulum Ca2+ release

    DEFF Research Database (Denmark)

    Jensen, Thomas Elbenhardt; Sylow, Lykke; Rose, Adam John

    2014-01-01

    signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca(2+) release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress......-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport...

  9. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

    Science.gov (United States)

    Cavaiola, Tricia Santos; Pettus, Jeremy

    2018-01-01

    As the first cardiovascular (CV) outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM), the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, which investigated the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. PMID:29695924

  10. Exercise-induced increase in glucose transport, GLUT-4, and VAMP-2 in plasma membrane from human muscle

    DEFF Research Database (Denmark)

    Kristiansen, S; Hargreaves, Mark; Richter, Erik

    1996-01-01

    contractions may induce trafficking of GLUT-4-containing vesicles via a mechanism similar to neurotransmitter release. Our results demonstrate for the first time exercise-induced translocation of GLUT-4 and VAMP-2 to the plasma membrane of human muscle and increased sarcolemmal glucose transport.......A major effect of muscle contractions is an increase in sarcolemmal glucose transport. We have used a recently developed technique to produce sarcolemmal giant vesicles from human muscle biopsy samples obtained before and after exercise. Six men exercised for 10 min at 50% maximal O2 uptake (Vo2max...

  11. Positioning of sodium-glucose cotransporter-2 inhibitors in national and international guidelines.

    Science.gov (United States)

    Morillas, Carlos

    2016-11-01

    Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) selectively and reversibly inhibit sodium-glucose cotransporter-2 (SGLT2), promoting renal glucose excretion and reducing plasma glycaemia. By increasing renal glucose excretion, these drugs favour a negative energy balance, leading to weight loss. Their glucoselowering effect is independent of insulin. Although these drugs have only recently been developed, they have been included in all the main national and international guidelines since 2014. The present review summarises the most important recommendations on the use of SGLT2 in patients with DM2 contained in the most recently published guidelines and consensus statements. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  12. Oxygen-Dependent Transcriptional Regulator Hap1p Limits Glucose Uptake by Repressing the Expression of the Major Glucose Transporter Gene RAG1 in Kluyveromyces lactis▿

    Science.gov (United States)

    Bao, Wei-Guo; Guiard, Bernard; Fang, Zi-An; Donnini, Claudia; Gervais, Michel; Passos, Flavia M. Lopes; Ferrero, Iliana; Fukuhara, Hiroshi; Bolotin-Fukuhara, Monique

    2008-01-01

    The HAP1 (CYP1) gene product of Saccharomyces cerevisiae is known to regulate the transcription of many genes in response to oxygen availability. This response varies according to yeast species, probably reflecting the specific nature of their oxidative metabolism. It is suspected that a difference in the interaction of Hap1p with its target genes may explain some of the species-related variation in oxygen responses. As opposed to the fermentative S. cerevisiae, Kluyveromyces lactis is an aerobic yeast species which shows different oxygen responses. We examined the role of the HAP1-equivalent gene (KlHAP1) in K. lactis. KlHap1p showed a number of sequence features and some gene targets (such as KlCYC1) in common with its S. cerevisiae counterpart, and KlHAP1 was capable of complementing the hap1 mutation. However, the KlHAP1 disruptant showed temperature-sensitive growth on glucose, especially at low glucose concentrations. At normal temperature, 28°C, the mutant grew well, the colony size being even greater than that of the wild type. The most striking observation was that KlHap1p repressed the expression of the major glucose transporter gene RAG1 and reduced the glucose uptake rate. This suggested an involvement of KlHap1p in the regulation of glycolytic flux through the glucose transport system. The ΔKlhap1 mutant showed an increased ability to produce ethanol during aerobic growth, indicating a possible transformation of its physiological property to Crabtree positivity or partial Crabtree positivity. Dual roles of KlHap1p in activating respiration and repressing fermentation may be seen as a basis of the Crabtree-negative physiology of K. lactis. PMID:18806211

  13. Cinnamon extract regulates glucose transporter and insulin-signaling gene expression in mouse adipocytes.

    Science.gov (United States)

    Cao, Heping; Graves, Donald J; Anderson, Richard A

    2010-11-01

    Cinnamon extracts (CE) are reported to have beneficial effects on people with normal and impaired glucose tolerance, the metabolic syndrome, type 2 diabetes, and insulin resistance. However, clinical results are controversial. Molecular characterization of CE effects is limited. This study investigated the effects of CE on gene expression in cultured mouse adipocytes. Water-soluble CE was prepared from ground cinnamon (Cinnamomum burmannii). Quantitative real-time PCR was used to investigate CE effects on the expression of genes coding for adipokines, glucose transporter (GLUT) family, and insulin-signaling components in mouse 3T3-L1 adipocytes. CE (100 μg/ml) increased GLUT1 mRNA levels 1.91±0.15, 4.39±0.78, and 6.98±2.18-fold of the control after 2-, 4-, and 16-h treatments, respectively. CE decreased the expression of further genes encoding insulin-signaling pathway proteins including GSK3B, IGF1R, IGF2R, and PIK3R1. This study indicates that CE regulates the expression of multiple genes in adipocytes and this regulation could contribute to the potential health benefits of CE. Published by Elsevier GmbH.

  14. CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

    Science.gov (United States)

    Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

    2016-10-04

    Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

  15. Construction of bioartificial renal tubule assist device in vitro and its function of transporting sodium and glucose.

    Science.gov (United States)

    Dong, Xinggang; Chen, Jianghua; He, Qiang; Yang, Yi; Zhang, Wei

    2009-08-01

    To explore a new way of constructing bioartificial renal tubule assist device (RAD) in vitro and its function of transporting sodium (Na(+)) and glucose and to evaluate the application of atomic force microscope in the RAD construction, rat renal tubular epithelial cell line NRK-52E was cultured in vitro, seeded onto the outer surfaces of hollow fibers in a bioreactor, and then cultured for two weeks to construct RAD. Bioreactor hollow fibers without NRK-52E cells were used as control. The morphologies of attached cells were observed with scanning electron microscope, and the junctions of cells and polysulfone membrane were observed with atomic force microscope. Transportation of Na(+) and glucose was measured. Oubaine and phlorizin were used to inhibit the transporting property. The results showed that NRK-52E cells and polysulfone membrane were closely linked, as observed under atomic force microscope. After exposure to oubaine and phlorizin, transporting rates of Na(+) and glucose were decreased significantly in the RAD group as compared with that in the control group (Pconstructed successfully in vitro, and it is able to selectively transport Na(+) and glucose.

  16. Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines

    International Nuclear Information System (INIS)

    Sasajima, Toshio; Miyagawa, Tadashi; Oku, Takamitsu; Gelovani, Juri G.; Finn, Ronald; Blasberg, Ronald

    2004-01-01

    Amino acid imaging is increasingly being used for assessment of brain tumor malignancy, extent of disease, and prognosis. This study explores the relationship between proliferative activity, amino acid transport, and glucose metabolism in three glioma cell lines (U87, Hs683, C6) at different phases of growth in culture. Growth phase was characterized by direct cell counting, proliferation index determined by flow cytometry, and [ 3 H]thymidine (TdR) accumulation, and was compared with the uptake of two non-metabolized amino acids ([ 14 C]aminocyclopentane carboxylic acid (ACPC) and [ 14 C]aminoisobutyric acid (AIB)), and [ 18 F]fluorodeoxyglucose (FDG). Highly significant relationships between cell number (density), proliferation index, and TdR accumulation rate were observed in all cell lines (r>0.99). Influx (K 1 ) of both ACPC and AIB was directly related to cell density, and inversely related to the proliferation index and TdR accumulation in all cell lines. The volume of distribution (V d ) for ACPC and AIB was lowest during rapid growth and highest during the near-plateau growth phase in all cell lines. FDG accumulation in Hs683 and C6 cells was unaffected by proliferation rate, growth phase, and cell density, whereas FDG accumulation was correlated with TdR accumulation, growth phase, and cell density in U87 cells. This study demonstrates that proliferation rate and glucose metabolism are not necessarily co-related in all glioma cell lines. The values of K 1 and V d for ACPC and AIB under different growth conditions suggest that these tumor cell lines can up-regulate amino acid transporters in their cell membranes when their growth conditions become adverse and less than optimal. (orig.)

  17. Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes.

    Science.gov (United States)

    Biswas, Joyshree; Gupta, Sonam; Verma, Dinesh Kumar; Singh, Sarika

    2017-07-25

    The study was undertaken to explore the cell-specific streptozotocin (STZ)-induced mechanistic alterations. STZ-induced rodent model is a well-established experimental model of Alzheimer's disease (AD) and in our previous studies we have established it as an in vitro screening model of AD by employing N2A neuronal cells. Therefore, STZ was selected in the present study to understand the STZ-induced cell-specific alterations by utilizing neuronal N2A and astrocytes C6 cells. Both neuronal and astrocyte cells were treated with STZ at 10, 50, 100 and 1000μM concentrations for 48h. STZ exposure caused significant decline in cellular viability and augmented cytotoxicity of cells involving astrocytes activation. STZ treatment also disrupted the energy metabolism by altered glucose uptake and its transport in both cells as reflected with decreased expression of glucose transporters (GLUT) 1/3. The consequent decrease in ATP level and decreased mitochondrial membrane potential was also observed in both the cells. STZ caused increased intracellular calcium which could cause the initiation of endoplasmic reticulum (ER) stress. Significant upregulation of ER stress-related markers were observed in both cells after STZ treatment. The cellular communication of astrocytes and neurons was altered as reflected by increased expression of connexin 43 along with DNA fragmentation. STZ-induced apoptotic death was evaluated by elevated expression of caspase-3 and PI/Hoechst staining of cells. In conclusion, study showed that STZ exert alike biochemical alterations, ER stress and cellular apoptosis in both neuronal and astrocyte cells. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. AMP-activated protein kinase-mediated glucose transport as a novel target of tributyltin in human embryonic carcinoma cells.

    Science.gov (United States)

    Yamada, Shigeru; Kotake, Yaichiro; Sekino, Yuko; Kanda, Yasunari

    2013-05-01

    Organotin compounds such as tributyltin (TBT) are known to cause various forms of cytotoxicity, including developmental toxicity and neurotoxicity. However, the molecular target of the toxicity induced by nanomolar levels of TBT has not been identified. In the present study, we found that exposure to 100 nM TBT induced growth arrest in human pluripotent embryonic carcinoma cell line NT2/D1. Since glucose provides metabolic energy, we focused on the glycolytic system. We found that exposure to TBT reduced the levels of both glucose-6-phosphate and fructose-6-phosphate. To investigate the effect of TBT exposure on glycolysis, we examined glucose transporter (GLUT) activity. TBT exposure inhibited glucose uptake via a decrease in the level of cell surface-bound GLUT1. Furthermore, we examined the effect of AMP-activated protein kinase (AMPK), which is known to regulate glucose transport by facilitating GLUT translocation. Treatment with the potent AMPK activator, AICAR, restored the TBT-induced reduction in cell surface-bound GLUT1 and glucose uptake. In conclusion, these results suggest that exposure to nanomolar levels of TBT causes growth arrest by targeting glycolytic systems in human embryonic carcinoma cells. Thus, understanding the energy metabolism may provide new insights into the mechanisms of metal-induced cytotoxicity.

  19. Electron transport phosphorylation in rumen butyrivibrios: unprecedented ATP yield for glucose fermentation to butyrate

    Directory of Open Access Journals (Sweden)

    Timothy eHackmann

    2015-06-01

    Full Text Available From a genomic analysis of rumen butyrivibrios (Butyrivibrio and Pseudobutyrivibrio spp., we have re-evaluated the contribution of electron transport phosphorylation to ATP formation in this group. This group is unique in that most (76% genomes were predicted to possess genes for both Ech and Rnf transmembrane ion pumps. These pumps act in concert with the NifJ and Bcd-Etf to form a electrochemical potential (ΔμH+ and ΔμNa+, which drives ATP synthesis by electron transport phosphorylation. Of the 62 total butyrivibrio genomes currently available from the Hungate 1000 project, all 62 were predicted to possess NifJ, which reduces oxidized ferredoxin (Fdox during pyruvate conversion to acetyl-CoA. All 62 possessed all subunits of Bcd-Etf, which reduces Fdox and oxidizes reduced NAD (NADred during crotonyl-CoA reduction. Additionally, 61 genomes possessed all subunits of the Rnf, which generates ΔμH+ or ΔμNa+ from oxidation of reduced Fd and reduction of oxidized NAD (NADox. Further, 47 genomes possessed all 6 subunits of the Ech, which generates ΔμH+ from oxidation of reduced Fd (Fdred. For glucose fermentation to butyrate and H2, the electrochemical potential established should drive synthesis of ~1.5 ATP by the F0F1-ATP synthase (possessed by all 62 genomes. The total yield is ~4.5 ATP/glucose after accounting for 3 ATP formed by classic substrate-level phosphorylation, and it is one the highest yields for any glucose fermentation. The yield was the same when unsaturated fatty acid bonds, not H+, served as the electron acceptor (as during biohydrogenation. Possession of both Ech and Rnf had been previously documented in only a few sulfate-reducers, was rare in other rumen prokaryotic genomes in our analysis, and may confer an energetic advantage to rumen butyrivibrios. This unique energy conservation system might enhance the butyrivibrios’ ability to overcome growth inhibition by unsaturated fatty acids, as postulated herein.

  20. Fat gain with physical detraining is correlated with increased glucose transport and oxidation in periepididymal white adipose tissue in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sertié, R.A.L.; Andreotti, S. [Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil); Proença, A.R.G. [Laboratório de Biotecnologia, Faculdade de Ciências Aplicadas, Universidade Estadual de Campinas, Limeira, SP (Brazil); Campaña, A.B.; Lima, F.B. [Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2015-05-26

    As it is a common observation that obesity tends to occur after discontinuation of exercise, we investigated how white adipocytes isolated from the periepididymal fat of animals with interrupted physical training transport and oxidize glucose, and whether these adaptations support the weight regain seen after 4 weeks of physical detraining. Male Wistar rats (45 days old, weighing 200 g) were divided into two groups (n=10): group D (detrained), trained for 8 weeks and detrained for 4 weeks; and group S (sedentary). The physical exercise was carried out on a treadmill for 60 min/day, 5 days/week for 8 weeks, at 50-60% of the maximum running capacity. After the training protocol, adipocytes isolated from the periepididymal adipose tissue were submitted to glucose uptake and oxidation tests. Adipocytes from detrained animals increased their glucose uptake capacity by 18.5% compared with those from sedentary animals (P<0.05). The same cells also showed a greater glucose oxidation capacity in response to insulin stimulation (34.55%) compared with those from the S group (P<0.05). We hypothesize that, owing to the more intense glucose entrance into adipose cells from detrained rats, more substrate became available for triacylglycerol synthesis. Furthermore, this increased glucose oxidation rate allowed an increase in energy supply for triacylglycerol synthesis. Thus, physical detraining might play a role as a possible obesogenic factor for increasing glucose uptake and oxidation by adipocytes.

  1. Fat gain with physical detraining is correlated with increased glucose transport and oxidation in periepididymal white adipose tissue in rats

    International Nuclear Information System (INIS)

    Sertié, R.A.L.; Andreotti, S.; Proença, A.R.G.; Campaña, A.B.; Lima, F.B.

    2015-01-01

    As it is a common observation that obesity tends to occur after discontinuation of exercise, we investigated how white adipocytes isolated from the periepididymal fat of animals with interrupted physical training transport and oxidize glucose, and whether these adaptations support the weight regain seen after 4 weeks of physical detraining. Male Wistar rats (45 days old, weighing 200 g) were divided into two groups (n=10): group D (detrained), trained for 8 weeks and detrained for 4 weeks; and group S (sedentary). The physical exercise was carried out on a treadmill for 60 min/day, 5 days/week for 8 weeks, at 50-60% of the maximum running capacity. After the training protocol, adipocytes isolated from the periepididymal adipose tissue were submitted to glucose uptake and oxidation tests. Adipocytes from detrained animals increased their glucose uptake capacity by 18.5% compared with those from sedentary animals (P<0.05). The same cells also showed a greater glucose oxidation capacity in response to insulin stimulation (34.55%) compared with those from the S group (P<0.05). We hypothesize that, owing to the more intense glucose entrance into adipose cells from detrained rats, more substrate became available for triacylglycerol synthesis. Furthermore, this increased glucose oxidation rate allowed an increase in energy supply for triacylglycerol synthesis. Thus, physical detraining might play a role as a possible obesogenic factor for increasing glucose uptake and oxidation by adipocytes

  2. The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

    Science.gov (United States)

    Schernthaner, Guntram; Mogensen, Carl Erik; Schernthaner, Gerit-Holger

    2014-09-01

    Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © The Author(s) 2014.

  3. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

    Directory of Open Access Journals (Sweden)

    Vickers SP

    2014-07-01

    Full Text Available Steven P Vickers,1 Sharon C Cheetham,1 Katie R Headland,1 Keith Dickinson,1 Rolf Grempler,2 Eric Mayoux,2 Michael Mark,2 Thomas Klein2 1RenaSci, BioCity Nottingham, Nottingham, UK; 2Boehringer Ingelheim Pharma, Biberach an der Riss, Germany Abstract: The present study assessed the potential of the sodium glucose-linked transporter (SGLT-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. Keywords

  4. Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle

    DEFF Research Database (Denmark)

    Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu

    2010-01-01

    The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related prot...

  5. The ontogeny of nutrient transporter and digestive enzyme gene expression in domestic pigeon (Columba livia) intestine and yolk sac membrane during pre- and posthatch development.

    Science.gov (United States)

    Dong, X Y; Wang, Y M; Yuan, C; Zou, X T

    2012-08-01

    To better understand the digestive capacity in domestic pigeons (Columba livia), this study was conducted to evaluate nutrient transporters and digestive enzymes gene expression in small intestine and yolk sac membrane (YSM) during pre- and posthatch development. We investigated the oligopeptide transporter Pept1, sodium glucose transporter SGLT1, glucose transporter GLUT2, aminopeptidase-N (APN), and sucrase-isomaltase (SI). Intestine was collected at embryo d 12, 14, and 16, day of hatch, and d 1, 3, 5, 8, and 14 posthatch. The YSM was collected at embryo d 12, 14, 16, and day of hatch. The cDNA fragments for Pept1, SGLT1, GLUT2, APN, and SI were isolated and cloned using reverse-transcription PCR. The sequences data showed that these genes were highly identical to the gene of chicken. The mRNA expression of each gene was assayed using real-time PCR. Expression of intestinal nutrient transporters increased linearly (Ppigeons and establish a foundation for future research on the nutrients requirements for young pigeons.

  6. Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation

    DEFF Research Database (Denmark)

    Barres, Romain; Grémeaux, Thierry; Gual, Philippe

    2006-01-01

    a critical role in actin cytoskeleton organization in fibroblastic cells. Because actin rearrangement is important for insulin-induced glucose transporter 4 (Glut 4) translocation, we studied the potential involvement of Enigma in insulin-induced glucose transport in 3T3-L1 adipocytes. Enigma m...

  7. Evaluating Drug Cost per Response with SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Lopez, Janice M S; Macomson, Brian; Ektare, Varun; Patel, Dipen; Botteman, Marc

    2015-09-01

    The sodium-glucose cotransporter 2 (SGLT2) inhibitors, which include canagliflozin, dapagliflozin, and empagliflozin, represent a new class of antihyperglycemic agents. Few studies have assessed their cost per response, with "cost per response" being the total cost of a select drug, divided by the resulting change in glycated hemoglobin (HbA1c) levels. To examine the drug cost of SGLT2 inhibitors per a reduction in placebo-adjusted 1% HbA1c in patients with type 2 diabetes mellitus who received treatment during 26 weeks with canagliflozin, dapagliflozin, or empagliflozin. The drug cost per response for each of the 3 agents individually was assessed based on data from a subset of clinical trials discussed in the prescribing information for each drug that were all placebo-controlled studies evaluating each drug as monotherapy, dual therapy (combined with metformin), and triple therapy (combined with metformin and a sulfonylurea) in patients with uncontrolled, type 2 diabetes mellitus. The US 2015 wholesale acquisition cost for each drug was used to calculate each drug's treatment costs over 26 weeks. The average cost per response for each drug was defined as the prescription drug cost of each SGLT2 inhibitor, divided by the average, placebo-adjusted HbA1c reduction at 26 weeks. The drug cost per unit dose was the same for canagliflozin (100 mg or 300 mg), dapagliflozin (5 mg or 10 mg), and empagliflozin (10 mg or 25 mg), at $11.43. The drug cost per placebo-adjusted 1% HbA1c reduction varied by agent and by dose, as a result of the differences in the treatment responses for each of the 3 drugs. The costs per response for canagliflozin 100 mg as monotherapy, dual therapy, and triple therapy regimens ranged from $2286 to $3355, and for canagliflozin 300 mg, from $1793 to $2702. The costs per response for dapagliflozin 5 mg as monotherapy and dual therapy (triple therapy was not available at the time of the study) ranged from $4161 to $5201; the cost for dapagliflozin

  8. Humanin (HN and glucose transporter 8 (GLUT8 in pregnancies complicated by intrauterine growth restriction.

    Directory of Open Access Journals (Sweden)

    Carla Janzen

    Full Text Available Intrauterine growth restriction (IUGR results from a lack of nutrients transferred to the developing fetus, particularly oxygen and glucose. Increased expression of the cytoprotective mitochondrial peptide, humanin (HN, and the glucose transporter 8, GLUT8, has been reported under conditions of hypoxic stress. However, the presence and cellular localization of HN and GLUT8 in IUGR-related placental pathology remain unexplored. Thus, we undertook this study to investigate placental expression of HN and GLUT8 in IUGR-affected versus normal pregnancies.We found 1 increased HN expression in human IUGR-affected pregnancies on the maternal aspect of the placenta (extravillous trophoblastic (EVT cytoplasm compared to control (i.e. appropriate for gestational age pregnancies, and a concomitant increase in GLUT8 expression in the same compartment, 2 HN and GLUT8 showed a protein-protein interaction by co-immunoprecipitation, 3 elevated HN and GLUT8 levels in vitro under simulated hypoxia in human EVT cells, HTR8/SVneo, and 4 increased HN expression but attenuated GLUT8 expression in vitro under serum deprivation in HTR8/SVneo cells.There was elevated HN expression with cytoplasmic localization to EVTs on the maternal aspect of the human placenta affected by IUGR, also associated with increased GLUT8 expression. We found that while hypoxia increased both HN and GLUT8, serum deprivation increased HN expression alone. Also, a protein-protein interaction between HN and GLUT8 suggests that their interaction may fulfill a biologic role that requires interdependency. Future investigations delineating molecular interactions between these proteins are required to fully uncover their role in IUGR-affected pregnancies.

  9. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption

    Science.gov (United States)

    Patel, Chirag; Douard, Veronique; Yu, Shiyan; Gao, Nan; Ferraris, Ronaldo P.

    2015-01-01

    Dietary fructose that is linked to metabolic abnormalities can up-regulate its own absorption, but the underlying regulatory mechanisms are not known. We hypothesized that glucose transporter (GLUT) protein, member 5 (GLUT5) is the primary fructose transporter and that fructose absorption via GLUT5, metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein-in-brain 11 (Rab11)a-dependent endosomes are each required for regulation. Introducing fructose but not lysine and glucose solutions into the lumen increased by 2- to 10-fold the heterogeneous nuclear RNA, mRNA, protein, and activity levels of GLUT5 in adult wild-type mice consuming chow. Levels of GLUT5 were >100-fold that of candidate apical fructose transporters GLUTs 7, 8, and 12 whose expression, and that of GLUT 2 and the sodium-dependent glucose transporter protein 1 (SGLT1), was not regulated by luminal fructose. GLUT5-knockout (KO) mice exhibited no facilitative fructose transport and no compensatory increases in activity and expression of SGLT1 and other GLUTs. Fructose could not up-regulate GLUT5 in GLUT5-KO, KHK-KO, and intestinal epithelial cell-specific Rab11a-KO mice. The fructose-specific metabolite glyceraldehyde did not increase GLUT5 expression. GLUT5 is the primary transporter responsible for facilitative absorption of fructose, and its regulation specifically requires fructose uptake and metabolism and normal GLUT5 trafficking to the apical membrane.—Patel, C., Douard, V., Yu, S., Gao, N., Ferraris, R. P. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. PMID:26071406

  10. Biological and Clinical Study of 6-Deoxy-6-Iodo-D-Glucose: a iodinated tracer of glucose transport and of insulin-resistance in human

    International Nuclear Information System (INIS)

    Barone-Rochette, Gilles

    2013-01-01

    Insulin resistance (IR), characterized by a depressed cellular sensitivity to insulin in insulin-sensitive organs, is a central feature to obesity, the metabolic syndrome, and diabetes mellitus and leads to increase cardiovascular diseases, particularly heart failure. All these events are today serious public health problems. But actually, there is no simple tool to measure insulin resistance. The gold standard technique remains the hyperinsulinemic euglycemic clamp. However, the complexity and length of this technique render it unsuitable for routine clinical use. Many methods or index have been proposed to assess insulin resistance in human, but none have shown enough relevance to be used in clinical use. The U1039 INSERM unit previously has validated a new tracer of glucose transport, radiolabelled with 123 iodine and has developed a fast and simple imaging protocol with a small animal gamma camera, which allows the obtaining of an IR index for each organ, showing more discriminating for the heart. The project of my thesis was the human transfer of this measurement technique, perfectly validated in animal. The first part of this thesis evaluated to tolerance, in vivo kinetics, distribution and dosimetry of novel tracer of glucose transport, the [ 123 I]-6DIG. The safeties of new tracer and measurement technique were adequate. There were no adverse effects with excellent tolerance of the whole protocol. 6DIG eliminating was fast, primarily in the urine and complete within 72 h. The effective whole-body absorbed dose for a complete scan with injection of 92.5 * 2 MBq was between 3 to 4 mSv. The second part of this thesis evaluated in human feasibility and reproducibility of the measurement technique validated in animal. The third part showed techniques used to allow human transfer of this method. The study protocol was applied on 12 subjects (healthy volunteers (n=6) and type 2 diabetic patients (n=6)). With a method adapted to measure in humans, we determined an

  11. Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34 motor neuron-like cells via AMPK pathway activation.

    Science.gov (United States)

    Daniel, Bareket; Green, Omer; Viskind, Olga; Gruzman, Arie

    2013-09-01

    Riluzole is the only approved ALS drug. Riluzole influences several cellular pathways, but its exact mechanism of action remains unclear. Our goal was to study the drug's influence on the glucose transport rate in two ALS relevant cell types, neurons and myotubes. Stably transfected wild-type or mutant G93A human SOD1 NSC-34 motor neuron-like cells and rat L6 myotubes were exposed to riluzole. The rate of glucose uptake, translocation of glucose transporters to the cell's plasma membrane and the main glucose transport regulatory proteins' phosphorylation levels were measured. We found that riluzole increases the glucose transport rate and up-regulates the translocation of glucose transporters to plasma membrane in both types of cells. Riluzole leads to AMPK phosphorylation and to the phosphorylation of its downstream target, AS-160. In conclusion, increasing the glucose transport rate in ALS affected cells might be one of the mechanisms of riluzole's therapeutic effect. These findings can be used to rationally design and synthesize novel anti-ALS drugs that modulate glucose transport in neurons and skeletal muscles.

  12. Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice.

    Science.gov (United States)

    Atageldiyeva, Kuralay; Fujita, Yukihiro; Yanagimachi, Tsuyoshi; Mizumoto, Katsutoshi; Takeda, Yasutaka; Honjo, Jun; Takiyama, Yumi; Abiko, Atsuko; Makino, Yuichi; Haneda, Masakazu

    2016-01-01

    A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.

  13. Energy metabolism and memory processing: role of glucose transport and glycogen in responses to adrenoceptor activation in the chicken.

    Science.gov (United States)

    Hutchinson, Dana S; Summers, Roger J; Gibbs, Marie E

    2008-06-15

    From experiments using a discriminated bead task in young chicks, we have defined when and where adrenoceptors (ARs) are involved in memory modulation. All three ARs subtypes (alpha(1)-, alpha(2)- and beta-ARs) are found in the chick brain and in regions associated with memory. Glucose and glycogen are important in the role of memory consolidation in the chick since increasing glucose levels improves memory consolidation while inhibiting glucose transporters (GLUTs) or glycogen breakdown inhibits memory consolidation. The selective beta(3)-AR agonist CL316243 enhances memory consolidation by a glucose-dependent mechanism and the administration of the non-metabolized glucose analogue 2-deoxyglucose reduces the ability of CL316243 to enhance memory. Agents that reduce glucose uptake by GLUTs and its incorporation into the glycolytic pathway also reduce the effectiveness of CL316243, but do not alter the dose-response relationship to the beta(2)-AR agonist zinterol. However, beta(2)-ARs do have a role in memory related to glycogen breakdown and inhibition of glycogenolysis reduces the ability of zinterol to enhance memory. Both beta(2)- and beta(3)-ARs are found on astrocytes from chick forebrain, and the actions of beta(3)-ARs on glucose uptake, and beta(2)-ARs on the breakdown of glycogen is consistent with an effect on astrocytic metabolism at the time of memory consolidation 30 min after training. We have shown that both beta(2)- and beta(3)-ARs can increase glucose uptake in chick astrocytes but do so by different mechanisms. This review will focus on the role of ARs on memory consolidation and specifically the role of energy metabolism on AR modulation of memory.

  14. Simultaneous measurement of glucose blood–brain transport constants and metabolic rate in rat brain using in-vivo 1H MRS

    Science.gov (United States)

    Du, Fei; Zhang, Yi; Zhu, Xiao-Hong; Chen, Wei

    2012-01-01

    Cerebral glucose consumption and glucose transport across the blood–brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMRglc) and glucose transport constants (KT: half-saturation constant; Tmax: maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMRglc, KT, and Tmax via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo 1H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMRglc, Tmax, and KT were determined to be 0.44±0.17 μmol/g per minute, 1.35±0.47 μmol/g per minute, and 13.4±6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMRglc and Tmax are more reliable than that of KT. The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. PMID:22714049

  15. Prognostic significance of glucose transporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy

    International Nuclear Information System (INIS)

    Saigusa, Susumu; Toiyama, Yuji; Tanaka, Koji; Okugawa, Yoshinaga; Fujikawa, Hiroyuki; Matsushita, Kohei; Uchida, Keiichi; Inoue, Yasuhiro; Kusunoki, Masato

    2012-01-01

    Most cancer cells exhibit increased glycolysis. The elevated glucose transporter 1 (GLUT1) expression has been reported to be associated with resistance to therapeutic agents and a poor prognosis. We wondered whether GLUT1 expression was associated with the clinical outcome in rectal cancer after preoperative chemoradiotherapy (CRT), and whether glycolysis inhibition could represent a novel anticancer treatment. We obtained total RNA from residual cancer cells using microdissection from a total of 52 rectal cancer specimens from patients who underwent preoperative CRT. We performed transcriptional analyzes, and studied the association of the GLUT1 gene expression levels with the clinical outcomes. In addition, we examined each proliferative response of three selected colorectal cancer cell lines to a glycolysis inhibitor, 3-bromopyruvic acid (3-BrPA), with regard to their expression of the GLUT1 gene. An elevated GLUT1 gene expression was associated with a high postoperative stage, the presence of lymph node metastasis, and distant recurrence. Moreover, elevated GLUT1 gene expression independently predicted both the recurrence-free and overall survival. In the in vitro studies, we observed that 3-BrPA significantly suppressed the proliferation of colon cancer cells with high GLUT1 gene expression, compared with those with low expression. An elevated GLUT1 expression may be a useful predictor of distant recurrence and poor prognosis in rectal cancer patients after preoperative CRT. (author)

  16. Glucose Transporter 1 Expression in Odontogenic Keratocyst, Dentigerous Cyst, and Ameloblastoma: An Immunohistochemical Study.

    Science.gov (United States)

    Bandyopadhyay, Alokenath; Panda, Abikshyeet; Behura, Shyam S; Ramachandra, Sujatha; Dash, Kailash C; Mishra, Pallavi

    2017-05-01

    An array of odontogenic lesions manifest in the maxillofacial region with variable presentations. The biological behavior of lesions, such as odontogenic keratocyst (OKC), dentigerous cyst (DC), and ameloblastoma (AM) always invite debate. Glucose transporter 1 (GLUT-1) is proven to be an indicator of metabolic behavior of several benign and malignant neoplasms. The purpose of this study was to evaluate the expression of GLUT-1 in OKC, DC, and AM to understand their metabolic behavior. Immunohistochemical expression of GLUT-1 was evaluated in each of the 15 cases of OKC, DC, and AM. The number of labeled cells, staining intensity, and membrane or cytoplasmic expressions were the parameters assessed and analyzed using chi-square test. All cases showed positive GLUT-1 expression: 86.6% OKC showed more than 50% labeled cells followed by DC (40%) and AM (26.5%); 53.3% OKC showed strong intensity in comparison to AM, which showed weak intensity in 53.3% cases; 86.6% of OKCs showed both membrane and cytoplasmic expression followed by DC (40%) and AM (26.6%), whereas 73.3% of AM showed only membrane expression followed by DC (60%) and OKC (13.3%). Odontogenic keratocyst was found out to be more metabolically active followed by DC and AM.

  17. Inhibitory effect of bofutsushosan (fang feng tong sheng san) on glucose transporter 5 function in vitro.

    Science.gov (United States)

    Gao, Shengli; Satsu, Hideo; Makino, Toshiaki

    2018-03-01

    Bofutsushosan (BTS; fang feng tong sheng san in Chinese) is a formula in traditional Japanese Kampo medicine and Chinese medicine comprising eighteen crude drugs, and is used to treat obesity and metabolic syndrome. Fructose is contained in refreshing beverages as high-fructose corn syrup, and is associated with obesity. Fructose is absorbed via glucose transporter 5 (GLUT5) in the intestine. Therefore, the inhibition of GLUT5 is considered to be a target of obesity drugs. We evaluated the inhibitory effects of BTS extract and its constituents on fructose uptake using Chinese hamster ovary K1 cells, i.e., cells stably expressing GLUT5. Boiled water extract of BTS significantly suppressed GLUT5 function in a concentration-dependent manner without cytotoxicities. Among 18 components of BTS, the boiled water extracts of the rhizome of Zingiber officinale, the root and rhizome of Saposhnikovia divaricata, and the root of Platycodon grandiflorum exhibited significant inhibitory effects on fructose uptake with IC 50 values of 314, 119 and 475 µg/ml, respectively. Among the constituents of the rhizome of Z. officinale extract, 6-gingerol significantly inhibited GLUT5 with an IC 50 value of 39 µM, while 6-shogaol exhibited a significant but weak inhibition on GLUT5 at 100 µM. One of the mechanisms of action of BTS may be the inhibition of fructose absorption in the intestine, and one of the active components of BTS is the rhizome of Z. officinale and 6-gingerol.

  18. Role of the water extract from Coccinia indica stem on the stimulation of glucose transport in L8 myotubes

    Directory of Open Access Journals (Sweden)

    Chaweewan Jansakul

    2006-11-01

    Full Text Available Hypoglycemic effect of Coccinia indica used for treatment of diabetes in traditional remedies has known to relate with increased transport of glucose into peripheral tissues. However, the cellular mechanisms for this effect remain unclear. This present study reports that the water extract (WE of C. indica stem exhibited a dose-dependent induction of 2-deoxyglucose (2-DG uptake in rat L8 myotubes. Maximal uptake was observed with approximately 3-fold increase in 2-DG transport in 16 h treatment compared with the control. Effect of WE was stronger than that of 1 mM metformin. The effects of insulin and WE were additive. WE-induced glucose uptake was significantly inhibited by cycloheximide and partially reversed by SB203580. GLUT1 protein was markedly increased in response to WE. Conversely, WE had no effect on GLUT4 protein level. Redistribution of GLUT4 to the plasma membrane was demonstrated. Triterpenoids and carbohydrates were detected in WE. In conclusion, new GLUT1 protein synthesis is necessary for WEstimulated glucose transport while p38-MAPK-dependent activation of transporter intrinsic activity partly contributes to WE action. These results may explain and support the use of C. indica for the prevention and treatment of diabetes.

  19. Photoaffinity labeling of the human erythrocyte monosaccharide transporter with an aryl azide derivative of D-glucose

    International Nuclear Information System (INIS)

    Shanahan, M.F.; Wadzinski, B.E.; Lowndes, J.M.; Ruoho, A.E.

    1985-01-01

    A photoreactive, radioiodinated derivative of glucose, N-(4-iodoazidosalicyl)-6-amido-6-deoxyglucopyranose (IASA-glc), has been synthesized and used as a photoaffinity label for the human erythrocyte monosaccharide transporter. Photoinactivation and photoinsertion are both light-dependent and result in a marked decrease in the absorption spectra of the compound. When [ 125 I]IASA-glc was photolyzed with erythrocyte ghost membranes, photoinsertion of radiolabel was observed in three major regions, spectrin, band 3, and a protein of 58,000 daltons located in the zone 4.5 region. Of the three regions which were photolabeled, only labeling of polypeptides in the zone 4.5 region was partially blocked by D-glucose. In the non-iodinated form, N-(4-azidosalicyl)-6-amido-6-deoxy-glucopyranose inhibited the labeling of the transporter by [ 125 I]IASA-glc more effectively than D-glucose. The ability to synthesize this [ 125 I]containing photoprobe for the monosaccharide transporter at carrier-free levels offers several new advantages for investigating the structure of this transport protein in the erythrocyte

  20. Gestational Protein Restriction Impairs Insulin-Regulated Glucose Transport Mechanisms in Gastrocnemius Muscles of Adult Male Offspring

    Science.gov (United States)

    Blesson, Chellakkan S.; Sathishkumar, Kunju; Chinnathambi, Vijayakumar

    2014-01-01

    Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet–exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet–fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor

  1. Inhibition of Glucose Transport by Tomatoside A, a Tomato Seed Steroidal Saponin, through the Suppression of GLUT2 Expression in Caco-2 Cells.

    Science.gov (United States)

    Li, Baorui; Terazono, Yusuke; Hirasaki, Naoto; Tatemichi, Yuki; Kinoshita, Emiko; Obata, Akio; Matsui, Toshiro

    2018-02-14

    We investigated whether tomatoside A (5α-furostane-3β,22,26-triol-3-[O-β-d-glucopyranosyl (1→2)-β-d-glucopyranosyl (1→4)-β-d-galactopyranoside] 26-O-β-d-glucopyranoside), a tomato seed saponin, may play a role in the regulation of intestinal glucose transport in human intestinal Caco-2 cells. Tomatoside A could not penetrate through Caco-2 cell monolayers, as observed in the transport experiments using liquid chromatography-mass spectrometry. The treatment of cells with 10 μM tomatoside A for 3 h resulted in a 46.0% reduction in glucose transport as compared to untreated cells. Western blotting analyses revealed that tomatoside A significantly (p transporter 2 (GLUT2) in Caco-2 cells, while no change in the expression of sodium-dependent glucose transporter 1 was observed. In glucose transport experiments, the reduced glucose transport by tomatoside A was ameliorated by a protein kinase C (PKC) inhibitor and a multidrug resistance-associated protein 2 (MRP2) inhibitor. The tomatoside A-induced reduction in glucose transport was restored in cells treated with apical sodium-dependent bile acid transporter (ASBT) siRNA or an ASBT antagonist. These findings demonstrated for the first time that the nontransportable tomato seed steroidal saponin, tomatoside A, suppressed GLUT2 expression via PKC signaling pathway during the ASBT-influx/MRP2-efflux process in Caco-2 cells.

  2. Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitors.

    Science.gov (United States)

    Yan, Qi; Ding, Ning; Li, Yingxia

    2016-02-08

    A series of novel C-aryl glucosides containing dioxa-bicycle were synthesized and evaluated for inhibition activity against hSGLT2. Among the compounds tested, compound 6a showed moderate SGLT2 inhibition activities at 700 nM. The results could benefit the discovery of new SGLT2 inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Studies of genetic variability of the glucose transporter 2 promoter in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Møller, A M; Jensen, N M; Pildal, J

    2001-01-01

    This study was performed to test the hypothesis that genetic variation in the promoter of the glucose transporter 2 (GLUT2) might predispose to prediabetic phenotypes or type 2 diabetes. A total of 1611 bp comprising the minimal promoter region of the GLUT2 gene were examined by combined single-s......-tolerant subjects. In conclusion, we found no evidence supporting the hypothesis that genetic variability in the minimal promoter of the GLUT2 is associated with type 2 diabetes or prediabetic phenotypes in the Danish population.......This study was performed to test the hypothesis that genetic variation in the promoter of the glucose transporter 2 (GLUT2) might predispose to prediabetic phenotypes or type 2 diabetes. A total of 1611 bp comprising the minimal promoter region of the GLUT2 gene were examined by combined single...

  4. Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives

    Directory of Open Access Journals (Sweden)

    Mathew John

    2016-01-01

    Full Text Available The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin leads to weight gain and increased risk of hypoglycemia. Sodium-glucose cotransporter 2 (SGLT2 inhibitors are a class of antihyperglycemic agents which act by blocking the SGLT2 in the proximal tubule of the kidney. They have potential benefits in terms of weight loss and reduction of blood pressure in addition to improvements in glycemic control. Further, one of the SGLT2 inhibitors, empagliflozin has proven benefits in reducing adverse cardiovascular (CV outcomes in a CV outcome trial. Adding SGLT2 inhibitors to insulin in subjects with type 2 diabetes produced favorable effects on glycemic control without the weight gain and hypoglycemic risks associated with insulin therapy. The general risks of increased genital mycotic infections, urinary tract infections, volume, and osmosis-related adverse effects in these subjects were similar to the pooled data of individual SGLT2 inhibitors. There are subsets of subjects with type 2 diabetes who may have insulin deficiency, beta cell autoimmunity, or is prone to diabetic ketoacidosis. In these subjects, SGLT2 inhibitors should be used with caution to prevent the rare risks of ketoacidosis.

  5. Identification of the glucose transporter in mammalian cell membranes using an 125(I)-forskolin photoaffinity label

    International Nuclear Information System (INIS)

    Ruoho, A.; Wadzinski, B.; Shanahan, M.

    1987-01-01

    The glucose transporter has been identified in a variety of mammlian cell membranes using a carrier-free photoactivatable radioiodinated derivative of forskolin, 3-iodo-4-azidophenethylamido-7-0-succinyldeacetyl-forskolin, [I-125]IAPS-Fsk, at 1-10 nM. The membranes which have been photolabeled with [I-125]IAPS-Fsk are: rat cardiac sarcolemmal membranes, rat cortex and cerebellum synaptic membranes, human placental membranes, and wild type S49 lymphoma cell membranes. The glucose transporter in rat cardiac sarcolemmal membranes and rat cortex and cerebellum synaptic membranes was determined to be 45 kDa by SDS-PAGE. Photolysis of human placental membranes and S49 lymphoma membranes with [I-125]IAPS-Fsk followed by SDS-PAGE indicated specific derivatization of a broad band (45-55 kDa) in placental membranes and a narrower band (45 kDa) in the S49 lymphoma membranes. Digestion of the [I-125]IPAS-Fsk labelled placental and S49 lymphoma membranes with endo-B-galactosidase showed a reduction in the apparent molecular weight of the radiolabelled band to 40 kDa. Trypsinization of labelled placental and lymphoma membranes produced an 18 kDa radiolabelled proteolytic fragment. [I-125]IAPS-Fsk is a highly effective probe for identifying low levels of glucose transporters in mammalian tissues

  6. Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

    Directory of Open Access Journals (Sweden)

    Archana Vijayakumar

    2017-10-01

    Full Text Available Lower adipose-ChREBP and de novo lipogenesis (DNL are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO mice with negligible sucrose-induced DNL in adipose tissue (AT. Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways.

  7. Immunohistochemical expression of glucose transporter 1 in keratin-producing odontogenic cysts.

    Science.gov (United States)

    Vera-Sirera, Beatriz; Forner-Navarro, Leopoldo; Vera-Sempere, Francisco

    2016-03-10

    Keratin-producing odontogenic cysts (KPOCs) are a group of cystic lesions that are often aggressive, with high rates of recurrence and multifocality. KPOCs included orthokeratinised odontogenic cyst (OOC) and parakeratotic odontogenic cysts, which are now considered true tumours denominated keratocystic odontogenic tumours (KCOTs). GLUT1 is a protein transporter that is involved in the active uptake of glucose across cell membranes and that is overexpressed in tumours in close correlation with the proliferation rate and positron emission tomography (PET) imaging results. A series of 58 keratin-producing odontogenic cysts was evaluated histologically and immunohistochemically in terms of GLUT1 expression. Different data were correlated using the beta regression model in relation to histological type and immunohistochemical expression of GLUT1, which was quantified using two different morphological methods. KPOC cases comprised 12 OOCs and 46 KCOTs, the latter corresponding to 6 syndromic and 40 sporadic KCOTs. GLUT1 expression was very low in OOC cases compared with KCOT cases, with statistical significant differences when quantification was considered. Different GLUT1 localisation patterns were revealed by immunostaining, with the parabasal cells showing higher reactivity in KCOTs. However, among KCOTs cases, GLUT1 expression was unable to establish differences between syndromic and sporadic cases. GLUT1 expression differentiated between OOC and KCOT cases, with significantly higher expression in KCOTs, but did not differentiate between syndromic and sporadic KCOT cases. However, given the structural characteristics of KCOTs, we hypothesised that PET imaging methodology is probably not a useful diagnostic tool for KCOTs. Further studies of GLUT1 expression and PET examination in KCOT series are needed to confirm this last hypothesis.

  8. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice

    Directory of Open Access Journals (Sweden)

    Atsuo Tahara

    2016-07-01

    Full Text Available Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.

  9. Case Reports That Illustrate the Efficacy of SGLT2 Inhibitors in the Type 1 Diabetic Patient

    Directory of Open Access Journals (Sweden)

    David S. H. Bell

    2015-01-01

    Full Text Available SGLT2 inhibitors are only approved for use in adults with type 2 diabetes. However, because SGLT2 inhibitors have a mechanism of action that does not require the presence of endogenous insulin, these drugs should also be efficacious in type 1 diabetes where endogenous insulin production is greatly reduced or absent. Herein, I present five cases which illustrate the benefits of utilizing an SGLT2 inhibitor with type 1 diabetes. In these cases the use of SGLT2 inhibitors resulted not only in better glycemic control in most patients but also in some patients’ less hypoglycemia, weight loss, and decreased doses of insulin. In type 1 diabetes Candida albicans vaginitis and balanitis may occur more frequently than in type 2 diabetes. These cases show that a large randomized clinical trial of SGLT2 inhibitors in type 1 diabetes needs to be performed.

  10. Striatal dopamine transporter, regional cerebral blood flow and glucose utilization in MPTP-induced parkinson disease mice model

    International Nuclear Information System (INIS)

    Gao Yunchao; Wu Chunying; Xiang Jingde; Lin Xiangtong; Zhu Huiqing

    2005-01-01

    Objective: To explore the variation of regional cerebral blood flow (rCBF), glucose utilization as well as the neurotoxic effect on dopaminergic neurons induced by neurotoxin 1-methy-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP). Methods: Eight-week old male C57BL/6 mice were given a total dose of 0-80 mg/kg MPTP intraperitoneally. Ten days later the mice were sacrificed for tyrosine hydroxylase (TH)-immunopositive cell count- ing in substantia nigra using SP immunohistochemistry. Vivo autoradiography was employed to measure striatal do- pamine transporter (DAT) loss, rCBF and glucose utilization in striatum and thalamus. Results: The extents of DAT depletion and TH-immunopositive cell loss were positively correlated (r=0.998, P O.2), while