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Sample records for attenuates glucose-stimulated insulin

  1. Insulin Augmentation of Glucose-Stimulated Insulin Secretion Is Impaired in Insulin-Resistant Humans

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    Halperin, Florencia; Lopez, Ximena; Manning, Raquel; Kahn, C. Ronald; Kulkarni, Rohit Narayan; Goldfine, Allison Braunwald

    2012-01-01

    Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin’s effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, a...

  2. Insulin enhances glucose-stimulated insulin secretion in healthy humans

    OpenAIRE

    Bouche, Clara; Lopez, Ximena; Fleischman, Amy; Cypess, Aaron M.; O'Shea, Sheila; Stefanovski, Darko; Bergman, Richard N.; Rogatsky, Eduard; Stein, Daniel T.; Kahn, C. Ronald; Kulkarni, Rohit N.; Goldfine, Allison B.

    2010-01-01

    Islet β-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates β-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) c...

  3. Mitochondrial superoxide generation is diminished during glucose-stimulated insulin secretion in INS-1E cells

    Czech Academy of Sciences Publication Activity Database

    Špaček, Tomáš; Hlavatá, Lydie; Ježek, Petr

    Elsevier. Roč. 1777, Suppl. (2008), S48-S48. ISSN 0005-2728. [European Bioenergetics Conference /15./. 19.07.2008-24.07.2008, Dublin] R&D Projects: GA AV ČR(CZ) IAA500110701; GA MZd NR9183 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * superoxide * INS-1E cells * glucose-stimulated insulin secretion Subject RIV: ED - Physiology

  4. Superoxide generation is diminished during glucose-stimulated insulin secretion in INS-1E cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Hlavatá, Lydie; Špaček, Tomáš

    2008-01-01

    Roč. 275, Suppl.1 (2008), s. 310-310. ISSN 1742-464X. [FEBS Congress /33./ and IUBMB Conference /11./. 28.06.2008-03.07.2008, Athens] R&D Projects: GA MZd(CZ) NR7917; GA AV ČR(CZ) IAA500110701 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * superoxide production * glucose-stimulated insulin secretion * INS-1E cells Subject RIV: ED - Physiology

  5. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol

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    Nøhr, Mark K.; Dudele, Anete; Poulsen, Morten M.; Ebbesen, Lene H.; Radko, Yulia; Christensen, Lars P.; Jessen, Niels; Richelsen, Bjørn; Lund, Sten; Pedersen, Steen B.

    2016-01-01

    Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin / delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. In conclusion: Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin

  6. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

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    Douillet, Christelle [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Currier, Jenna [Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Saunders, Jesse [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Bodnar, Wanda M. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States); Matoušek, Tomáš [Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic); Stýblo, Miroslav, E-mail: styblo@med.unc.edu [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  7. Mitochondrial Pyruvate Carrier 2 Hypomorphism in Mice Leads to Defects in Glucose-Stimulated Insulin Secretion

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    Patrick A. Vigueira

    2014-06-01

    Full Text Available Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. Mitochondrial pyruvate carrier 2 (Mpc2 is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2Δ16 was viable but exhibited a reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2Δ16 mice. Additionally, compared with wild-type controls, Mpc2Δ16 mice exhibited normal insulin sensitivity but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic β cell glucose sensing.

  8. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

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    Jianhui Liu

    Full Text Available Glucose-stimulated insulin secretion (GSIS is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM. Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

  9. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

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    Minglin Pan

    2011-01-01

    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  10. The influence of GLP-1 on glucose-stimulated insulin secretion

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    Kjems, Lise L; Holst, Jens Juul; Vølund, Aage;

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2...... diabetes and from 711 +/- 123 to 2,415 +/- 243 pmol/kg in the control subjects. The beta-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose...... in the patients and 11 times in the control subjects, but it was 3 to 5 times lower in the patients with type 2 diabetes compared with healthy subjects at the same GLP-1 dose. During infusion of GLP-1 at 0.5 pmol x kg(-1) x min(-1) in the patients, the slope of ISR versus glucose became...

  11. Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action.

    Science.gov (United States)

    Muzumdar, Radhika; Ma, Xiaohui; Atzmon, Gil; Vuguin, Patricia; Yang, Xiaoman; Barzilai, Nir

    2004-02-01

    While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes. PMID:14747296

  12. Exercise Intensity Modulates Glucose-Stimulated Insulin Secretion when Adjusted for Adipose, Liver and Skeletal Muscle Insulin Resistance

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    Malin, Steven K.; Rynders, Corey A.; Weltman, Judy Y.; Barrett, Eugene J.; Weltman, Arthur

    2016-01-01

    Little is known about the effects of exercise intensity on compensatory changes in glucose-stimulated insulin secretion (GSIS) when adjusted for adipose, liver and skeletal muscle insulin resistance (IR). Fifteen participants (8F, Age: 49.9±3.6yr; BMI: 31.0±1.5kg/m2; VO2peak: 23.2±1.2mg/kg/min) with prediabetes (ADA criteria, 75g OGTT and/or HbA1c) underwent a time-course matched Control, and isocaloric (200kcal) exercise at moderate (MIE; at lactate threshold (LT)), and high-intensity (HIE; 75% of difference between LT and VO2peak). A 75g OGTT was conducted 1 hour post-exercise/Control, and plasma glucose, insulin, C-peptide and free fatty acids were determined for calculations of skeletal muscle (1/Oral Minimal Model; SMIR), hepatic (HOMAIR), and adipose (ADIPOSEIR) IR. Insulin secretion rates were determined by deconvolution modeling for GSIS, and disposition index (DI; GSIS/IR; DISMIR, DIHOMAIR, DIADIPOSEIR) calculations. Compared to Control, exercise lowered SMIR independent of intensity (P<0.05), with HIE raising HOMAIR and ADIPOSEIR compared with Control (P<0.05). GSIS was not reduced following exercise, but DIHOMAIR and DIADIPOSEIR were lowered more following HIE compared with Control (P<0.05). However, DISMIR increased in an intensity based manner relative to Control (P<0.05), which corresponded with lower post-prandial blood glucose levels. Taken together, pancreatic insulin secretion adjusts in an exercise intensity dependent manner to match the level of insulin resistance in skeletal muscle, liver and adipose tissue. Further work is warranted to understand the mechanism by which exercise influences the cross-talk between tissues that regulate blood glucose in people with prediabetes. PMID:27111219

  13. Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

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    Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

    2015-11-01

    Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. PMID:26348137

  14. Intrinsic optical signal imaging of glucose-stimulated physiological responses in the insulin secreting INS-1 β-cell line

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    Li, Yi-Chao; Cui, Wan-Xing; Wang, Xu-Jing; Amthor, Franklin; Yao, Xin-Cheng

    2011-03-01

    Intrinsic optical signal (IOS) imaging has been established for noninvasive monitoring of stimulus-evoked physiological responses in the retina and other neural tissues. Recently, we extended the IOS imaging technology for functional evaluation of insulin secreting INS-1 cells. INS-1 cells provide a popular model for investigating β-cell dysfunction and diabetes. Our experiments indicate that IOS imaging allows simultaneous monitoring of glucose-stimulated physiological responses in multiple cells with high spatial (sub-cellular) and temporal (sub-second) resolution. Rapid image sequences reveal transient optical responses that have time courses comparable to glucose-evoked β-cell electrical activities.

  15. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

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    Kyle S. McCommis

    2016-08-01

    Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia.

  16. Polymorphism rs11085226 in the gene encoding polypyrimidine tract-binding protein 1 negatively affects glucose-stimulated insulin secretion.

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    Martin Heni

    Full Text Available OBJECTIVE: Polypyrimidine tract-binding protein 1 (PTBP1 promotes stability and translation of mRNAs coding for insulin secretion granule proteins and thereby plays a role in β-cells function. We studied whether common genetic variations within the PTBP1 locus influence insulin secretion, and/or proinsulin conversion. METHODS: We genotyped 1,502 healthy German subjects for four tagging single nucleotide polymorphisms (SNPs within the PTBP1 locus (rs351974, rs11085226, rs736926, and rs123698 covering 100% of genetic variation with an r(2≥0.8. The subjects were metabolically characterized by an oral glucose tolerance test with insulin, proinsulin, and C-peptide measurements. A subgroup of 320 subjects also underwent an IVGTT. RESULTS: PTBP1 SNP rs11085226 was nominally associated with lower insulinogenic index and lower cleared insulin response in the OGTT (p≤0.04. The other tested SNPs did not show any association with the analyzed OGTT-derived secretion parameters. In the IVGTT subgroup, SNP rs11085226 was accordingly associated with lower insulin levels within the first ten minutes following glucose injection (p = 0.0103. Furthermore, SNP rs351974 was associated with insulin levels in the IVGTT (p = 0.0108. Upon interrogation of MAGIC HOMA-B data, our rs11085226 result was replicated (MAGIC p = 0.018, but the rs351974 was not. CONCLUSIONS: We conclude that common genetic variation in PTBP1 influences glucose-stimulated insulin secretion. This underlines the importance of PTBP1 for beta cell function in vivo.

  17. Glucose-stimulated Cdc42 Signaling Is Essential for the Second Phase of Insulin Secretion*

    OpenAIRE

    Wang, Zhanxiang; Oh, Eunjin; Thurmond, Debbie C.

    2007-01-01

    The small Rho family GTPases Cdc42 and Rac1 have each been shown to function in insulin exocytosis and are presumed to function in actin remodeling and insulin granule mobilization. However, whether either GTPase is required for the mobilization phase of insulin release (second phase) and are linked in a common signaling pathway has remained unknown. Here we demonstrate that small interfering RNA-mediated depletion of Cdc42 from isolated islets results in the selective loss of second-phase in...

  18. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells

    DEFF Research Database (Denmark)

    Schisler, Jonathan C; Jensen, Per Bo; Harper, David Alexander Taylor; Becker, Thomas; Knop, Filip Krag; Takekawa, Shiro; German, Michael; Weir, Gordon C; Lu, Danhong; Mirmira, Raghavendra G; Newgard, Christopher B

    2005-01-01

    We have previously described rat insulinoma INS-1-derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive/glucagon-expressing; class 2, glucose-unresponsive/glu...

  19. Impact of PTBP1 rs11085226 on glucose-stimulated insulin release in adult Danes

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    Hansen, Tue H; Vestergaard, Henrik; Jørgensen, Torben; Jørgensen, Marit Eika; Lauritzen, Torsten; Brandslund, Ivan; Christensen, Cramer; Pedersen, Oluf; Hansen, Torben; Gjesing, Anette P

    2015-01-01

    Background: The variant rs11085226 (G) within the gene encoding polypyrimidine tract binding protein 1 (PTBP1) was reported to associate with reduced insulin release determined by an oral glucose tolerance test (OGTT) as well as an intravenous glucose tolerance test (IVGTT). The aim of the present...

  20. Intrinsic optical signal imaging of glucose-stimulated insulin secreting β-cells

    OpenAIRE

    Li, Yi-Chao; Cui, Wan-Xing; Wang, Xu-Jing; Amthor, Franklin; Lu, Rong-Wen; Thompson, Anthony; Yao, Xin-Cheng

    2010-01-01

    Simultaneous monitoring of many functioning β-cells is essential for understanding β-cell dysfunction as an early event in the progression to diabetes. Intrinsic optical signal (IOS) imaging has been shown to allow high resolution detection of stimulus-evoked physiological responses in the retina and other neural tissues. In this paper, we demonstrate the feasibility of using IOS imaging for functional examination of insulin secreting INS-1 cells, a popular model for investigating diabetes as...

  1. The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion.

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    Robert Spinnler

    Full Text Available AIMS/HYPOTHESIS: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt and its enzymatic product Nicotinamide mononucleotide (NMN, which has been associated with obesity and type 2 diabetes mellitus (T2DM directly influence beta-cell survival and function. METHODS: The effect of Nampt and NMN on viability of INS-1E cells was assessed by WST-1 assay. Apoptosis was measured by Annexin V/PI and TUNEL assay. Activation of apoptosis signaling pathways was evaluated. Adenylate kinase release was determined to assess cytotoxicity. Chronic and acute effects of the adipocytokine Nampt and its enzymatic product NMN on insulin secretion were assessed by glucose stimulated insulin secretion in human islets. RESULTS: While stimulation of beta-cells with the cytokines IL-1β, TNFα and IFN-γ or palmitate significantly decreased viability, Nampt and NMN showed no direct effect on viability in INS-1E cells or in human islets, neither alone nor in the presence of pro-diabetic conditions (elevated glucose concentrations and palmitate or cytokines. At chronic conditions over 3 days of culture, Nampt and its product NMN had no effects on insulin secretion. In contrast, both Nampt and NMN potentiated glucose stimulated insulin secretion acutely during 1 h incubation of human islets. CONCLUSION/INTERPRETATION: Nampt and NMN neither influenced beta-cell viability nor apoptosis but acutely potentiated glucose stimulated insulin secretion.

  2. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

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    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-01-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

  3. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells.

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    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-01-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

  4. Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

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    Sriskandarajah Nadarajah

    2004-09-01

    Full Text Available Abstract Background Elevated non-esterified fatty acids (NEFA concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL, 105 and 135 days gestational age (dGA, term 147+/- 3 days. Methods The plasma concentrations of insulin, growth hormone (GH and ovine placental lactogen (oPL were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA. Results Maternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p Conclusions Results suggest that despite an acute suppression of circulating NEFA concentrations during pregnancy, the associated steroids and hormones

  5. The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity

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    Kelly, Karen R; Brooks, Latina M; Solomon, Thomas; Kashyap, Sangeeta R; O'Leary, Valerie B; Kirwan, John P

    2009-01-01

    Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through...

  6. Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release

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    Nielsen, Trine; Sparsø, T; Grarup, N;

    2011-01-01

    By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from...

  7. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Bagge, Annika [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Clausen, Trine R. [Diabetes Biology, Novo Nordisk, Maaloev (Denmark); Larsen, Sylvester [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Ladefoged, Mette [Diabetes Biology, Novo Nordisk, Maaloev (Denmark); Rosenstierne, Maiken W. [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Department of Virology, Statens Serum Institut (Denmark); Larsen, Louise [Department of Biomedical Sciences, University of Copenhagen, Copenhagen (Denmark); Vang, Ole [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark); Nielsen, Jens H. [Department of Biomedical Sciences, University of Copenhagen, Copenhagen (Denmark); Dalgaard, Louise T., E-mail: ltd@ruc.dk [Department of Science, Systems and Models, Roskilde University, Roskilde (Denmark)

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. Black-Right-Pointing-Pointer miR-29a increases proliferation of INS-1E beta-cells. Black-Right-Pointing-Pointer Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). Black-Right-Pointing-Pointer Depletion of beta-cell miR-29a improves GSIS. Black-Right-Pointing-Pointer miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cells and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.

  8. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    International Nuclear Information System (INIS)

    Highlights: ► MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. ► miR-29a increases proliferation of INS-1E beta-cells. ► Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). ► Depletion of beta-cell miR-29a improves GSIS. ► miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cells and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.

  9. DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet

    Directory of Open Access Journals (Sweden)

    Katherine Veras

    2014-01-01

    Full Text Available Dehydroepiandrosterone (DHEA and the dehydroepiandrosterone sulfate (DHEA-S are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.

  10. Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release.

    Science.gov (United States)

    Mandal, Deep; Mandal, Subhra Kanti; Ghosh, Moumita; Das, Prasanta Kumar

    2015-08-17

    A pyrene-containing phenylboronic acid (PBA) functionalized low-molecular-weight hydrogelator was synthesized with the aim to develop glucose-sensitive insulin release. The gelator showed the solvent imbibing ability in aqueous buffer solutions of pH values, ranging from 8-12, whereas the sodium salt of the gelator formed a hydrogel at physiological pH 7.4 with a minimum gelation concentration (MGC) of 5 mg mL(-1) . The aggregation behavior of this thermoreversible hydrogel was studied by using microscopic and spectroscopic techniques, including transmission electron microscopy, FTIR, UV/Vis, luminescence, and CD spectroscopy. These investigations revealed that hydrogen bonding, π-π stacking, and van der Waals interactions are the key factors for the self-assembled gelation. The diol-sensitive PBA part and the pyrene unit in the gelator were judiciously used in fluorimetric sensing of minute amounts of glucose at physiological pH. The morphological change of the gel due to addition of glucose was investigated by scanning electron microscopy, which denoted the glucose-responsive swelling of the hydrogel. A rheological study indicated the loss of the rigidity of the native gel in the presence of glucose. Hence, the glucose-induced swelling of the hydrogel was exploited in the controlled release of insulin from the hydrogel. The insulin-loaded hydrogel showed thixotropic self-recovery property, which hoisted it as an injectable soft composite. Encouragingly, the gelator was found to be compatible with HeLa cells. PMID:26184777

  11. Advanced Glycation End Products Impair Glucose-Stimulated Insulin Secretion of a Pancreatic β-Cell Line INS-1-3 by Disturbance of Microtubule Cytoskeleton via p38/MAPK Activation

    Science.gov (United States)

    You, Jia; Xu, Shiqing; Zhang, Wenjian; Fang, Qing; Liu, Honglin; Peng, Liang; Deng, Tingting

    2016-01-01

    Advanced glycation end products (AGEs) are believed to be involved in diverse complications of diabetes mellitus. Overexposure to AGEs of pancreatic β-cells leads to decreased insulin secretion and cell apoptosis. Here, to understand the cytotoxicity of AGEs to pancreatic β-cells, we used INS-1-3 cells as a β-cell model to address this question, which was a subclone of INS-1 cells and exhibited high level of insulin expression and high sensitivity to glucose stimulation. Exposed to large dose of AGEs, even though more insulin was synthesized, its secretion was significantly reduced from INS-1-3 cells. Further, AGEs treatment led to a time-dependent increase of depolymerized microtubules, which was accompanied by an increase of activated p38/MAPK in INS-1-3 cells. Pharmacological inhibition of p38/MAPK by SB202190 reversed microtubule depolymerization to a stabilized polymerization status but could not rescue the reduction of insulin release caused by AGEs. Taken together, these results suggest a novel role of AGEs-induced impairment of insulin secretion, which is partially due to a disturbance of microtubule dynamics that resulted from an activation of the p38/MAPK pathway.

  12. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Bagge, Annika; Clausen, Trine R; Larsen, Sylvester;

    2012-01-01

    Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate...

  13. Overexpression of phospholipase cβ1 improves glucose-stimulated insulin secretion in INS cells%磷脂酶Cβ1过表达对葡萄糖刺激胰岛素分泌的影响

    Institute of Scientific and Technical Information of China (English)

    周恒宇; 邓华聪; 郑宏庭; 蒋文; 南静; 陈丹燕

    2009-01-01

    Objective To investigate the role of phospholipase Cβ1 (PLCβ1) in the glucose-stimulated mmoL/L was used to treat INS-1 cells respectively for 40 min. The content of insulin in the INS-1 supernatant was detected for the optimal concentration of glucose. Then the decided concentration was used to the cells for pression vector PCMV-HA-PLCβ1 was constrcted and then transiently transfeeted into INS-1 cells under the op-lin ELISA kit was used to detect the content of insulin in the INS-1 supernatant. Results Exposed to INS-1 cells to 40 mmoL/L glucose for 60 min, the content of insulin secretion reached the maximum and RT-PCR indi-cated the expression of PLCβ1 was raised. Compared to the control [(0.740±0.091) ng/ml], the insulin's content in the supernatant of INS-1 cells with overexpressed PLCβ1 was raised [(1.906±0.080) ng/ml](P <0.01). Conclusion Transient overexpression of PLCβ1 in INS-1 cells improves the insulin secretion, so PLCβ1 probably participates in the signal transduction pathway of GSIS in INS-1 cells.%目的 观察过表达磷脂酶Cβ1(phospholipaae C β1,PLCβ1)对葡萄糖刺激胰岛素分泌(glucose-stimulated insulin secretion,GSIS)的影响.方法 ①设定葡萄糖浓度梯度:10、20、40、80、100 mmol/L,分别刺激INS-1细胞40 min,检测细胞培养上清液中胰岛素含量,确定最适的葡萄糖刺激浓度;设定时间梯度:20、40、60、80、120 min,以最适葡萄糖浓度刺激,检测胰岛素含量,确定最适的刺激时间.②以最适葡萄糖浓度刺激INS-1细胞适当时间后,RT-PCR检测PLCβ1表达变化.③构建PLCβ1真核表达载体(PCMV-HA-PLCβ1),转染INS-1细胞,Western blot检测INS-1细胞中PLCβ1蛋白的表达.④收集转染后INS-1细胞培养上清液,检测胰岛素含量.结果 用40 mmol/L葡萄糖刺激60 min,INS-1细胞的胰岛素分泌量最大;RT-PCR观察刺激后PLCβ1表达显著升高;过表达PLCβ1的INS-1细胞培养上清液中胰岛素含量为(1.906±0.080)ng/ml,

  14. Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagon, lactate and TNF-alpha in patients with HIV-lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, S B; Andersen, O; Pedersen, S B; Dela, F; Deacon, C F; Holst, Jens Juul; Iversen, J; Madsbad, S

    2006-01-01

    lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp...... technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity. RESULTS: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO...... patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting...

  15. Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagons, lactate and TNF-alfa in patients with HIV-lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB; Dela, Flemming; Holst, JJ; Deacon, C; Iversen, Johan; Madsbad, Sten

    2006-01-01

    lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp...... technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity. RESULTS: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO...... patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting...

  16. A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study

    DEFF Research Database (Denmark)

    Staiger, Harald; Stancáková, Alena; Zilinskaite, Jone;

    2008-01-01

    OBJECTIVE: In recent genome-wide association studies, two single nucleotide polymorphisms (SNPs) near the HHEX locus were shown to be more frequent in type 2 diabetic patients than in control subjects. Based on HHEX's function during embryonic development of the ventral pancreas in mice, we...... contrast, the minor A-allele of HHEX SNP rs7923837 was significantly associated with higher IVGTT-derived first-phase insulin release before and after appropriate adjustment (P = 0.013 and P = 0.014, respectively). CONCLUSIONS: A common genetic variation in the 3'-flanking region of the HHEX locus, i...

  17. Nephrin expression and its promotion on glucose-stimulated insulin secretion%胰岛素囊泡nephrin的表达及促进葡萄糖诱导下的胰岛素分泌

    Institute of Scientific and Technical Information of China (English)

    曹雯; 丘岗峰

    2012-01-01

    [Objective]To study nephrin expression in huaman pancreas and whether diabetes regulate nephrin expression, and explore the function of nephrin in βcells of pancreas islet simulataneously. [Methods] The nephrin expression of huamna islets and MIN6 insulinoma cells from diabetic (n = 5) and nondiabetic (n = 7) patients were detected by Western blot, PCR, confocal microscopy, subcellular fractionation, and immunogold labeling. MIN6 insulinoma cells and human islets cells were transfected by nephrin or siRNA-nephrin, then the function of nephrin in vitro was studied. Nephrin endocytosis was investigated by GFP-nephrin transfected cells. [Results] Nephrin was found at the plasma membrane and on insulin vesicles. Compared with nondiabetic control subjects, its expression was decreased in islets from diabetic patients. MIN-6 cells/pseudoislets transfected by nephrin lead to higher glucose-stimulated insulin release in vitro, while transfected cells by siRNA-nephrin abolished stimulated insulin release. GFP-nephrin-transfected cells stimulated by glucose resulted in nephrin endocytosis observed by Confocal microscopy. Actin stabilization could prevent nephrin trafficking as well as nephrin-positive effect on insulin release. [ Conclusion ] Nephrin on insulin vesicle is an active component and may affect vesicle actin interaction and mobilization. Development of drugs targeting at nephrin may represent a novel approach to treat diabetes.%目的 研究在人类胰岛nephrin的表达及糖尿病是否调控nephrin的表达,同时初步探索nephrin在β细胞中的功能.方法 试验分糖尿病患者(n=5)和非糖尿病患者(n=7)组.采用western blot、PCR、共聚焦显微镜、亚细胞分离和免疫金标等方法研究人类胰岛和MIN6胰岛素瘤细胞中nephrin的表达.在MIN-6细胞或人类胰岛细胞中稳定转染nephrin和以siRNA技术沉默nephrin,然后研究体外nephrin的功能.采用GFP-nephrin转染细胞活动图像

  18. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans

    DEFF Research Database (Denmark)

    Sparsø, Thomas; Bonnefond, Amélie; Andersson, Ehm;

    2009-01-01

    (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4...... of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P insulin resistance (P...... = 0.017). CONCLUSIONS: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance....

  19. GRP40介导游离脂肪酸对葡萄糖刺激的胰岛素分泌和β细胞内钙离子浓度的变化%GPR40 mediates the effects of FFAs on glucose stimulated insulin secretion and the change of intracellular calcium concentration in pancreatic β cells

    Institute of Scientific and Technical Information of China (English)

    张莹; 程桦; 徐明彤; 张少玲; 黎峰; 杨川; 严励; 李焱

    2009-01-01

    目的 探讨G蛋白耦联受体40(GPR40)是否介导游离脂肪酸(FFAs)短期、长期作用对小鼠胰岛NIT-1 β细胞葡萄糖刺激的胰岛素分泌(GSIS)及胞内钙离子浓度的影响.方法 利用siRNA技术抑制GPR40在NIT-1细胞的表达,ELISA法检测棕榈酸、油酸短期(2 h)、长期(48 h)干预对NIT-1细胞GSIS的影响,激光共聚焦显微镜下观察GSIS过程中细胞内钙离子的变化.结果 FFAs短期干预促进空转染组、对照siRNA转染组GSIS水平(P<0.01),而对GPR40 siRNA组GSIS无明显影响,该组细胞GSIS水平明显低于空转染组和对照siRNA转染组(P<0.01).FFAs长期干预明显抑制空转染组、对照siRNA转染组细胞GSIS水平,对GPR40 siRNA组GSIS无明显影响.空转染组、对照siRNA组GSIS水平低于GPR40siRNA组(P<0.05).激光共聚焦显微镜结果显示,在GSIS过程中,FFAs短期干预后,GPR40 siRNA组胞内钙离子浓度峰值明显低于对照siRNA组(棕榈酸:5.10 vs 7.02,油酸:4.27 vs 6.21,均P<0.05);而FFAs长期干预后,GPR40 siRNA组胞内钙离子浓度峰值明显高于对照siRNA组(棕榈酸:3.24 vs 1.21,油酸:2.83 vs 1.18,均P<0.05).结论 GPR40介导FFAs对GSIS和胞内钙离子浓度变化的短期刺激和长期抑制作用.%Objective To investigate whether G-protein coupled receptor 40(GPR40)mediates short-term and long-term effects of free fatty acids (FFAs) on glucose stimulated insulin secretion (GSIS) and the change of [Ca2+]i in mouse insulinoma NIT-1 cells.Methods The expression of GPR40 in NIT-1 cells was inhibited by siRNA.The short-term and long-term effects of saturated (palmitate) or unsaturated (oleate) fatty acids on GSIS in NIT-1 cells transfected with GPR40 siRNA were examined.Insulin was measured by ELISA.The change in intracellular calcium concentration was observed by laser confocal scanning microscopy after NIT-1 cells were incubated with Fluo-3/AM.Results The short-term treatment of FFAs increased GSIS from NIT-1 cells transfected

  20. Insulin attenuates the systemic inflammatory response to thermal trauma.

    OpenAIRE

    Jeschke, Marc G.; Einspanier, Ralf; Klein, Dagmar; Jauch, Karl-Walter

    2002-01-01

    BACKGROUND: Insulin has been recently shown to decrease mortality and prevent the incidence of multi-organ failure in critically ill patients. The molecular mechanisms by which insulin improves survival have not been defined. The purpose of the present study was to determine the effect of insulin therapy on the systemic inflammatory response. In vivo we determined the effect of insulin therapy on the inflammatory cascade, which was induced by thermal injury. MATERIALS AND METHODS: Thermally i...

  1. Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes.

    Science.gov (United States)

    Han, Xiaojuan; Yang, Liling; Du, Heng; Sun, Qinjian; Wang, Xiang; Cong, Lin; Liu, Xiaohui; Yin, Ling; Li, Shan; Du, Yifeng

    2016-08-01

    The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer's disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1-42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1-42 oligomers in a dose-dependent manner (p  0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1-42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions. PMID:26358886

  2. High Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance

    OpenAIRE

    Phielix, Esther; Meex, Ruth; Ouwens, D Margriet; Sparks, Lauren; Hoeks, Joris; Schaart, Gert; Moonen-Kornips, Esther; Hesselink, Matthijs K. C.; Schrauwen, Patrick

    2012-01-01

    Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m2) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22...

  3. Bioactives of Artemisia dracunculus L. Mitigate the Role of Ceramides in Attenuating Insulin Signaling in Rat Skeletal Muscle Cells

    OpenAIRE

    Diana N Obanda; Hernandez, Amy; RIBNICKY, DAVID; Yu, Yongmei; Zhang, Xian H.; Wang, Zhong Q.; Cefalu, William T.

    2012-01-01

    Ectopic lipids in peripheral tissues have been implicated in attenuating insulin action in vivo. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which PMI 5011 improves insulin signaling is through regulation of lipid metabolism. After differentiation, cells were separately preincubated with free fatty acids (FFAs) and ceramide C2, and the effects on glycogen content, ...

  4. Insulin

    Science.gov (United States)

    ... Short Acting Humulin N NPH Human Insulin (Human Insulin Isophane Suspension) Intermediate Acting Novolin N NPH Human Insulin (Human Insulin Isophane Suspension) Intermediate Acting Lantus Insulin Glargine Long Acting ...

  5. Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action

    International Nuclear Information System (INIS)

    Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) plays key roles in gluconeogenesis, glyceroneogenesis, and cataplerosis. Experiments were designed to examine the effects of endogenous lipid molecules from rat livers on the expression of PEPCK-C gene in primary rat hepatocytes. The lipid extracts prepared from livers of Zucker fatty, lean, and Wistar rats induced the expression levels of PEPCK-C transcripts. Insulin-mediated reduction of PEPCK-C gene expression was attenuated by the same treatment. The lipid extracts induced the relative luciferase activity of reporter gene constructs that contain a 2.2-kb 5' promoter fragment of PEPCK-C gene, but not the construct that contains only the 3' untranslated region (UTR) of its mRNA. The estimated half life of PEPCK-C transcripts in the presence of the lipid extract is the same as that in the absence of it. My results demonstrate for the first time that endogenous lipid molecules induce PEPCK-C gene transcription and attenuate insulin action in liver

  6. Relationship between adiponectin and the first phase of glucose-stimulated insulin secretion from pancreatic β-cell in patients with type 2 diabetes mellitus%2型糖尿病患者脂联素与胰岛β细胞第一时相分泌功能的关系探讨

    Institute of Scientific and Technical Information of China (English)

    秦登优; 邓华聪; 艾艳琴; 龚明; 刘强; 李永玲; 糜公仆

    2010-01-01

    Objective To investigate the relationship between adiponectin and the first-phase of pancreatic P-cell insulin secretion in subjects with different statuses of glucose tolerance. Methods Thirty-seven patients with newly diagnosed type 2 diabetes mellitus (DM) , 30 patients with abnormal glucose tolerance (IGR) , and 40 normal control subjects (NGT) underwent intravenous glucose tolerance test (IVGTT). Fasting adiponectin and proinsulin (PI) was assayed by EL1SA. Fasting free fatty acid ( FFA) was measured by colorimetry. Insulin area under the curve ( AUC ) , incremental AUC (iAUC) from 0 min to 10 min, AIR3-5, homeostasis model assessment for insnlin resistance (HOMA-IR) , and for β cell function ( HOMA-p) were calculated. The relationship between adiponectin and AUC, iAUC, AIR3-5, proinsulin, FFA, and HOMA-IR was explored. Results (1) The levels of AUC, iAUC, AIR3-5, and adiponectin in DM group and IGR group were significantly lower than those in NGT group (P<0.05), reduced in DM group than those in IGR group(P<0.05). (2) The levels of PI in DM group and IGR group were significantly higher than that in NGT (P<0.05). (3) Adiponectin was positively correlated with HOMA-p,AUC,iAUC,AIR3-5, and HDL-C,while negatively correlated with proinsulin, HOMA-IR, and LDL-C. (4) Proinsulin was positively correlated with HOMA-IR. (5 ) Multiple regression stepwise analysis showed that adiponectin was independently associated with AUC. Conclusions Adiponectin was an independent factor affecting the first phase of pancreatic p-cell insulin secretion. Low adiponectin level could predict the dysfunction of the first phase pancreatic p-cell secretion as well as insulin resistance in patients with type 2 diabetes.%目的 探讨不同糖耐量个体脂联素与胰岛β细胞第一时相分泌功能的关系.方法 37例新诊断的2型糖尿病患者(DM组),30例糖耐量异常者(IGR组),40名正常对照组(NGT组),行静脉葡萄糖耐量试验(IVGTT),ELISA法测定空腹脂联素

  7. Dopamine-Mediated Autocrine Inhibitory Circuit Regulating Human Insulin Secretion in Vitro

    Science.gov (United States)

    Simpson, Norman; Maffei, Antonella; Freeby, Matthew; Burroughs, Steven; Freyberg, Zachary; Javitch, Jonathan; Leibel, Rudolph L.

    2012-01-01

    We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity. PMID:22915827

  8. Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

    Science.gov (United States)

    Carreras, Alba; Zhang, Shelley X L; Almendros, Isaac; Wang, Yang; Peris, Eduard; Qiao, Zhuanhong; Gozal, David

    2015-02-01

    Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea. PMID:25406018

  9. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

    International Nuclear Information System (INIS)

    Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

  10. Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ying [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 (China); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 (China); Gu, Tieguang [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences, Sydney, NSW 2000 Australia (Australia); Yamahara, Johji [Pharmafood Institute, Kyoto 602-8136 (Japan); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences, Sydney, NSW 2000 Australia (Australia)

    2014-06-01

    Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

  11. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Czech Academy of Sciences Publication Activity Database

    Doulliet, Ch.; Currier, J. M.; Saunders, J.; Bodnar, W. M.; Matoušek, Tomáš; Stýblo, M.

    2013-01-01

    Roč. 267, č. 1 (2013), s. 11-15. ISSN 0041-008X R&D Projects: GA MŠk LH12040 Institutional support: RVO:68081715 Keywords : arsenic speciation * tissue * hydride generation Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.630, year: 2013

  12. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Czech Academy of Sciences Publication Activity Database

    Doulliet, Ch.; Currier, J. M.; Saunders, J.; Bodnar, W. M.; Matoušek, Tomáš; Stýblo, M.

    -, July-28 (2013), PMID: 23261974. ISSN 2328-0166 R&D Projects: GA MŠk LH12040 Institutional support: RVO:68081715 Keywords : arsenic speciation * tissue * hydride generation Subject RIV: CB - Analytical Chemistry, Separation http://biomedfrontiers.org/ diabetes -2013-july-28/

  13. Molecular Mechanisms of Glucose-Stimulated GLP-1 Secretion From Perfused Rat Small Intestine

    DEFF Research Database (Denmark)

    Kuhre, Rune E.; Frost, Charlotte R.; Svendsen, Berit;

    2015-01-01

    (20%) of the nonmetabolizable sodium-glucose transporter 1 (SGLT1) substrate, methyl-α-d-glucopyranoside (α-MGP), stimulated release, whereas the SGLT1 inhibitor phloridzin (luminally) abolished responses to α-MGP and glucose. Furthermore, in the absence of luminal NaCl, luminal glucose (20%) did not...... stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal α-MGP in matched concentrations....... Glucose transported by GLUT2 may act after metabolization, closing KATP channels similar to sulfonylureas, which also stimulated secretion. Our data indicate that SGLT1 activity is the driving force for glucose-stimulated GLP-1 secretion and that KATP-channel closure is required to stimulate a full...

  14. A two-week reduction of ambulatory activity attenuates peripheral insulin sensitivity

    DEFF Research Database (Denmark)

    Krogh-Madsen, Rikke; Thyfault, John P; Broholm, Christa;

    2009-01-01

    activity would influence peripheral insulin sensitivity. We aimed to explore if healthy, non-exercising subjects who went from a normal to a low level of ambulatory activity for two weeks would display metabolic alterations including reduced peripheral insulin sensitivity. -To do this, ten healthy young...... number of daily steps induced a significant reduction of 17% in the glucose infusion rate (GIR) during the clamp. This reduction was due to a decline in peripheral insulin sensitivity with no effect on hepatic endogenous glucose production. The insulin-stimulated ratio of pAkt(thr308)/total Akt decreased...... possible biological cause for the public health problem of type 2 diabetes has been identified. Reduced ambulatory activity for two weeks in healthy, non-exercising young men significantly reduced peripheral insulin sensitivity, cardiovascular fitness, and lean leg mass. Key words: Inactivity, Insulin...

  15. Attenuation of insulin resistance in rats by agmatine: role of SREBP-1c, mTOR and GLUT-2.

    Science.gov (United States)

    Sharawy, Maha H; El-Awady, Mohammed S; Megahed, Nirmeen; Gameil, Nariman M

    2016-01-01

    Insulin resistance is a serious health condition worldwide; however, its exact mechanisms are still unclear. This study investigates agmatine (AGM; an endogenous metabolite of L-arginine) effects on insulin resistance induced by high fructose diet (HFD) in rats and the possible involved mechanisms. Sprague Dawley rats were fed 60% HFD for 12 weeks, and AGM (10 mg/kg/day, orally) was given from week 9 to 12. AGM significantly reduced HFD-induced elevation in fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) index and liver glycogen content from 3.44-, 3.62- and 2.07- to 2.59-, 2.78- and 1.3-fold, respectively, compared to the control group, while it increased HFD-induced reduction in glucose tolerance. Additionally, AGM significantly decreased HFD-induced elevation in serum triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol levels from 3.18-, 2.97- and 4.75- to 1.25-, 1.25- and 1.07-fold, respectively, compared to control group. Conversely, AGM had no significant effect on HFD-induced changes in fasting glucose, glycosylated hemoglobin, insulin tolerance and high density lipoprotein cholesterol. Furthermore, AGM significantly reduced HFD-induced elevation in mRNA expression of glucose transporter type-2 (GLUT-2), mammalian target of rapamycin (mTOR) and sterol regulatory element-binding protein-1c (SREBP-1c) without affecting that of peroxisome proliferator-activated receptor-alpha (PPAR-α) in the liver. Additionally, AGM enhanced ACh-induced aortic relaxation and attenuated liver steatosis induced by HFD. In conclusion, AGM may have a therapeutic potential in insulin resistance through suppressing SREBP-1c, mTOR and GLUT-2 in liver. PMID:26449613

  16. Spirulina vesicolor Improves Insulin Sensitivity and Attenuates Hyperglycemia-Mediated Oxidative Stress in Fructose-Fed Rats

    Directory of Open Access Journals (Sweden)

    Walaa Hozayen

    2016-03-01

    Full Text Available Aim: The current study aimed to investigate the anti-hyperglycemic, anti-hyperlipidemic and insulin sensitizing effects of the cyanobacterium Spirulina vesicolor extract in fructose-fed rats. Materials and Methods: Rats were fed 30% fructose solution in drinking water for 4 weeks. Animals exhibited hyperglycemia and hyperinsulinemia were selected for further investigations. Diabetic and control rats were orally supplemented with 50 mg/kg body weight S. vesicolor extract for 4 weeks. Results: At the end of 8 weeks, fructose-fed rats showed significant increase in serum glucose, insulin, cholesterol, triglycerides, cardiovascular risk indices and insulin resistance. Treatment of the fructose-fed rats with S. vesicolor extract improved this metabolic profile. Fructose feeding produced a significant increase in serum tumor necrosis factor alpha (TNF- and #945; and a decrease in adiponectin levels. In addition, fructose-fed rats exhibited a significant increase in liver, kidney and heart lipid peroxidation levels, and declined antioxidant defenses. Supplementation of the fructose-fed rats with S. vesicolor extract reversed these alterations. Conclusion: S. vesicolor attenuates hyperglycemia-mediated oxidative stress and inflammation, and is thus effective in improving insulin sensitivity in fructose-fed rats. [J Intercult Ethnopharmacol 2016; 5(1.000: 57-64

  17. Leptin, Insulin, and Cinnamon Polyphenols Attenuate Glial Swelling and Mitochondrial Dysfunction in Ischemic Injury

    Science.gov (United States)

    Obesity is a major risk factor for stroke, and tissue injury following a stroke may be more severe in the obese. A key feature of obesity is increased serum levels of obesity-related hormones including leptin and insulin, indicating a state of resistance to these hormones. Insulin resistance is gen...

  18. Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians

    DEFF Research Database (Denmark)

    de Courten, Barbora; Weyer, Christian; Stefan, Norbert;

    2004-01-01

    atropine was administered for 120 min at the following doses: 0, 2.5, 5, and 10 micro g. kg fat-free mass (FFM)(-1). h(-1). Areas under the curve for early (AUC(0-30 min)) and total (AUC(0-120 min)) postprandial insulin and PP secretory responses were calculated. Early postprandial insulin and PP secretory...

  19. AT1 receptor blockade attenuates insulin resistance and myocardial remodeling in rats with diet-induced obesity.

    Directory of Open Access Journals (Sweden)

    Silvio A Oliveira-Junior

    Full Text Available BACKGROUND: Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. MATERIAL AND METHODS: Wistar-Kyoto (n = 40 rats were subjected to control (C; 3.2 kcal/g and hypercaloric diets (OB; 4.6 kcal/g for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE, and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP, echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2, c-Jun amino-terminal kinases (JNK, insulin receptor subunit β (βIR, and phosphatidylinositol 3-kinase (PI3K by Western Blot. RESULTS: Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. CONCLUSION: Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.

  20. Effects of AMPK on high glucose stimulated apoptosis of endothelial cells via regulation of calcium influx

    Directory of Open Access Journals (Sweden)

    Ting LU

    2015-11-01

    Full Text Available Objective To investigate the inhibitory effect of adenosine monophosphate (AMP-dependent protein kinase (AMPK on high glucose-stimulated endothelial cell apoptosis and its mechanism. Methods MS-1 endothelial cells were cultured in vitro, and they were treated with AMPK agonist, AMPK inhibitor, 2-APB (a blocker of store operated Ca2+ channel (SOCC and (or high glucose, and a control group without any intervention were set up. TUNEL assay was performed to determine apoptotic cells. Laser scanning confocal microscopy was used to assess the Ca2+ influx into cells, and Western-blotting was performed to determine the expressions of Stim1 and Orai1 of the store operated Ca2+ channel (SOCC proteins. Results Apoptosis of endothelial cells was induced significantly, and the expressions of Stim1 and Orai1 were upregulated in high glucose group compared with that in control group (P<0.05. The rate of apoptosis of high glucose-induced endothelial cell was found to be increased in AMPK inhibitor group and decreased in AMPK agonist group, and the expressions of Stim1 and Orai1 were found to be down-regulated in AMPK agonist group as compared with that in high glucose group (P<0.05. Compared with the control group, high glucose stimulation significantly induced the Ca2+ influx to endothelial cells; compared with high glucose group, 2-APB significantly inhibited high glucose-induced Ca2+ influx to endothelial cells, and blocked the inducing effect of high-glucose on endothelial cell apoptosis. Compared with high glucose group, AMPK agonist significantly inhibited high glucose-induced cell Ca2+ influx. Conclusion By reducing the expressions of Stim1 and Orai1, AMPK may inhibit SOCC-mediated Ca2+ influx, and block the high glucose-stimulated endothelial cell apoptosis, thus play an important protective role in sustaining endothelial cell function. DOI: 10.11855/j.issn.0577-7402.2015.10.01

  1. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

    Directory of Open Access Journals (Sweden)

    Fernandez Rayne

    2010-08-01

    Full Text Available Abstract Background Activation of glucagon-like peptide-1 (GLP-1 receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS rats. Methods DSS rats were fed low salt (LS, 0.3% NaCl or high salt (HS, 8% NaCl diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min, or GLP-1 (25 pmol/kg/min for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day or AC3174 plus captopril. Results HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p Conclusions Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

  2. PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice

    Directory of Open Access Journals (Sweden)

    Unger Thomas

    2010-10-01

    Full Text Available Abstract Background Inflammation of adipose tissue (AT has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD develop systemic insulin resistance (IR and glucose intolerance (GI associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model in mice. Methods In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD for 10-weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle. Results Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT-inflammation, ligand-activated PPARgamma improved diet-induced IR and GI. Conclusion Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma´s action.

  3. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity

    DEFF Research Database (Denmark)

    Krogh-Madsen, Rikke; Thyfault, John P; Broholm, Christa; Mortensen, Ole Hartvig; Olsen, Rasmus H.; Mounier, Remi; Plomgaard, Peter; van Hall, Gerrit; Booth, Frank W; Pedersen, Bente K

    2010-01-01

    US adults take between approximately 2,000 and approximately 12,000 steps per day, a wide range of ambulatory activity that at the low range could increase risk for developing chronic metabolic diseases. Dramatic reductions in physical activity induce insulin resistance; however, it is uncertain if...... and how low ambulatory activity would influence peripheral insulin sensitivity. We aimed to explore if healthy, nonexercising subjects who went from a normal to a low level of ambulatory activity for 2 wk would display metabolic alterations including reduced peripheral insulin sensitivity. To do this......, ten healthy young men decreased their daily activity level from a mean of 10,501+/-808 to 1,344+/-33 steps/day for 2 wk. Hyperinsulinemic-euglycemic clamps with stable isotopes and muscle biopsies, maximal oxygen consumption (VO2 max) tests, and blood samples were performed pre- and postintervention...

  4. A new glycotoxins inhibitor attenuates insulin resistance in liver and fat cells.

    Science.gov (United States)

    Afridi, Shabbir Khan; Aftab, Meha Fatima; Murtaza, Munazza; Ghaffar, Safina; Karim, Aneela; Mughal, Uzma Rasool; Khan, Khalid Mohammed; Waraich, Rizwana Sanaullah

    2016-08-01

    Glycotoxins/Advanced glycation end products (AGEs) have implications in development of diabetes and related diseases. In the present study we deciphered the mechanisms of action of URM-II-81, a new derivative of isatin, in alleviation of insulin resistance in human hepatocytes and murine adipocytes. URM-II-81 reduced AGEs formation and receptor for advanced glycation end products (RAGE) expression in both cell types. We also observed suppression of methylglyoxal (MGO) mediated ROS production and deactivation of PKC-α. URM-II-81 restored proximal insulin signaling by modulating IRS-1 phosphorylation. URM-II-81 also alleviated MGO mediated diminished distal insulin signaling by increasing protein kinase B (PKB) and glycogen synthase kinase 3-beta (GSK-3-beta) phosphorylation. Glycogen synthesis was also increased in hepatocytes after treatment with URM-II-81. In adipocytes URM-II-81 prevented MGO induced reduced glucose uptake. We conclude that URM-II-81 can be a possible treatment target to address glycotoxins induced insulin resistance. PMID:27233608

  5. Decaffeinated green coffee bean extract attenuates diet-induced obesity and insulin resistance in mice.

    Science.gov (United States)

    Song, Su Jin; Choi, Sena; Park, Taesun

    2014-01-01

    This study investigated whether decaffeinated green coffee bean extract prevents obesity and improves insulin resistance and elucidated its mechanism of action. Male C57BL/6N mice (N = 48) were divided into six dietary groups: chow diet, HFD, HFD-supplemented with 0.1%, 0.3%, and 0.9% decaffeinated green coffee bean extract, and 0.15% 5-caffeoylquinic acid. Based on the reduction in HFD-induced body weight gain and increments in plasma lipids, glucose, and insulin levels, the minimum effective dose of green coffee bean extract appears to be 0.3%. Green coffee bean extract resulted in downregulation of genes involved in WNT10b- and galanin-mediated adipogenesis and TLR4-mediated proinflammatory pathway and stimulation of GLUT4 translocation to the plasma membrane in white adipose tissue. Taken together, decaffeinated green coffee bean extract appeared to reverse HFD-induced fat accumulation and insulin resistance by downregulating the genes involved in adipogenesis and inflammation in visceral adipose tissue. PMID:24817902

  6. Morin attenuates hepatic insulin resistance in high-fat-diet-induced obese mice.

    Science.gov (United States)

    Naowaboot, Jarinyaporn; Wannasiri, Supaporn; Pannangpetch, Patchareewan

    2016-06-01

    Morin is a natural bioflavonoid that exhibits antioxidant and anti-inflammatory properties. The present study was designed to evaluate the effect of morin on insulin resistance, oxidative stress, and inflammation in a high-fat-diet (HFD)-induced obese mice. Obesity was induced in ICR mice by feeding a HFD (60 % kcal from fat) for 12 weeks. After the first 6 weeks, obese mice were treated with morin (50 or 100 mg/kg/day) once daily for further 6 weeks. Blood glucose, lipid profile, insulin, leptin, adiponectin, and markers of oxidative stress and inflammation were then measured. Liver was excised, subjected to histopathology, glycogen determination, and gene and protein expression analysis. Morin administration reduced blood glucose, serum insulin, leptin, malondialdehyde, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) levels and increased serum adiponectin levels. Moreover, there was a reduction in serum lipid and liver triglyceride levels. Liver histology indicated that morin limited accumulation of lipid droplets. Interestingly, morin reduced expression of hepatic sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and up-regulated hepatic carnitine palmitoyltransferase 1a (CPT1a) expression. Morin also stimulated glycogen storage and suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) protein expression. Furthermore, hepatic superoxide dismutase (SOD) and catalase (CAT) expression were increased after morin treatment. These findings indicate that morin has a positive effect in the HFD-induced obesity condition by suppressing lipogenesis, gluconeogenesis, inflammation, and oxidative stress activities. PMID:26976296

  7. Intraportal Infusion of Ghrelin Could Inhibit Glucose-Stimulated GLP-1 Secretion by Enteric Neural Net in Wistar Rat

    Directory of Open Access Journals (Sweden)

    Xiyao Zhang

    2014-01-01

    Full Text Available As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1 when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor, which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect.

  8. Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

    OpenAIRE

    Wang, S Y; Halban, P A; Rowe, J W

    1988-01-01

    Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma m...

  9. Oleanolic Acid Attenuates Insulin Resistance via NF-κB to Regulate the IRS1-GLUT4 Pathway in HepG2 Cells

    Directory of Open Access Journals (Sweden)

    Ming Li

    2015-01-01

    Full Text Available The aim of our study is to elucidate the mechanisms of oleanolic acid (OA on insulin resistance (IR in HepG2 cells. HepG2 cells were induced with FFA as the insulin resistance model and were treated with OA. Then the glucose content and the levels of tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6 were analyzed. Moreover, protein expression of nuclear factor kappa B (NF-κB, insulin receptor substrate 1(IRS1, and glucose transporter 4 (GLUT4 in cells treated with OA were measured by Western blot analysis. Additionally, IRS1 protein expression exposed to OA was detected after using pyrrolidine dithiocarbamate (PDTC.Our results revealed that OA decreased the glucose content in HepG2 cells in vitro. Moreover, OA reduced the levels of TNF-α and IL-6 and upregulated IRS1 and GLUT4 protein expression. Furthermore, OA also reduced NF-κB protein expression in insulin-resistant HepG2 cells. After blocking NF-κB, the expression of IRS1 protein had no obvious changes when treated with OA. OA attenuated insulin resistance and decreased the levels of TNF-α and IL-6. Meanwhile, OA decreased NF-κB protein expression and upregulated IRS1 and GLUT4 protein expression. Therefore, regulating the IRS1-GLUT4 pathway via NF-κB was the underlying mechanism of OA on insulin resistance.

  10. Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Minglong Shao

    Full Text Available BACKGROUND: Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR plays a critical role in attenuating insulin resistance, inflammation and oxidative stress. OBJECTIVE: The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms. METHODS: Mice were fed with a high-fat diet (HFD, 40% of calories from fat for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured. RESULTS: HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2 expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks. CONCLUSION: These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity

  11. Molecular mechanisms underlying the glucose-dependent transcription of the insulin and glucokinase genes in the pancreatic beta-cell

    OpenAIRE

    Moede, Tilo

    2002-01-01

    Background: Insulin is of vital importance in the maintenance of the glucose homeostasis in mammals. This necessitates a tight regulation of both insulin release and biosynthesis. Although pancreatic beta-cells secrete only a fraction of the stored insulin upon glucose stimulation, insulin biosynthesis starts immediately in order to replenish the insulin store. It is well documented that glucose exerts its immediate effects at the posttranscriptional and translational levels...

  12. Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets

    DEFF Research Database (Denmark)

    Luciani, Dan Seriano; Misler, S.; Polonsky, K.S.

    2006-01-01

    Exposure of pancreatic islets of Langerhans to physiological concentrations of glucose leads to secretion of insulin in an oscillatory pattern. The oscillations in insulin secretion are associated with oscillations in cytosolic Ca2+ concentration ([Ca2+](c)). Evidence suggests that the oscillations...

  13. Interleukin-10 Prevents Diet-Induced Insulin Resistance by Attenuating Macrophage and Cytokine Response in Skeletal Muscle

    OpenAIRE

    Hong, Eun-Gyoung; Ko, Hwi Jin; Cho, You-Ree; Kim, Hyo-Jeong; Ma, Zhexi; Yu, Tim Y.; Friedline, Randall H; Kurt-Jones, Evelyn; Finberg, Robert; Matthew A Fischer; Granger, Erica L.; Norbury, Christopher C.; Hauschka, Stephen D.; Philbrick, William M.; Lee, Chun-Geun

    2009-01-01

    OBJECTIVE Insulin resistance is a major characteristic of type 2 diabetes and is causally associated with obesity. Inflammation plays an important role in obesity-associated insulin resistance, but the underlying mechanism remains unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine with lower circulating levels in obese subjects, and acute treatment with IL-10 prevents lipid-induced insulin resistance. We examined the role of IL-10 in glucose homeostasis using transgenic mice with m...

  14. Amino Acids Attenuate Insulin Action on Gluconeogenesis and Promote Fatty Acid Biosynthesis via mTORC1 Signaling Pathway in trout Hepatocytes

    Directory of Open Access Journals (Sweden)

    Weiwei Dai

    2015-06-01

    Full Text Available Background/Aims: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. Methods: We stimulated trout primary hepatocytes with different AA levels and employed acute administration of rapamycin to inhibit mTORC1 activation. Results: Increased AA levels enhanced the phosphorylation of ribosomal protein S6 kinase (S6K1, S6, and insulin receptor substrate 1 (IRS-1 on Ser302 but suppressed Akt and p38 phosphorylation; up-regulated the expression of genes related to gluconeogenesis and fatty acid biosynthesis. mTORC1 inhibition not only inhibited the phosphorylation of mTORC1 downstream targets, but also blunted IRS-1 Ser302 phosphorylation and restored excessive AAs-suppressed Akt phosphorylation. Rapamycin also inhibited fatty acid biosynthetic and gluconeogenic gene expression. Conclusion: High levels of AAs up-regulate hepatic fatty acid biosynthetic gene expression through an mTORC1-dependent manner, while attenuate insulin-mediated repression of gluconeogenesis through elevating IRS-1 Ser302 phosphorylation, which in turn impairs Akt activation and thereby weakening insulin action. We propose that p38 MAPK probably also involves in these AAs-induced metabolic changes.

  15. Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance

    DEFF Research Database (Denmark)

    Haus, Jacob M; Solomon, Thomas; Marchetti, Christine M;

    2010-01-01

    The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans.......The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans....

  16. Tectorigenin Attenuates Palmitate-Induced Endothelial Insulin Resistance via Targeting ROS-Associated Inflammation and IRS-1 Pathway.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available Tectorigenin is a plant isoflavonoid originally isolated from the dried flower of Pueraria thomsonii Benth. Although its anti-inflammatory and anti-hyperglycosemia effects have been well documented, the effect of tectorigenin on endothelial dysfunction insulin resistance involved has not yet been reported. Herein, this study aims to investigate the action of tectorigenin on amelioration of insulin resistance in the endothelium. Palmitic acid (PA was chosen as a stimulant to induce ROS production in endothelial cells and successfully established insulin resistance evidenced by the specific impairment of insulin PI3K signaling. Tectorigenin effectively inhibited the ability of PA to induce the production of reactive oxygen species and collapse of mitochondrial membrane potential. Moreover, tectorigenin presented strong inhibition effect on ROS-associated inflammation, as TNF-α and IL-6 production in endothelial cells was greatly reduced with suppression of IKKβ/NF-κB phosphorylation and JNK activation. Tectorigenin also can inhibit inflammation-stimulated IRS-1 serine phosphorylation and restore the impaired insulin PI3K signaling, leading to a decreased NO production. These results demonstrated its positive regulation of insulin action in the endothelium. Meanwhile, tectorigenin down-regulated endothelin-1 and vascular cell adhesion molecule-1 overexpression, and restored the loss of insulin-mediated vasodilation in rat aorta. These findings suggested that tectorigenin could inhibit ROS-associated inflammation and ameliorated endothelial dysfunction implicated in insulin resistance through regulating IRS-1 function. Tectorigenin might have potential to be applied for the management of cardiovascular diseases involved in diabetes and insulin resistance.

  17. Two common genetic variants near nuclear encoded OXPHOS genes are associated with insulin secretion in vivo.

    OpenAIRE

    Olsson, Anders H.; Rönn, Tina; Ladenvall, Claes; Parikh, Hemang; Isomaa, Bo; Groop, Leif; Ling, Charlotte

    2011-01-01

    Context Mitochondrial ATP production is important in the regulation of glucose-stimulated insulin secretion. Genetic factors may modulate the capacity of the β-cells to secrete insulin and thereby contribute to the risk of type 2 diabetes. OBJECTIVE: The aim of this study was to identify genetic loci in or adjacent to nuclear encoded genes of the oxidative phosphorylation (OXPHOS) pathway that are associated with insulin secretion in vivo. DESIGN AND METHODS: To find polymorphisms associated ...

  18. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells.

    OpenAIRE

    Schuit, F C; In't Veld, P A; Pipeleers, D. G

    1988-01-01

    Glucose is a well-known stimulus of proinsulin biosynthesis. In purified beta cells, the sugar induces a 25-fold increase in the synthesis of insulin immunoreactive material over 60-min incubation. Autoradiographic analysis of the individual cells shows that this effect is achieved via dose-dependent recruitment of pancreatic beta cells to biosynthetic activity. Recruitment of beta cells is also seen in isolated islets exposed to glucose. The sigmoidal dose-response curve for glucose-induced ...

  19. Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice

    DEFF Research Database (Denmark)

    Brandt, Claus; Hansen, Rasmus Hvass; Hansen, Jakob Bondo;

    2015-01-01

    through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance. METHODS: Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high...... adipose tissue. Fstl3 mice displayed improved insulin sensitivity and muscle insulin signalling. In contrast, glucose tolerance was impaired in high-fat fed fstl3 mice, which was explained by increased hepatic glucagon sensitivity and glucose output, as well as a decrease in the pancreatic insulin......OBJECTIVE: Follistatin-like 3 (fstl3), a natural inhibitor of members of the TGF-β family, increases during resistance training in human plasma. Fstl3 primarily binds myostatin and activin A, and thereby inhibits their functions. We hypothesize that blocking myostatin and activin A signalling...

  20. Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance

    OpenAIRE

    Ye, Risheng; Jung, Dae Young; Jun, John Y.; Li, Jianze; Luo, Shengzhan; Ko, Hwi Jin; Kim, Jason K.; Lee, Amy S

    2009-01-01

    OBJECTIVE To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. RESEARCH DESIGN AND METHODS Male Grp78 +/− mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsulinemic-eug...

  1. Effects of tetracaine on insulin release and calcium handling by rat pancreatic islets

    International Nuclear Information System (INIS)

    The effects of tetracaine on insulin release and 45Ca2+ handling by rat pancreatic islets have been studied under basal, glucose-stimulated, and 3-isobutyl-1-methylxanthine (IBMX)-stimulated conditions. Islets were isolated by the use of collagenase and used either directly (freshly isolated islets) or after a period under tissue culture conditions. Tetracaine was found to stimulate insulin release under basal conditions, to inhibit glucose-stimulated insulin release, and to potentiate insulin release stimulated by IBMX. In studies on the mechanisms underlying these effects, tetracaine was found to decrease glucose-stimulated net retention of 45Ca2+ (by an action to block the voltage-dependent Ca channels) and to mobilize Ca2+ from intracellular stores. These two actions form the basis for the inhibition of glucose-stimulated insulin release, which depends heavily on Ca2+ entry via the voltage-dependent channels and the synergism with IBMX to potentiate release. No inhibition of IBMX-stimulated release occurs because IBMX does not use the voltage-dependent channels to raise intracellular Ca2+

  2. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice

    OpenAIRE

    Haizhao Song; Zihuan Zheng; Jianan Wu; Jia Lai; Qiang Chu; Xiaodong Zheng

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed ...

  3. STEAROYL-CoA DESATURASE-1 DEFICIENCY ATTENUATES OBESITY AND INSULIN RESISTANCE IN LEPTIN-RESISTANT OBESE MICE

    OpenAIRE

    Miyazaki, Makoto; Sampath, Harini; Liu, Xueqing; Flowers, Matthew T.; Chu, Kiki; Dobrzyn, Agnieszka; Ntambi, James M.

    2009-01-01

    Obesity and adiposity greatly increase the risk for secondary conditions such as insulin resistance. Mice deficient in the enzyme stearoyl-CoA desaturase-1 (SCD1) are lean and protected from diet-induced obesity and insulin resistance. In order to determine the effect of SCD1 deficiency on various mouse models of obesity, we introduced a global deletion of the Scd1 gene into leptin-deficient ob/ob mice, leptin-resistant Agouti (Ay/a) mice, and high-fat diet-fed obese (DIO) mice. SCD1 deficien...

  4. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

    Science.gov (United States)

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism. PMID:26914024

  5. White Pitaya (Hylocereus undatus Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

    Directory of Open Access Journals (Sweden)

    Haizhao Song

    Full Text Available Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2 but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos. In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism.

  6. Anorexigenic Lipopeptides Ameliorate Central Insulin Signaling and Attenuate Tau Phosphorylation in Hippocampi of Mice with Monosodium Glutamate-Induced Obesity

    Czech Academy of Sciences Publication Activity Database

    Špolcová, Andrea; Mikulášková, Barbora; Holubová, Martina; Nagelová, Veronika; Pirník, Zdenko; Zemenová, Jana; Haluzík, M.; Železná, Blanka; Galas, M. C.; Maletínská, Lenka

    2015-01-01

    Roč. 45, č. 3 (2015), s. 823-835. ISSN 1387-2877 R&D Projects: GA ČR GAP303/12/0576 Institutional support: RVO:61388963 Keywords : Alzheimer's disease * insulin signaling * liraglutide * monosodium glutamate-obese mice * obesity * pre- diabetes * prolactin-releasing peptide Subject RIV: CE - Biochemistry Impact factor: 4.151, year: 2014

  7. Mulberry ethanol extract attenuates hepatic steatosis and insulin resistance in high-fat diet-fed mice.

    Science.gov (United States)

    Song, Haizhao; Lai, Jia; Tang, Qiong; Zheng, Xiaodong

    2016-07-01

    Nonalcoholic fatty liver disease is one of the most common complications of obesity. Mulberry is an important source of phytochemicals, such as anthocyanins, polyphenols and flavonoids, which are related to its antioxidant activity. In this study, we developed a hypothesis that mulberry exerted beneficial effects on metabolic disorders and evaluated the influence of the mulberry ethanol extract (MEE) on high-fat diet-induced hepatic steatosis and insulin resistance in mice. Thirty-six male C57BL/6J mice were assigned into 3 groups and fed either a low-fat diet or a high-fat diet with or without supplementation with MEE. Our results showed that administration of MEE reduced diet-induced body weight gain, improved high-fat diet-induced hepatic steatosis and adipose hypertrophy, alleviated insulin resistance, and improved glucose homeostasis. Analysis of hepatic gene expression indicated that MEE treatment changed the expression profile of genes involved in lipid and cholesterol metabolism. In conclusion, the present study demonstrated that MEE supplementation protected mice from high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, the protective effects of MEE were associated with the induction of fatty acid oxidation and decreased fatty acid and cholesterol biosynthesis. PMID:27262537

  8. Glucose-stimulated calcium dynamics in islets of Langerhans in acute mouse pancreas tissue slices.

    Directory of Open Access Journals (Sweden)

    Andraž Stožer

    Full Text Available In endocrine cells within islets of Langerhans calcium ions couple cell stimulation to hormone secretion. Since the advent of modern fluorimetry, numerous in vitro studies employing primarily isolated mouse islets have investigated the effects of various secretagogues on cytoplasmic calcium, predominantly in insulin-secreting beta cells. Due to technical limitations, insights of these studies are inherently limited to a rather small subpopulation of outermost cells. The results also seem to depend on various factors, like culture conditions and duration, and are not always easily reconcilable with findings in vivo. The main controversies regard the types of calcium oscillations, presence of calcium waves, and the level of synchronized activity. Here, we set out to combine the in situ acute mouse pancreas tissue slice preparation with noninvasive fluorescent calcium labeling and subsequent confocal laser scanning microscopy to shed new light on the existing controversies utilizing an innovative approach enabling the characterization of responses in many cells from all layers of islets. Our experiments reproducibly showed stable fast calcium oscillations on a sustained plateau rather than slow oscillations as the predominant type of response in acute tissue slices, and that calcium waves are the mechanistic substrate for synchronization of oscillations. We also found indirect evidence that even a large amplitude calcium signal was not sufficient and that metabolic activation was necessary to ensure cell synchronization upon stimulation with glucose. Our novel method helped resolve existing controversies and showed the potential to help answer important physiological questions, making it one of the methods of choice for the foreseeable future.

  9. Inhibition of Type I Insulin-Like Growth Factor Receptor Signaling Attenuates the Development of Breast Cancer Brain Metastasis

    OpenAIRE

    Saldana, Sandra M.; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B.; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of ...

  10. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging [v2; ref status: indexed, http://f1000r.es/5a7

    Directory of Open Access Journals (Sweden)

    Oge Arum

    2015-04-01

    Full Text Available The correlation of physiological sensitivity to insulin (vis-à-vis glycemic regulation and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity. The growth hormone receptor/ binding protein gene-disrupted (GHR-KO mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L. counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.

  11. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging [v1; ref status: indexed, http://f1000r.es/4fk

    Directory of Open Access Journals (Sweden)

    Oge Arum

    2014-10-01

    Full Text Available The correlation of physiological sensitivity to insulin (vis-à-vis glycemic regulation and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity. The growth hormone receptor/ binding protein gene-disrupted (GHR-KO mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L. counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice.

  12. Biocompounds Attenuating the Development of Obesity and Insulin Resistance Produced by a High-fat Sucrose Diet.

    Science.gov (United States)

    Etxeberria, Usune; de la Garza, Ana Laura; Martíinez, J Alfredo; Milagro, I

    2015-08-01

    The use of biocompounds as agents with potential anti-obesity effects might be a feasible alternative to the prescription of traditional drugs in the near future. The goal of the present study was to screen five different compounds in relation to their ability to prevent body weight gain and ameliorate obesity-associated metabolic impairments, namely insulin resistance. For this purpose, seventy Wistar rats were randomly assigned into seven experimental groups. A standard diet-fed control group (control, n=10); a high-fat, high-sucrose diet-fed group (HFS, n=10) and five experimental groups which were fed the HFS diet supplemented with one of the following biocompounds; curcumin (100 mg/kg bw, n=10), chlorogenic acid (50 mg/kg bw, n=10), coumaric acid (100 mg/kg bw, n=10), naringin (100 mg/kg bw, n=10) and leucine (1% of diet, n=10). These results confirm the effectiveness of all the compounds to reduce significantly food efficiency, despite the significant higher food intake. Moreover, visceral fat mass percentage was significantly decreased after naringin and coumaric acid supplementation. In fact, this finding might be related to the considerable amelioration of HOMA-IR index detected in naringin-treated animals. A significant reduction in serum insulin levels and an improvement in the intraperitoneal glucose tolerance test and AUC were found in leucine- and coumaric acid-treated rats, respectively. In summary, the tested biocompounds, particularly naringin, coumaric acid and leucine, showed potential benefits in the prevention of obesity-related complications in rats, at least at the proved doses. PMID:26434131

  13. Supplementation of Lactobacillus plantarum K68 and Fruit-Vegetable Ferment along with High Fat-Fructose Diet Attenuates Metabolic Syndrome in Rats with Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Hui-Yu Huang

    2013-01-01

    Full Text Available Lactobacillus plantarum K68 (isolated from fu-tsai and fruit-vegetable ferment (FVF have been tested for antidiabetic, anti-inflammatory, and antioxidant properties in a rat model of insulin resistance, induced by chronic high fat-fructose diet. Fifty rats were equally assigned into control (CON, high fat-fructose diet (HFFD, HFFD plus K68, HFFD plus FVF, and HFFD plus both K68 and FVF (MIX groups. Respective groups were orally administered with K68 (1×109 CFU/0.5 mL or FVF (180 mg/kg or MIX for 8 weeks. We found that HFFD-induced increased bodyweights were prevented, and progressively increased fasting blood glucose and insulin levels were reversed (P<0.01 by K68 and FVF treatments. Elevated glycated hemoglobin (HbA1c and HOMA-IR values were controlled in supplemented groups. Furthermore, dyslipidemia, characterized by elevated total cholesterol (TC, triglyceride (TG, and low-density lipoproteins (LDLs with HFFD, was significantly (P<0.01 attenuated with MIX. Elevated pro-inflammatory cytokines, interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α (TNF-α, were controlled (P<0.01 by K68, FVF, and MIX treatments. Moreover, decreased superoxide dismutase (SOD, catalase (CAT, and glutathione peroxidase (GPx activities were substantially (P<0.01 restored by all treatments. Experimental evidences demonstrate that K68 and FVF may be effective alternative medicine to prevent HFFD-induced hyperglycemia, hyperinsulinemia, and hyperlipidemia, possibly associated with anti-inflammatory and antioxidant efficacies.

  14. Long-term exposure to genistein improves insulin secretory function of pancreatic β-cells

    OpenAIRE

    Fu, Zhuo; Liu, Dongmin

    2009-01-01

    We recently found that genistein, a plant-derived natural compound, is a novel cAMP signaling agonist in pancreatic β-cells. In the present study, we further show that exposure of clonal insulin secreting (INS-1E) cells to genistein for 48 h enhanced glucose-stimulated insulin secretion (GSIS), whereas insulin content was not altered, suggesting that genistein-enhanced GSIS is not due to a modulation of insulin synthesis. This genistein’s effect is protein tyrosine kinase- and KATP channel-in...

  15. Diazoxide unmasks glucose inhibition of insulin release by counteracting entry of Ca2+

    International Nuclear Information System (INIS)

    The interaction of diazoxide with the effects of glucose on the insulin-releasing mechanism was analyzed in β-cell-rich pancreatic islets isolated from ob/ob mice. When added at a concentration of 400 μM to a medium containing 1.28 mM Ca2+, diazoxide converted glucose stimulation of insulin release into inhibition. Further addition of 2 mM theophylline restored the insulin secretory response to glucose. The paradoxical glucose inhibition of insulin release was accounted for by a diazoxide interaction with the entry of Ca2+, unmasking a capacity of the sugar to lower cytoplasmic Ca2+ below its resting concentration

  16. Central resistance to the inhibitory effects of leptin on stimulated insulin secretion with aging.

    Science.gov (United States)

    Muzumdar, Radhika H; Ma, Xiaohui; Yang, Xiaoman; Atzmon, Gil; Barzilai, Nir

    2006-09-01

    Aging is associated with resistance to the effects of leptin on food intake and energy homeostasis. We examined if old rats were resistant to the effects of leptin on glucose stimulated insulin secretion. When leptin was infused intravenously (0.5 microg/kg/min) under hyperglycemic clamp conditions (11 mM) in young (n=5) and old rats (n=10, 5 ad libitum fed and five with surgical removal of visceral fat), glucose stimulated insulin secretion was significantly decreased by 44% in the young rats, but not in old rats (31.8+/-2.8 to 17.9+/-1.0 versus 33.7+/-1.4 versus 31.0+/-1.7 and 24.7+/-1.6 versus 21.0+/-2.8 in young versus old versus old VF- respectively, p<0.01). To identify if the resistance to leptin is secondary to impaired transport across the blood brain barrier (BBB), we infused leptin into the third ventricle (intra-cerebro ventricular, ICV). ICV infusion of leptin elicited a partial effect on glucose stimulated insulin secretion in the old (25.7+/-2.5 to 15.4+/-2.4 versus 24.4+/-2.4 to 19.0+/-2.0 in young versus old, respectively) suggesting that part of the leptin resistance was beyond the BBB. Resistance to the effects of leptin on insulin secretion in aging may protect against the onset of diabetes in old subjects. PMID:16122839

  17. Insulin Biosynthetic Interaction Network Component, TMEM24, Facilitates Insulin Reserve Pool Release

    Directory of Open Access Journals (Sweden)

    Anita Pottekat

    2013-09-01

    Full Text Available Insulin homeostasis in pancreatic β cells is now recognized as a critical element in the progression of obesity and type II diabetes (T2D. Proteins that interact with insulin to direct its sequential synthesis, folding, trafficking, and packaging into reserve granules in order to manage release in response to elevated glucose remain largely unknown. Using a conformation-based approach combined with mass spectrometry, we have generated the insulin biosynthetic interaction network (insulin BIN, a proteomic roadmap in the β cell that describes the sequential interacting partners of insulin along the secretory axis. The insulin BIN revealed an abundant C2 domain-containing transmembrane protein 24 (TMEM24 that manages glucose-stimulated insulin secretion from a reserve pool of granules, a critical event impaired in patients with T2D. The identification of TMEM24 in the context of a comprehensive set of sequential insulin-binding partners provides a molecular description of the insulin secretory pathway in β cells.

  18. HISS-dependent insulin resistance (HDIR) in aged rats is associated with adiposity, progresses to syndrome X, and is attenuated by a unique antioxidant cocktail

    OpenAIRE

    Lautt, W. Wayne; Ming, Zhi; Macedo, M Paula; Legare, Dallas J.

    2008-01-01

    The hypotheses were: HISS-dependent insulin resistance (HDIR) accounts for insulin resistance that occurs with aging; HDIR is the initiating metabolic defect that leads progressively to type 2 diabetes and the metabolic syndrome; a synergistic antioxidant cocktail in chow confers protection against HDIR, subsequent symptoms of diabetes, and the metabolic syndrome. Male Sprague Dawley rats were tested at 9, 26, and 52 weeks to determine their dynamic response to insulin, the HISS (hepatic insu...

  19. Aged insulin granules display reduced microtubule-dependent mobility and are disposed within actin-positive multigranular bodies

    Science.gov (United States)

    Hoboth, Peter; Müller, Andreas; Ivanova, Anna; Mziaut, Hassan; Dehghany, Jaber; Sönmez, Anke; Lachnit, Martina; Meyer-Hermann, Michael; Kalaidzidis, Yannis; Solimena, Michele

    2015-01-01

    Insulin secretion is key for glucose homeostasis. Insulin secretory granules (SGs) exist in different functional pools, with young SGs being more mobile and preferentially secreted. However, the principles governing the mobility of age-distinct SGs remain undefined. Using the time-reporter insulin-SNAP to track age-distinct SGs we now show that their dynamics can be classified into three components: highly dynamic, restricted, and nearly immobile. Young SGs display all three components, whereas old SGs are either restricted or nearly immobile. Both glucose stimulation and F-actin depolymerization recruit a fraction of nearly immobile young, but not old, SGs for highly dynamic, microtubule-dependent transport. Moreover, F-actin marks multigranular bodies/lysosomes containing aged SGs. These data demonstrate that SGs lose their responsiveness to glucose stimulation and competence for microtubule-mediated transport over time while changing their relationship with F-actin. PMID:25646459

  20. Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans

    DEFF Research Database (Denmark)

    Simon, Marie-Christine; Strassburger, Klaus; Nowotny, Bettina;

    2015-01-01

    OBJECTIVE: Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of...... production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays. RESULTS: In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2...

  1. 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

    , which causes hyperpolarization, eliminated the response. Luminal inhibition of the sodium-glucose cotransporter 1 (SGLT1) (by phloridzin) eliminated glucose-stimulated release as well as secretion stimulated by luminal methyl-α-d-glucopyranoside (20% wt/vol), a metabolically inactive SGLT1 substrate...... stimulates NT secretion by uptake through SGLT1 and GLUT2, both causing depolarization either as a consequence of sodium-coupled uptake (SGLT1) or by closure of KATP channels (GLUT2 and SGLT1) secondary to the ATP-generating metabolism of glucose....

  2. Effect of lithium on plasma glucose, insulin and glucagon in normal and streptozotocin-diabetic rats: role of glucagon in the hyperglycaemic response.

    OpenAIRE

    Hermida, O. G.; Fontela, T.; Ghiglione, M.; Uttenthal, L. O.

    1994-01-01

    1. Lithium salts, used in the treatment of affective disorders, may have adverse effects on glucose tolerance in man, and suppress glucose-stimulated insulin secretion in rats. 2. To study the interaction of these effects with pre-existing diabetes mellitus, plasma glucose and insulin responses to lithium chloride were measured in male Wistar rats made diabetic with intraperitoneal streptozotocin, and in normal controls. 3. In both normal and diabetic anaesthetized rats, intravenous lithium (...

  3. suPAR associates to glucose metabolic aberration during glucose stimulation in HIV-infected patients on HAART

    DEFF Research Database (Denmark)

    Andersen, Ove; Eugen-Olsen, Jesper; Kofoed, Kristian;

    2008-01-01

    extend these findings by investigating the association of suPAR to glucose metabolic insufficiency during an oral glucose challenge (OGTT). METHODS: In 16 HIV-infected patients with lipodystrophy and 15 HIV-infected patients without lipodystrophy, glucose tolerance, insulin sensitivity (ISI......PAR associated to important glucose metabolic aberrations in HIV-infected patients on HAART. Moreover, suPAR was stable after a glucose challenge. Future research is required to confirm these findings and explore the potential of suPAR as marker of dysmetabolism in HIV-infected patients.......OBJECTIVE: We have recently shown that the level of soluble urokinase plasminogen activator receptor (suPAR), which is associated with the immune status of HIV-infected patients undergoing highly active antiretroviral therapy (HAART), correlates with the insulin action of such patients. Here we...

  4. Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Chow, S.A.; Falany, J.L.; Fischer, L.J. (Univ. of Iowa, Iowa City (USA))

    1989-06-01

    The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.

  5. Cyproheptadine metabolites inhibit proinsulin and insulin biosynthesis and insulin release in isolated rat pancreatic islets

    International Nuclear Information System (INIS)

    The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic beta-cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals

  6. Role of mitochondrial calcium in metabolism-secretion coupling in nutrient-stimulated insulin release

    OpenAIRE

    Kennedy, Eleanor; Wollheim, Claes

    1998-01-01

    Glucose-stimulated insulin release from pancreatic beta cells involves a complex series of signalling pathways. In many forms of diabetes, lesions in this process cause or aggravate the diabetic phenotype. A common motif in these cascades is the elevation of intracellular Ca2+ both in the cytosolic compartment ([Ca2+]c) and within the mitochondria ([Ca2+]m). These parameters can be effectively monitored using the photoprotein aequorin which can be targeted to subcellular compartments by trans...

  7. Overexpression of insulin-like growth factor-1 attenuates skeletal muscle damage and accelerates muscle regeneration and functional recovery after disuse.

    Science.gov (United States)

    Ye, Fan; Mathur, Sunita; Liu, Min; Borst, Stephen E; Walter, Glenn A; Sweeney, H Lee; Vandenborne, Krista

    2013-05-01

    Skeletal muscle is a highly dynamic tissue that responds to endogenous and external stimuli, including alterations in mechanical loading and growth factors. In particular, the antigravity soleus muscle experiences significant muscle atrophy during disuse and extensive muscle damage upon reloading. Given that insulin-like growth factor-1 (IGF-1) has been implicated as a central regulator of muscle repair and modulation of muscle size, we examined the effect of virally mediated overexpression of IGF-1 on the soleus muscle following hindlimb cast immobilization and upon reloading. Recombinant IGF-1 cDNA virus was injected into one of the posterior hindlimbs of the mice, while the contralateral limb was injected with saline (control). At 20 weeks of age, both hindlimbs were immobilized for 2 weeks to induce muscle atrophy in the soleus and ankle plantarflexor muscle group. Subsequently, the mice were allowed to reambulate, and muscle damage and recovery were monitored over a period of 2-21 days. The primary finding of this study was that IGF-1 overexpression attenuated reloading-induced muscle damage in the soleus muscle, and accelerated muscle regeneration and force recovery. Muscle T2 assessed by magnetic resonance imaging, a non-specific marker of muscle damage, was significantly lower in IGF-1-injected compared with contralateral soleus muscles at 2 and 5 days reambulation (P<0.05). The reduced prevalence of muscle damage in IGF-1-injected soleus muscles was confirmed on histology, with a lower fractional area of abnormal muscle tissue in IGF-1-injected muscles at 2 days reambulation (33.2±3.3 versus 54.1±3.6%, P<0.05). Evidence of the effect of IGF-1 on muscle regeneration included timely increases in the number of central nuclei (21% at 5 days reambulation), paired-box transcription factor 7 (36% at 5 days), embryonic myosin (37% at 10 days) and elevated MyoD mRNA (7-fold at 2 days) in IGF-1-injected limbs (P<0.05). These findings demonstrate a potential role

  8. Alpha-lipoic acid attenuates endoplasmic reticulum stress-induced insulin resistance by improving mitochondrial function in HepG2 cells.

    Science.gov (United States)

    Lei, Lin; Zhu, Yiwei; Gao, Wenwen; Du, Xiliang; Zhang, Min; Peng, Zhicheng; Fu, Shoupeng; Li, Xiaobing; Zhe, Wang; Li, Xinwei; Liu, Guowen

    2016-10-01

    Alpha-lipoic acid (ALA) has been reported to have beneficial effects for improving insulin sensitivity. However, the underlying molecular mechanism of the beneficial effects remains poorly understood. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are considered causal factors that induce insulin resistance. In this study, we investigated the effect of ALA on the modulation of insulin resistance in ER-stressed HepG2 cells, and we explored the potential mechanism of this effect. HepG2 cells were incubated with tunicamycin (Tun) for 6h to establish an ER stress cell model. Tun treatment induced ER stress, mitochondrial dysfunction and insulin resistance. Interestingly, ALA had no significant effect on ER stress signals. Pretreatment of the ER stress cell model with ALA for 24h improved insulin sensitivity, restored the expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes and increased intracellular ATP production. Moreover, ALA augmented the β-oxidation capacity of the mitochondria. Importantly, ALA treatment could decrease oligomycin-induced mitochondrial dysfunction and then improved insulin resistance. Taken together, our data suggest that ALA prevents ER stress-induced insulin resistance by enhancing mitochondrial function. PMID:27377964

  9. The adipocytokine Nampt and its product NMN have no effect on beta-cell survival but potentiate glucose stimulated insulin secretion

    NARCIS (Netherlands)

    Spinnler, R.; Gorski, T.; Stolz, K.; Schuster, S.; Garten, A.; Beck-Sickinger, A.G.; Engelse, M.A.; de Koning, E.J.; Korner, A.; Kiess, W.; Maedler, K.

    2013-01-01

    AIMS/HYPOTHESIS: Obesity is associated with a dysregulation of beta-cell and adipocyte function. The molecular interactions between adipose tissue and beta-cells are not yet fully elucidated. We investigated, whether or not the adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) and its enz

  10. Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Halsall, Ian;

    2007-01-01

    The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue...... SP and IP during the early phase (0, 10, and 20 minutes) and during the late phase (45, 75, and 105 minutes) of the OGTT compared with NONLIPO patients (Ps < .05). LIPO patients exhibited significantly increased fasting SP/IP ratio, fasting SP/insulin ratio, and total proinsulin to C-peptide ratio...

  11. Gamma Amino Butyric Acid Attenuates Liver and Kidney Damage Associated with Insulin Alteration in γ-Irradiated and Streptozotocin-Treated Rats

    International Nuclear Information System (INIS)

    Gamma aminobutyric acid (GABA) is one of the inhibitory neurotransmitters that may have the ability to relive the intensity of stress. The aim of the current study was to evaluate the role of γ-amino butyric acid (GABA) in modulating insulin disturbance associated with liver and kidney damage in γ-irradiated and streptozotocin-treated rats. Irradiation was performed by whole body exposure to 6 Gy from a Cs-137 source. Streptozotocin (STZ) was administered in a single intraperitoneal dose (60 mg/kg body weight). GABA (200 mg/Kg body weight/day) was administered daily via gavages during 3 weeks to γ-irradiated and STZ-treated-rats. The results obtained showed that γ-irradiation induced hyperglycemia, hyperinsulinaemia and insulin resistance (similar to type 2 Diabetes), while STZ-treatment produced hyperglycemia, insulin deficiency with no insulin resistance detected (similar to type 1 Diabetes). In both cases, significant increases of alanine amino transferase (ALT) and aspartate amino transferase (AST) activities, urea and creatinine levels were recorded in the serum. These changes were associated with oxidative damage to the liver and kidney tissues notified by significant decreases of superoxide dismutase (SOD ), catalase and glutathione peroxidase ( GSH-Px) activities in parallel to significant increases of malondialdehyde (MDA) and advanced oxidation protein products ( AOPP) levels. The administration of GABA to irradiated as well as STZ-treated rats regulated insulin and glucose levels, minimized oxidative stress and reduced the severity of liver and kidney damage. It could be concluded that GABA could be a useful adjunct to reduce some metabolic complications associated with insulin deficiency and insulin resistance

  12. Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Halsall, Ian;

    2007-01-01

    The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue......, the secretion patterns of SP and IP of 16 HIV-infected men with lipodystrophy (LIPO) and 15 HIV-infected men without lipodystrophy (NONLIPO) were studied during an oral glucose tolerance test (OGTT). All patients received highly active antiretroviral therapy. Insulin secretion rates were determined by...... deconvolution of plasma C-peptide concentrations. More LIPO than NONLIPO patients displayed diabetes mellitus and impaired glucose tolerance than normal glucose tolerance (LIPO 2/8/6 vs NONLIPO 1/2/12, P = .05). LIPO patients had increased fasting levels of SP and IP, ratio of SP/IP, and area under the curve of...

  13. Impact of TCF7L2 rs7903146 on insulin secretion and action in young and elderly Danish twins

    DEFF Research Database (Denmark)

    Wegner, Lise; Hussain, Meena S; Pilgaard, Kasper;

    2008-01-01

    nondiabetic T-allele carriers had increased peripheral insulin sensitivity (P = 0.03). Young T-allele carriers had impaired hepatic insulin sensitivity (P = 0.04) independent of plasma insulin levels. TCF7L2 gene expression in skeletal muscle and adipose tissue was not explained by genotype, sex, aerobic...... capacity, birth, or adult anthropometry and was not associated with in vivo glucose metabolism. CONCLUSIONS: The rs7903146 T-allele associates with hepatic insulin resistance and diminished glucose-stimulated plasma insulin secretion. Our study does not provide evidence of a role of TCF7L2 gene expression......OBJECTIVE: We investigated the regulation and metabolic effects of TCF7L2 gene expression in human sc fat and skeletal muscle and the impact of the TCF7L2, rs7903146, T-allele on gene expression and measures of glucose metabolism including insulin secretion and peripheral and hepatic insulin action...

  14. Developed beverage from roselle calyx and selected fruits modulates β-cell function, improves insulin sensitivity, and attenuates hyperlipidaemia in diabetic rats

    Directory of Open Access Journals (Sweden)

    Ochuko L. Erukainure

    2015-12-01

    Full Text Available The aim of this study is to report the antidiabetic properties of a beverage developed from roselle calyx and selected fruits in male albino rats. The beverage was designed to contain 30% pawpaw (Carica papaya L., 10% grapefruit (Citrus paradisi, 20% guava leaves (Psidium guajava L. and 40% roselle calyx aqueous extracts. Four groups of five rats each were acclimatized on pelletized mouse chow for seven days, after which diabetes was induced by a single ip injection of alloxan in all groups except group 1, which served as control. Group 2 served as negative control while groups 3 and 4 were treated with the beverage at 2.5 and 5 ml/kg bw respectively. Food intake, body weight, and blood glucose levels were monitored. They were sacrificed by cervical dislocation after a 2 week treatment. Blood serum was analysed to evaluate insulin levels, β cell function, insulin resistance and lipid profile. Histological studies were carried out on pancreatic tissues. Treatment with both doses of the beverage led to a significant reduction (p < 0.05 in blood glucose, total cholesterol triglyceride, LDL and increased HDL levels. It also improved serum insulin levels, β cell function, reduced insulin resistance and restored pancreatic beta cells compared to the diabetic group. These antidiabetic properties may be as a consequence of modulation of the β-cell function, reduction of insulin resistance and preservation/restoration of β-cell integrity. However, treatment with the single dose showed signs of hyperinsulinaemia.

  15. Insulin Secretagogues

    Science.gov (United States)

    ... Your Body in Balance › Insulin Secretagogues Fact Sheet Insulin Secretagogues March, 2012 Download PDFs English Espanol Editors ... medicines can help you stay healthy. What are insulin secretagogues? Insulin secretagogues (pronounced seh-KREET-ah-gogs) ...

  16. Electroacupuncture-attenuated ischemic brain injury increases insulin-like growth factor-1expression in a rat model of focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Huanmin Gao; Ling Wang; Yunliang Guo

    2010-01-01

    Acupuncture has recently gained popularity in many countries as an alternative and complementary therapeutic intervention.Previous studies have shown that changes in genes,proteins,and their metabolites were measureable during acupuncture for treatment of cerebral ischemia.Through the use of in situ hybridization and immunohistochemistry,the present study confirmed that electroacupuncture increased insulin-like growth factor-1 mRNA and protein expression in the corpus striatum following cerebral ischemia,reduced brain edema following middle cerebral artery occlusion repeffusion,and decreased infarct volume.Results suggested that electroacupuncture is effective in the relief of cerebral ischemia by increasing endogenous insulin-like growth factor-1 expression.

  17. Oxidative stress, insulin resistance, dyslipidemia and type 2diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Surapon Tangvarasittichai

    2015-01-01

    Oxidative stress is increased in metabolic syndromeand type 2 diabetes mellitus (T2DM) and this appearsto underlie the development of cardiovascular disease,T2DM and diabetic complications. Increased oxidativestress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM.

  18. Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines.

    Science.gov (United States)

    Turpaev, Kyril; Welsh, Nils

    2016-08-01

    We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin-producing βTC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in βTC6 and counteract to impairments of glucose-stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway. Our present results indicate that in respect of inhibition of IL-1β-dependent iNOS induction, βTC6 cells are more sensitive to EMK 1071 (2-((5-methylthiophen-2-yl)methylene)malononitrile) and EMK 31 (2-(4-hydroxy-3-methoxybenzylidene)malononitrile) as compared to other analyzed AMN compounds. We suggest that the ability of AMN compounds to inhibit iNOS induction and other cytokine-induced transcriptional events might be a tool to achieve improved β-cell survival and functionality. PMID:27178899

  19. Amino acids attenuate insulin action on gluconeogenesis and promote fatty acid biosynthesis via mTORC1 signaling pathway in trout hepatocytes

    OpenAIRE

    Dai, Wei Wei; Panserat, Stephane; Plagnes- Juan, Elisabeth; Seiliez, Iban; Skiba-Cassy, Sandrine

    2015-01-01

    Background/Aims: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs)-induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. Methods: We stimulated trout primary hepatocytes with different AA levels and emplo...

  20. Regulation of Insulin Secretion and Expression of SUR1 Gene by Chronic Exposure to Free Fatty Acids in Rat Pancreatic β Cells

    Institute of Scientific and Technical Information of China (English)

    袁莉; 邓秀玲; 陈璐璐; 周愍

    2004-01-01

    To study the effects of free fatty acids on insulin secretion and expression of SUR1 gene in rat pancreatic B cells in vitro, and to explore the molecular mechanisms in lipotoxicity inducing insulin secretion dysfunction, pancreatic islet cells were isolated and digested from male SD rats.Purified islets were incubated with either 0.25 mmol/L palmitate or 0. 125 mmol/L oleate for 48 h in vitro. Then islets were stimulated with either 5.6 mmol/L or 16.7 mmol/L glucose for 1 h. Insulin release was measured by using radioimmunoassay, and the expression of SUR1 gene mRNA was quantified by reserve transcription-polymerase chain reaction (RT-PCR). The islets exposed to both palmitate and oleate for 48 h showed an increased basal and a decreased glucose-indused insulin release as compared with control islets. Palmitate increased basal insulin secretion by 110 % (P<0.01), decreased glucose stimulated insulin secretion by 43 % (P<0.01) ; while oleate increased basal insulin secretion by 80 % (P<0.01) and decreased glucose stimulated insulin secretion by 32 % (P<0.05). RT-PCR showed that oleate significantly suppressed SUR1 gene expression by 64 % (P<0.01)as compared with the control group, while palmitate group manifested a light decrease of 15 % (P >0.05) of SUR1 gene expression. Our results suggested that chronic exposure to free fatty acids of pancreatic β cells inhibited glucose stimulated insulin secretion. Regulation of SUR1 gene expression may be involved in such effects, which may also be one of the molecular mechanisms in lipotoxocity inducing β cells secretion dysfunction.

  1. SIRT1 attenuates palmitate-induced endoplasmic reticulum stress and insulin resistance in HepG2 cells via induction of oxygen-regulated protein 150

    Science.gov (United States)

    Jung, T.W.; Lee, K.T.; Lee, M.W.; Ka, K.H.

    2012-01-01

    Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.

  2. Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.

    Science.gov (United States)

    Septembre-Malaterre, Axelle; Le Sage, Fanny; Hatia, Sarah; Catan, Aurélie; Janci, Laurent; Gonthier, Marie-Paule

    2016-07-01

    Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016. PMID:27094023

  3. Cinnamon extract attenuates TNF-alpha-induced intestinal lipoprotein ApoB48 overproduction by regulating inflammatory, insulin, and lipoprotein pathways in enterocytes

    Science.gov (United States)

    We evaluated whether a water extract of cinnamon (CE = Cinnulin PF®) attenuates the dyslipidemia induced by TNF-alpha in Triton WR-1339-treated hamsters, and whether CE inhibited the over-secretion of apoB48-induced by TNF-alpha in enterocytes in a 35S-labelling study. In vivo, oral treatment with C...

  4. Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J Mice

    DEFF Research Database (Denmark)

    Fjære, Even; Aune, Ulrike Liisberg; Røen, Kristin;

    2014-01-01

    a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo...... by treatment with indomethacin. We demonstrate that indomethacin did not inhibit GSIS per se, but activation of GPR40 in the presence of indomethacin inhibited glucose-dependent insulin secretion in MIN6 cells. We conclude that constitutive high hepatic glucose output combined with impaired GSIS in response...

  5. Insulin Test

    Science.gov (United States)

    ... especially as a result of taking non-human (animal or synthetic) insulin, these can interfere with insulin testing. In this case, a C-peptide may be performed as an alternative way to evaluate insulin production. Note also that ...

  6. Supplementation of Lactobacillus plantarum K68 and Fruit-Vegetable Ferment along with High Fat-Fructose Diet Attenuates Metabolic Syndrome in Rats with Insulin Resistance

    OpenAIRE

    Hui-Yu Huang; Mallikarjuna Korivi; Chun-Han Tsai; Jo-Hsuan Yang; Ying-Chieh Tsai

    2013-01-01

    Lactobacillus plantarum K68 (isolated from fu-tsai) and fruit-vegetable ferment (FVF) have been tested for antidiabetic, anti-inflammatory, and antioxidant properties in a rat model of insulin resistance, induced by chronic high fat-fructose diet. Fifty rats were equally assigned into control (CON), high fat-fructose diet (HFFD), HFFD plus K68, HFFD plus FVF, and HFFD plus both K68 and FVF (MIX) groups. Respective groups were orally administered with K68 (1 × 109 CFU/0.5 mL) or FVF (180 mg/kg...

  7. Alternative Respiration Induced by Glucose Stimulation and Variation of Adenylate Energy Charge in Glucose-Starved Cells of Green Alga Chlorella Protothecoides

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Effects of inhibitors and glucose on cytochrome and alternative respiration and on adenylate energy charge (AEC) in glucose-starved Chlorella protothecoides were investigated. 1 mmol/L azide (NaN3), which immediately caused an increase of O2 uptake by inhibiting the cytochrome pathway and stimulating alternative respiration, resulted in a decrease of AEC value from 0. 83 to 0. 34 within 3 minutes. When 1 mmol/L salicylhydroxamic acid (SHAM) was added into the cell suspension, there was no apparent variation in AEC. Adding NaN3 and SHAM together into cell suspension to inhibit both cytochrome and alternative pathways showed a same change of AEC as that of adding NaN3 alone. When 2.0 mmol/L of glucose was added to a suspension of glucose-starved cells, the O2 uptake rate was immediately stimulated from 0.81 up to 1.34 [μrnol/L O2 · min-] · (mL PCV)-1]. The respiration stimulated by glucose could be inhibited about 20% by adding 1 mmol/L SHAM. It was found by titration with SHAM in the absence and presence of NaN3 that 53% of O2 uptake went through the cytochrome pathway and 45% of the alternate pathway was operational in enhanced respiration. It implied that induced operation of the alternative respiratory pathway probably resulted from the burst of the electron flux into the electron transport chain by glucose stimulation.

  8. Rising Intracellular Zinc by Membrane Depolarization and Glucose in Insulin-Secreting Clonal HIT-T15 Beta Cells

    OpenAIRE

    Slepchenko, Kira G.; Li, Yang V

    2012-01-01

    Zinc (Zn2+) appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30–60 mM) was able to induce a rapid increase in...

  9. Genetic and phenotypic correlations between surrogate measures of insulin release obtained from OGTT data

    DEFF Research Database (Denmark)

    Gjesing, Anette P; Ribel-Madsen, Rasmus; Harder, Marie N; Eiberg, Hans; Grarup, Niels; Jørgensen, Torben; Ekstrøm, Claus T; Pedersen, Oluf; Hansen, Torben

    2015-01-01

    closely related to fasting insulin with a genetic correlation of 0.85. The effects of 82 selected susceptibility single nucleotide polymorphisms on these insulin secretion indices supported our interpretation of the data and added insight into the biological differences between the examined traits......AIMS/HYPOTHESIS: We examined the extent to which surrogate measures of insulin release have shared genetic causes. METHODS: Genetic and phenotypic correlations were calculated in a family cohort (n = 315) in which beta cell indices were estimated based on fasting and oral glucose-stimulated plasma....... RESULTS: We found a notable difference between the phenotypic and genetic correlations for the traits, emphasising that the phenotypic correlation is an insufficient measure of the magnitude of shared genetic impact. In addition, we found that corrected insulin response, insulinogenic index and incAUC for...

  10. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lepob/ob mice

    International Nuclear Information System (INIS)

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic β-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lepob/ob/HSL-/-) and explored the role of HSL in pancreatic β-cells in the setting of obesity. Lepob/ob/HSL-/- developed elevated blood glucose levels and reduced plasma insulin levels compared with Lepob/ob/HSL+/+ in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep+/+ background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lepob/ob islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lepob/ob mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  11. Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis

    DEFF Research Database (Denmark)

    Carobbio, Stefania; Frigerio, Francesca; Rubi, Blanca;

    2009-01-01

    secretion was reduced by 37% in betaGlud1(-/-). Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in betaGlud1(-/-) islets fully restored......Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been...... glucose-induced insulin release. Thus, GDH appears to account for about 40% of glucose-stimulated insulin secretion and to lack redundant mechanisms. In betaGlud1(-/-) mice, the reduced secretory capacity resulted in lower plasma insulin levels in response to both feeding and glucose load, while body...

  12. Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Maria Jose Garcia Barrado

    Full Text Available The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen, and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01, by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01 after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01 following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets.

  13. VAMP7 Regulates Autophagy to Maintain Mitochondrial Homeostasis and to Control Insulin Secretion in Pancreatic β-Cells.

    Science.gov (United States)

    Aoyagi, Kyota; Ohara-Imaizumi, Mica; Itakura, Makoto; Torii, Seiji; Akimoto, Yoshihiro; Nishiwaki, Chiyono; Nakamichi, Yoko; Kishimoto, Takuma; Kawakami, Hayato; Harada, Akihiro; Takahashi, Masami; Nagamatsu, Shinya

    2016-06-01

    VAMP7 is a SNARE protein that mediates specific membrane fusions in intracellular trafficking and was recently reported to regulate autophagosome formation. However, its function in pancreatic β-cells is largely unknown. To elucidate the physiological role of VAMP7 in β-cells, we generated pancreatic β-cell-specific VAMP7 knockout (Vamp7(flox/Y);Cre) mice. VAMP7 deletion impaired glucose-stimulated ATP production and insulin secretion, though VAMP7 was not localized to insulin granules. VAMP7-deficient β-cells showed defective autophagosome formation and reduced mitochondrial function. p62/SQSTM1, a marker protein for defective autophagy, was selectively accumulated on mitochondria in VAMP7-deficient β-cells. These findings suggest that accumulation of dysfunctional mitochondria that are degraded by autophagy caused impairment of glucose-stimulated ATP production and insulin secretion in Vamp7(flox/Y);Cre β-cells. Feeding a high-fat diet to Vamp7(flox/Y);Cre mice exacerbated mitochondrial dysfunction, further decreased ATP production and insulin secretion, and consequently induced glucose intolerance. Moreover, we found upregulated VAMP7 expression in wild-type mice fed a high-fat diet and in db/db mice, a model for diabetes. Thus our data indicate that VAMP7 regulates autophagy to maintain mitochondrial quality and insulin secretion in response to pathological stress in β-cells. PMID:26953164

  14. Effect of physical training on insulin secretion and action in skeletal muscle and adipose tissue of first-degree relatives of type 2 diabetic patients

    DEFF Research Database (Denmark)

    Dela, Flemming; Stallknecht, Bente Merete

    2010-01-01

    Physical training affects insulin secretion and action, but there is a paucity of data on the direct effects in skeletal muscle and adipose tissue and on the effect of training in first-degree relatives (FDR) of patients with type 2 diabetes. We studied insulin action at the whole body level and...... peripherally in skeletal muscle and adipose tissue as well as insulin-secretory capacity in seven FDR and eight control (CON) subjects before and after 12 wk of endurance training. Training improved physical fitness. Insulin-mediated glucose uptake (GU) increased (whole body and leg; P <0.05) after training in...... <0.05) in subcutaneous abdominal than in femoral adipose tissue and quadriceps muscle with no difference between FDR and CON. Glucose-stimulated insulin secretion was lower in FDR compared with CON, but no effect of training was seen. Glucagon-like peptide-1 stimulated insulin secretion five- to...

  15. Polyphenol- and fibre-rich dried fruits with green tea attenuate starch-derived postprandial blood glucose and insulin: a randomised, controlled, single-blind, cross-over intervention.

    Science.gov (United States)

    Nyambe-Silavwe, H; Williamson, G

    2016-08-01

    Polyphenol- and fibre-rich foods (PFRF) have the potential to affect postprandial glycaemic responses by reducing glucose absorption, and thus decreasing the glycaemic response of foods when consumed together. A randomised, single-blind, cross-over study was conducted on sixteen healthy volunteers to test whether PFRF could attenuate postprandial blood glucose in healthy volunteers when added to a source of carbohydrate (starch in bread). This is the first study to examine the effects of a meal comprised of components to inhibit each stage of the biochemical pathway, leading up to the appearance of glucose in the blood. The volunteers were fasted and attended four visits: two control visits (bread, water, balancing sugars) and two test visits (single and double dose of PFRF) where they consumed bread, water and PFRF. Blood samples were collected at 0 (fasted), 15, 30, 45, 60, 90, 120, 150 and 180 min after consumption. The PFRF components were tested for α-amylase and α-glucosidase inhibitory potential in vitro. Plasma glucose was lower after consumption of both doses compared with controls: lower dose, change in mean incremental areas under the glucose curves (IAUC)=-27·4 (sd 7·5) %, Pamylase (green tea, strawberry, blackberry and blackcurrant) and α-glucosidase (green tea) activities in vitro. The PFRF have a pronounced and significant lowering effect on postprandial blood glucose and insulin response in humans, due in part to inhibition of α-amylase and α-glucosidase, as well as glucose transport. PMID:27278405

  16. Reduced insulin secretion and glucose intolerance are involved in the fasting susceptibility of common vampire bats.

    Science.gov (United States)

    Freitas, Mariella B; Queiroz, Joicy F; Dias Gomes, Carolinne I; Collares-Buzato, Carla B; Barbosa, Helena C; Boschero, Antonio C; Gonçalves, Carlos A; Pinheiro, Eliana C

    2013-03-01

    Susceptibility during fasting has been reported for the common vampire bat (Desmodus rotundus), to the point of untimely deaths after only 2-3 nights of fasting. To investigate the underlying physiology of this critical metabolic condition, we analyzed serum insulin levels, pancreatic islets morphometry and immunocytochemistry (ICC), static insulin secretion in pancreas fragments, and insulin signaling mechanism in male vampire bats. A glucose tolerance test (ipGTT) was also performed. Serum insulin was found to be lower in fed vampires compared to other mammals, and was significantly reduced after 24h fasting. Morphometrical analyses revealed small irregular pancreatic islets with reduced percentage of β-cell mass compared to other bats. Static insulin secretion analysis showed that glucose-stimulated insulin secretion was impaired, as insulin levels did not reach significance under high glucose concentrations, whereas the response to the amino acid leucin was preserved. Results from ipGTT showed a failure on glucose clearance, indicating glucose intolerance due to diminished pancreatic insulin secretion and/or decreased β-cell response to glucose. In conclusion, data presented here indicate lower insulinemia and impaired insulin secretion in D. rotundus, which is consistent with the limited ability to store body energy reserves, previously reported in these animals. Whether these metabolic and hormonal features are associated with their blood diet remains to be determined. The peculiar food sharing through blood regurgitation, reported to this species, might be an adaptive mechanism overcoming this metabolic susceptibility. PMID:23262275

  17. Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Stefan Z Lutz

    Full Text Available AIMS/HYPOTHESIS: Recently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans. METHODS: We genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707. The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps. RESULTS: After appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels. CONCLUSIONS: In conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin-desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity.

  18. Munc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release

    OpenAIRE

    Oh, Eunjin; Thurmond, Debbie C.

    2009-01-01

    OBJECTIVE The Sec1/Munc18 protein Munc18c has been implicated in Syntaxin 4–mediated exocytosis events, although its purpose in exocytosis has remained elusive. Given that Syntaxin 4 functions in the second phase of glucose-stimulated insulin secretion (GSIS), we hypothesized that Munc18c would also be required and sought insight into the possible mechanism(s) using the islet β-cell as a model system. RESEARCH DESIGN AND METHODS Perifusion analyses of isolated Munc18c- (−/+) or Munc18c-deplet...

  19. Insulin Protects against Hepatic Damage Postburn

    OpenAIRE

    Jeschke, Marc G.; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G.; Cox, Robert A.; Brooks, Natasha C; Finnerty, Celeste C.; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subs...

  20. Both fasting and glucose-stimulated proinsulin levels predict hyperglycemia and incident type 2 diabetes: a population-based study of 9,396 Finnish men.

    Directory of Open Access Journals (Sweden)

    Jagadish Vangipurapu

    Full Text Available Hyperproinsulinemia is an indicator of β-cell dysfunction, and fasting proinsulin levels are elevated in patients with hyperglycemia. It is not known whether proinsulin levels after a glucose load are better predictors of hyperglycemia and type 2 diabetes than fasting proinsulin.Participants were 9,396 Finnish men (mean±SD, age 57.3±7.1 years, BMI 27.0±4.0 kg/m2 of the population-based METabolic Syndrome In Men Study who were non-diabetic at the recruitment, and who participated in a 6-year follow-up study. Proinsulin and insulin levels were measured in the fasting state and 30 and 120 min after an oral glucose load. Area under the curve (AUC and proinsulin to insulin ratios were calculated.Fasting proinsulin, proinsulin at 30 min and proinsulin AUC during the first 30 min of an oral glucose tolerance test significantly predicted both the worsening of hyperglycemia and type 2 diabetes after adjustment for confounding factors. Further adjustment for insulin sensitivity (Matsuda index or insulin secretion (Disposition index weakened these associations. Insulin sensitivity had a major impact on these associations.Our results suggest that proinsulin in the fasting state and after an oral glucose load similarly predict the worsening of hyperglycemia and conversion to type 2 diabetes.

  1. Insulin Injection

    Science.gov (United States)

    ... placed in dosing pens. Be sure you know what type of container your insulin comes in and what other supplies, such as needles, syringes, or pens, ... name and letter on your insulin are exactly what your doctor prescribed.If ... a syringe marked for that type of insulin. Always use the same brand and ...

  2. Oral Insulin

    OpenAIRE

    Kalra Sanjay; Kalra Bharti; Agrawal Navneet

    2010-01-01

    Abstract Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation.

  3. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    Science.gov (United States)

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. PMID:27094035

  4. Isolation and amino acid sequences of squirrel monkey (Saimiri sciurea) insulin and glucagon

    International Nuclear Information System (INIS)

    It was reported two decades ago that insulin was not detectable in the glucose-stimulated state in Saimiri sciurea, the New World squirrel monkey, by a radioimmunoassay system developed with guinea pig anti-pork insulin antibody and labeled park insulin. With the same system, reasonable levels were observed in rhesus monkeys and chimpanzees. This suggested that New World monkeys, like the New World hystricomorph rodents such as the guinea pig and the coypu, might have insulins whose sequences differ markedly from those of Old World mammals. In this report the authors describe the purification and amino acid sequences of squirrel monkey insulin and glucagon. They demonstrate that the substitutions at B29, B27, A2, A4, and A17 of squirrel monkey insulin are identical with those previously found in another New World primate, the owl monkey (Aotus trivirgatus). The immunologic cross-reactivity of this insulin in their immunoassay system is only a few percent of that of human insulin. It appears that the peptides of the New World monkeys have diverged less from those of the Old World mammals than have those of the New World hystricomorph rodents. The striking improvements in peptide purification and sequencing have the potential for adding new information concerning the evolutionary divergence of species

  5. Isolation and amino acid sequences of squirrel monkey (Saimiri sciurea) insulin and glucagon

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Jinghua (Veterans Administration Medical Center, Bronx, NY (United States)); Eng, J.; Yalow, R.S. (Veterans Administration Medical Center, Bronx, NY (United States) City Univ. of New York, NY (United States))

    1990-12-01

    It was reported two decades ago that insulin was not detectable in the glucose-stimulated state in Saimiri sciurea, the New World squirrel monkey, by a radioimmunoassay system developed with guinea pig anti-pork insulin antibody and labeled park insulin. With the same system, reasonable levels were observed in rhesus monkeys and chimpanzees. This suggested that New World monkeys, like the New World hystricomorph rodents such as the guinea pig and the coypu, might have insulins whose sequences differ markedly from those of Old World mammals. In this report the authors describe the purification and amino acid sequences of squirrel monkey insulin and glucagon. They demonstrate that the substitutions at B29, B27, A2, A4, and A17 of squirrel monkey insulin are identical with those previously found in another New World primate, the owl monkey (Aotus trivirgatus). The immunologic cross-reactivity of this insulin in their immunoassay system is only a few percent of that of human insulin. It appears that the peptides of the New World monkeys have diverged less from those of the Old World mammals than have those of the New World hystricomorph rodents. The striking improvements in peptide purification and sequencing have the potential for adding new information concerning the evolutionary divergence of species.

  6. Voluntary wheel-running attenuates insulin and weight gain and affects anxiety-like behaviors in C57BL6/J mice exposed to a high-fat diet.

    Science.gov (United States)

    Hicks, Jasmin A; Hatzidis, Aikaterini; Arruda, Nicole L; Gelineau, Rachel R; De Pina, Isabella Monteiro; Adams, Kenneth W; Seggio, Joseph A

    2016-09-01

    It is widely accepted that lifestyle plays a crucial role on the quality of life in individuals, particularly in western societies where poor diet is correlated to alterations in behavior and the increased possibility of developing type-2 diabetes. While exercising is known to produce improvements to overall health, there is conflicting evidence on how much of an effect exercise has staving off the development of type-2 diabetes or counteracting the effects of diet on anxiety. Thus, this study investigated the effects of voluntary wheel-running access on the progression of diabetes-like symptoms and open field and light-dark box behaviors in C57BL/6J mice fed a high-fat diet. C57BL/6J mice were placed into either running-wheel cages or cages without a running-wheel, given either regular chow or a high-fat diet, and their body mass, food consumption, glucose tolerance, insulin and c-peptide levels were measured. Mice were also exposed to the open field and light-dark box tests for anxiety-like behaviors. Access to a running-wheel partially attenuated the obesity and hyperinsulinemia associated with high-fat diet consumption in these mice, but did not affect glucose tolerance or c-peptide levels. Wheel-running strongly increased anxiety-like and decreased explorative-like behaviors in the open field and light-dark box, while high-fat diet consumption produced smaller increases in anxiety. These results suggest that voluntary wheel-running can assuage some, but not all, of the physiological problems associated with high-fat diet consumption, and can modify anxiety-like behaviors regardless of diet consumed. PMID:27154535

  7. Insulin Protects against Hepatic Damage Postburn

    Science.gov (United States)

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

  8. Plasma insulin levels are increased by sertraline in rats under oral glucose overload

    Directory of Open Access Journals (Sweden)

    Gomez R.

    2001-01-01

    Full Text Available Recognition and control of depression symptoms are important to increase patient compliance with treatment and to improve the quality of life of diabetic patients. Clinical studies indicate that selective serotonin reuptake inhibitors (SSRI are better antidepressants for diabetic patients than other drugs. However, preclinical trials have demonstrated that not all SSRI reduce plasma glucose levels. In fact, fluoxetine increases and sertraline decreases glycemia in diabetic and non-diabetic rats. In the present study we evaluated plasma insulin levels during fasting and after glucose overload after treatment with sertraline. Adult male Wistar rats were fasted and treated with saline or 30 mg/kg sertraline and submitted or not to glucose overload (N = 10. Blood was collected and plasma insulin was measured. The mean insulin levels were: fasting group: 25.9 ± 3.86, sertraline + fasting group: 31.10 ± 2.48, overload group: 34.1 ± 3.40, and overload + sertraline group: 43.73 ± 5.14 µU/ml. Insulinemia was significantly increased in the overload + sertraline group. There were no differences between the other groups. No difference in glucose/insulin ratios could be detected between groups. The overload + sertraline group was the only one in which a significant number of individuals exceeded the upper confidence limit of insulin levels. This study demonstrates that sertraline increases glucose-stimulated insulin secretion without any change in peripheral insulin sensitivity.

  9. Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

    DEFF Research Database (Denmark)

    Schmidt, Johannes; Liebscher, Kathrin; Merten, Nicole;

    2011-01-01

    of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat...... type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis......-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type...

  10. Glucose enhances collectrin protein expression in insulin-producing MIN6 {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Saisho, Kenji; Fukuhara, Atsunori [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Yasuda, Tomoko [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Sato, Yoshifumi; Fukui, Kenji; Iwahashi, Hiromi; Imagawa, Akihisa [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Hatta, Mitsutoki [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan); Shimomura, Iichiro [Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka (Japan); Yamagata, Kazuya, E-mail: k-yamaga@kumamoto-u.ac.jp [Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto (Japan)

    2009-11-06

    Collectrin is a novel target gene of hepatocyte nuclear factor-1{alpha} in pancreatic {beta}-cells and controls insulin exocytosis. Although glucose is known to stimulate the expression of genes of the insulin secretory pathway, there is no information on how glucose regulates collectrin expression. We investigated the effects of glucose on the expression of collectrin in MIN6 {beta}-cell line. Glucose, in a dose-dependent manner, increased collectrin protein levels without changing collectrin mRNA levels and protein stability, indicating that glucose stimulation of collectrin protein expression is primarily mediated at a translational level. Although mannose and pyruvate also increased collectrin protein expression level, neither 2-deoxyglucose, mitochondrial fuels leucine and glutamate, sulphonylurea nor Ca{sup 2+} channel blockers, mimicked the effects of glucose. These data indicate the involvement of mitochondrial TCA cycle intermediates, distal to pyruvate, in the regulation of collectrin protein expression in {beta}-cells.

  11. Glutamate Acts as a Key Signal Linking Glucose Metabolism to Incretin/cAMP Action to Amplify Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Ghupurjan Gheni

    2014-10-01

    Full Text Available Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.

  12. Newer insulin analogues and inhaled insulin

    OpenAIRE

    Girish C; Manikandan S; Jayanthi M

    2006-01-01

    Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin.Insulin glulisine is a short acting analogue with a rapid...

  13. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis.

    Science.gov (United States)

    Boparai, Ravneet K; Arum, Oge; Khardori, Romesh; Bartke, Andrzej

    2010-10-01

    In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging. PMID:20707609

  14. Insulin Injection

    Science.gov (United States)

    ... not use any type of insulin after the expiration date printed on the bottle has passed.Some ... or itching over the whole body shortness of breath wheezing dizziness blurred vision fast heartbeat sweating difficulty ...

  15. [Differentiation of human amniotic mesenchymal stem cells into insulin-secreting cells induced by regenerating pancreatic extract].

    Science.gov (United States)

    Zhang, Yanmei; Wang, Dianliang; Zeng, Hongyan; Wang, Lieming; Sun, Jinwei; Zhang, Zhen; Dong, Shasha

    2012-02-01

    In this study, the natural biological inducer, rat regenerating pancreatic extract (RPE), was used to induce human amniotic mesenchymal stem cells (hAMSCs) into insulin-secreting cells. We excised 60% of rat pancreas in order to stimulate pancreatic regeneration. RPE was extracted and used to induce hAMSCs at a final concentration of 20 microg/mL. The experiment methods used were as follows: morphological-identification, dithizone staining, immumofluorescence analysis, reverse transcription-PCR (RT-PCR) and insulin secretion stimulated by high glucose. The results show that the cell morphology of passge3 hAMSCs changed significantly after the induction of RPE, resulting in cluster shape after induction for 15 days. Dithizone staining showed that there were scarlet cell masses in RPE-treated culture. Immumofluorescence analysis indicated that induced cells were insulin-positive expression. RT-PCR showed the positive expression of human islet-related genes Pdx1 and insulin in the induced cells. The result of insulin secretion stimulated by high glucose indicated that insulin increasingly secreted and then kept stable with prolongation of high glucose stimulation. In conclusion, hAMSCs had the potential to differentiate into insulin-secreting cells induced by RPE in vitro. PMID:22667123

  16. Polysaccharide isolated from Triticum aestivum stimulates insulin release from pancreatic cells via the ATP-sensitive K+ channel.

    Science.gov (United States)

    Lee, Sun-Hee; Lim, Sung-Won; Lee, Young-Mi; Lee, Hoi-Seon; Kim, Dae-Ki

    2012-05-01

    Traditional natural plants have been used throughout the world for their antidiabetic effects. The aim of the present study was to investigate the stimulating activity of a polysaccharide extract derived from T. aestivum sprout (TASP) on insulin secretion in vitro using the RIN-5F pancreatic β-cell line and rat pancreatic islets. In these experiments, TASP (0.1 to 2 mg/ml) augmented glucose-stimulated insulin secretion in a dose-dependent manner in the presence of a stimulatory glucose concentration (16.7 mM), but not of a basal concentration (1.1 mM). Although TASP failed to enhance the high K+-induced insulin secretion, the insulinotropic effect of TASP was significantly inhibited by diazoxide, an opener of ATP-sensitive K+ channel blocking insulin release. TASP potentiated the insulin secretion induced by other secretagogues, such as IBMX and tolbutamide. Moreover, glucose-derived blood insulin levels were significantly elevated by oral administration of TASP to mice, similarly to antidiabetic drugs. We also demonstrated that TASP significantly increased glucose-induced 45Ca2+ uptake and proinsulin mRNA expression in rat islets. Overall, our results suggest that TASP has a stimulating effect on insulin secretion and production in pancreatic β-cells via K+ channel closure and calcium influx. These results suggest that TASP may be useful as a candidate for the therapy of diabetes mellitus. PMID:22322245

  17. Disrupted dynamics of F-actin and insulin granule fusion in INS-1 832/13 beta-cells exposed to glucotoxicity: partial restoration by glucagon-like peptide 1.

    Science.gov (United States)

    Quinault, Aurore; Gausseres, Blandine; Bailbe, Danielle; Chebbah, Nella; Portha, Bernard; Movassat, Jamileh; Tourrel-Cuzin, Cecile

    2016-08-01

    Actin dynamics in pancreatic β-cells is involved in insulin exocytosis but the molecular mechanisms of this dynamics and its role in biphasic insulin secretion in pancreatic β-cells is largely unknown. Moreover, the impact of a glucotoxic environment on the sub-cortical actin network dynamics is poorly studied. In this study, we investigate the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 β-cells submitted to a normal or glucotoxic environment. Our results show that glucose stimulation leads to a reorganization of the subcortical actin network with a rupture of its interactions with t-SNARE proteins (Syntaxin 1A and SNAP-25), promoting insulin secretion in INS-1 832/13 β-cells. Prolonged exposure of INS-1 832/13 β-cells to high-glucose levels (glucotoxicity) leads to the densification of the cortical actin network, which prevents its reorganization under acute glucose, and diminishes the glucose-stimulated insulin secretion, as shown by the decreased number of fusion events. The most interesting in our results is the partial restoration by GLP-1 of the insulin secretion ability from high-glucose treated INS-1 832/13 cells. This improved insulin exocytosis is associated with partial restored actin dynamics and fusion events during the two phases of the secretion, with a preferential involvement of Epac2 signaling in the first phase and a rather involvement of PKA signaling in the second phase of insulin exocytosis. All these data provide some new insights into the mechanism by which current therapeutics may be improving insulin secretion. PMID:27101990

  18. Potentiation of insulin-mediated glucose lowering without elevated hypoglycemia risk by a small molecule insulin receptor modulator.

    Directory of Open Access Journals (Sweden)

    Margaret Wu

    Full Text Available Insulin resistance is the key feature of type 2 diabetes and is manifested as attenuated insulin receptor (IR signaling in response to same levels of insulin binding. Several small molecule IR activators have been identified and reported to exhibit insulin sensitization properties. One of these molecules, TLK19781 (Cmpd1, was investigated to examine its IR sensitizing action in vivo. Our data demonstrate that Cmpd1, at doses that produced minimal efficacy in the absence of insulin, potentiated insulin action during an OGTT in non-diabetic mice and enhanced insulin-mediated glucose lowering in diabetic mice. Interestingly, different from insulin alone, Cmpd1 combined with insulin showed enhanced efficacy and duration of action without increased hypoglycemia. To explore the mechanism underlying the apparent glucose dependent efficacy, tissue insulin signaling was compared in healthy and diabetic mice. Cmpd1 enhanced insulin's effects on IR phosphorylation in both healthy and diabetic mice. In contrast, the compound potentiated insulin's effects on Akt phosphorylation in diabetic but not in non-diabetic mice. These differential effects on signaling corresponding to glucose levels could be part of the mechanism for reduced hypoglycemia risk. The in vivo efficacy of Cmpd1 is specific and dependent on IR expression. Results from these studies support the idea of targeting IR for insulin sensitization, which carries low hypoglycemia risk by standalone treatment and could improve the effectiveness of insulin therapies.

  19. New method to differentiate human peripheral blood monocytes into insulin producing cells: Human hematosphere culture.

    Science.gov (United States)

    Hur, Jin; Yang, Ji Min; Choi, Jae-Il; Yun, Ji-Yeon; Jang, Jae Hee; Kim, Joonoh; Kim, Ju-Young; Oh, Il-Young; Yoon, Chang-Hwan; Cho, Hyun-Jai; Park, Young-Bae; Kim, Hyo-Soo

    2012-02-24

    Strategy to differentiate stem cells into insulin producing cells (IPCs) in vitro has been a promising one to get cell source of β-cell replacement therapy for diabetes. It has been suggested that islets and neurons share features and nestin-positive cells could differentiate into IPCs. We have recently developed a three-dimensional culture system using human peripheral blood cells named as blood-born hematosphere (BBHS). Here we showed that most of BBHS were composed of nestin-positive cells. Under the four-stage differentiation protocol for IPCs, we plated nestin-positive BBHS onto fibronectin-coated dish. These cells form islet-like clusters and most of them expressed insulin. Pancreatic specific genes were turned on, such as transcription factors (Pdx-1, Ngn3 and Nkx6.1), genes related to endocrine function (Glut-2 and PC2) or β cell function (Kir6.2, SUR1). Furthermore islet differentiation was confirmed by dithizone (DTZ) staining to detect zinc ion which binds insulin protein within the cells. Finally, IPCs derived from BBHS showed capability to secrete insulin in response to glucose stimulation. Taken together, our novel protocol successfully induced islet-like human insulin producing cells out of BBHS. This strategy of ex vivo expansion of IPCs using BBHS provides an autologous therapeutic cell source for the treatment of diabetes. PMID:22310720

  20. A role for SPARC in the moderation of human insulin secretion.

    Directory of Open Access Journals (Sweden)

    Lorna W Harries

    Full Text Available AIMS/HYPOTHESIS: We have previously shown the implication of the multifunctional protein SPARC (Secreted protein acidic and rich in cysteine/osteonectin in insulin resistance but potential effects on beta-cell function have not been assessed. We therefore aimed to characterise the effect of SPARC on beta-cell function and features of diabetes. METHODS: We measured SPARC expression by qRT-PCR in human primary pancreatic islets, adipose tissue, liver and muscle. We then examined the relation of SPARC with glucose stimulated insulin secretion (GSIS in primary human islets and the effect of SPARC overexpression on GSIS in beta cell lines. RESULTS: SPARC was expressed at measurable levels in human islets, adipose tissue, liver and skeletal muscle, and demonstrated reduced expression in primary islets from subjects with diabetes compared with controls (p< = 0.05. SPARC levels were positively correlated with GSIS in islets from control donors (p< = 0.01. Overexpression of SPARC in cultured beta-cells resulted in a 2.4-fold increase in insulin secretion in high glucose conditions (p< = 0.01. CONCLUSIONS: Our data suggest that levels of SPARC are reduced in islets from donors with diabetes and that it has a role in insulin secretion, an effect which appears independent of SPARC's modulation of obesity-induced insulin resistance in adipose tissue.

  1. A Role for SPARC in the Moderation of Human Insulin Secretion

    Science.gov (United States)

    Harries, Lorna W.; McCulloch, Laura J.; Holley, Janet E.; Rawling, Thomas J.; Welters, Hannah J.; Kos, Katarina

    2013-01-01

    Aims/Hypothesis We have previously shown the implication of the multifunctional protein SPARC (Secreted protein acidic and rich in cysteine)/osteonectin in insulin resistance but potential effects on beta-cell function have not been assessed. We therefore aimed to characterise the effect of SPARC on beta-cell function and features of diabetes. Methods We measured SPARC expression by qRT-PCR in human primary pancreatic islets, adipose tissue, liver and muscle. We then examined the relation of SPARC with glucose stimulated insulin secretion (GSIS) in primary human islets and the effect of SPARC overexpression on GSIS in beta cell lines. Results SPARC was expressed at measurable levels in human islets, adipose tissue, liver and skeletal muscle, and demonstrated reduced expression in primary islets from subjects with diabetes compared with controls (p< = 0.05). SPARC levels were positively correlated with GSIS in islets from control donors (p< = 0.01). Overexpression of SPARC in cultured beta-cells resulted in a 2.4-fold increase in insulin secretion in high glucose conditions (p< = 0.01). Conclusions Our data suggest that levels of SPARC are reduced in islets from donors with diabetes and that it has a role in insulin secretion, an effect which appears independent of SPARC’s modulation of obesity-induced insulin resistance in adipose tissue. PMID:23840838

  2. Response of Chick B Islets to Insulin Secretagogues is Comparable to those of Human Islet Equivalents

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    Bhawna Chandravanshi

    2015-05-01

    Full Text Available Context The B islets isolated from 3-5 day old chick respond well to glucose challenge in a similar fashion to those isolated from mouse pancreas. Objective To compare insulin secretory response of chick B islets with that of human Islet Equivalents (hIEqs generated from stem cells. Methods Human Umbilical Cord Mesenchymal Stem Cells (UC-MSCs were differentiated into hIEqs employing three step sequential serum free protocols. Results Immunofluorescence staining demonstrated Insulin, C peptide and Glut 2 positivity of both these islets. Static insulin stimulation of these islets in response to glucose, metformin and Gama Amino Butyric Acid (GABA resulted in increased insulin secretion as compared to basal glucose stimulation. Our results demonstrate that insulin secretory response of Chick B islets to Metformin and GABA is comparable to those of hIEqs. Moreover, both chick and hIEqs could be successfully cryopreserved and revived in a commercially available cryomix - Cryostore 5, indicating resemblance in their behaviour at sub-zero temperatures. Inference Present study advocates Chick islets as an alternative source for diabetes research and islet banking.

  3. Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity

    DEFF Research Database (Denmark)

    Skovbro, M; Baranowski, M; Skov-Jensen, C;

    2008-01-01

    AIMS/HYPOTHESIS: In skeletal muscle, ceramides may be involved in the pathogenesis of insulin resistance through an attenuation of insulin signalling. This study investigated total skeletal muscle ceramide fatty acid content in participants exhibiting a wide range of insulin sensitivities. METHODS...

  4. A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes.

    Science.gov (United States)

    Alghamdi, Farah; Guo, Merry; Abdulkhalek, Samar; Crawford, Nicola; Amith, Schammim Ray; Szewczuk, Myron R

    2014-06-01

    Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRβ and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance. PMID:24583283

  5. Glucose-raising genetic variants in MADD and ADCY5 impair conversion of proinsulin to insulin.

    Directory of Open Access Journals (Sweden)

    Robert Wagner

    Full Text Available INTRODUCTION: Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism. METHODS: In this cross-sectional study 1782 non-diabetic volunteers at increased risk for type 2 diabetes underwent an oral glucose tolerance test. Insulin, C-peptide and proinsulin were measured and genotyping was performed for 12 single nucleotide polymorphisms (SNP in or near the genes GCK (rs4607517, DGKB (rs2191349, GCKR (rs780094, ADCY5 (rs11708067, MADD (rs7944584, ADRA2A (rs10885122, FADS1 (rs174550, CRY2 (rs11605924, SLC2A2 (rs11920090, PROX1 (rs340874, GLIS3 (rs7034200 and C2CD4B (rs11071657. Parameters of insulin secretion (AUC Insulin(0-30/AUC Glucose(0-30, AUC C-peptide(0-120/AUC Glucose(0-120, proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin(0-120/AUCInsulin(0-120 and insulin resistance (HOMA-IR, Matsuda-Index were assessed. RESULTS: After adjustment for confounding variables, the effect alleles of the ADCY5 and MADD SNPs were associated with an impaired proinsulin-to-insulin conversion (p = 0.002 and p = 0.0001, respectively. GLIS3 was nominally associated with impaired proinsulin-to-insulin conversion and insulin secretion. The diabetogenic alleles of DGKB and PROX1 were nominally associated with reduced insulin secretion. Nominally significant effects on insulin sensitivity could be found for MADD and PROX1. DISCUSSION: By examining parameters of glucose-stimulated proinsulin-to-insulin conversion during an OGTT, we show that the SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion. In addition, we confirmed previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion. These

  6. Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load.

    Directory of Open Access Journals (Sweden)

    Thomas Krusenstjerna-Hafstrøm

    Full Text Available INTRODUCTION: GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load. METHODS: Eight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1 after an intravenous GH bolus 2 after an intravenous GH bolus plus an oral glucose load (OGTT, and 3 after intravenous saline plus OGTT. Muscle biopsies were taken at t = 0, 30, 60, and 120. Blood was sampled at frequent intervals for assessment of GH, insulin, glucose, and free fatty acids (FFA. RESULTS: GH increased AUC(glucose after an OGTT (p<0.05 without significant changes in serum insulin levels. GH induced phosphorylation of STAT5 independently of the OGTT. Conversely, the OGTT induced acute phosphorylation of the insulin signaling proteins Akt (ser(473 and thr(308, and AS160.The combination of OGTT and GH suppressed Akt activation, whereas the downstream expression of AS160 was amplified by GH. WE CONCLUDED THE FOLLOWING: 1 A physiological GH bolus activates STAT5 signaling pathways in skeletal muscle irrespective of ambient glucose and insulin levels 2 Insulin resistance induced by GH occurs without a distinct suppression of insulin signaling proteins 3 The accentuation of the glucose-stimulated activation of AS 160 by GH does however indicate a potential crosstalk between insulin and GH. TRIAL REGISTRATION: ClinicalTrials.gov NCT00477997.

  7. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T;

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IR...

  8. Newer insulin analogues and inhaled insulin

    Directory of Open Access Journals (Sweden)

    Girish C

    2006-03-01

    Full Text Available Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin.Insulin glulisine is a short acting analogue with a rapid onset of action. The antiapoptotic property, mediated through insulin substrate receptor-2 has a favourable protective action on beta cells. Insulin detemir is a long acting analogue, soluble at neutral pH, which reversibly binds to albumin in plasma, prolonging its action. Its lower affinity for insulin receptors necessitates higher doses compared to human insulin. The reduction in body weight is an additional advantage of detemir. A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use. Albulin is a latest addition of insulin analogue which is under various in vitro and in vivo studies. Inhaled insulin in powder form (Exubera is recently approved by FDA and appears promising.

  9. Generation of insulin-producing cells from gnotobiotic porcine skin-derived stem cells

    International Nuclear Information System (INIS)

    A major problem in the treatment of type 1 diabetes mellitus is the limited availability of alternative sources of insulin-producing cells for islet transplantation. In this study, we investigated the effect of bone morphogenetic protein 4 (BMP-4) treatments of gnotobiotic porcine skin-derived stem cells (gSDSCs) on their reprogramming and subsequent differentiation into insulin-producing cells (IPCs). We isolated SDSCs from the ear skin of a gnotobiotic pig. During the proliferation period, the cells expressed stem-cell markers Oct-4, Sox-2, and CD90; nestin expression also increased significantly. The cells could differentiate into IPCs after treatments with activin-A, glucagon-like peptide-1 (GLP-1), and nicotinamide. After 15 days in the differentiation medium, controlled gSDSCs began expressing endocrine progenitor genes and proteins (Ngn3, Neuro-D, PDX-1, NKX2.2, NKX6.1, and insulin). The IPCs showed increased insulin synthesis after glucose stimulation. The results indicate that stem cells derived from the skin of gnotobiotic pigs can differentiate into IPCs under the appropriate conditions in vitro. Our three-stage induction protocol could be applied without genetic modification to source IPCs from stem cells in the skin of patients with diabetes for autologous transplantation.

  10. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice.

    Science.gov (United States)

    González-Mariscal, Isabel; Krzysik-Walker, Susan M; Kim, Wook; Rouse, Michael; Egan, Josephine M

    2016-03-01

    The cannabinoid 1 receptor (CB1) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose-stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular cAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion. PMID:26724516

  11. Preadipocyte factor 1 induces pancreatic ductal cell differentiation into insulin-producing cells.

    Science.gov (United States)

    Rhee, Marie; Lee, Seung-Hwan; Kim, Ji-Won; Ham, Dong-Sik; Park, Heon-Seok; Yang, Hae Kyung; Shin, Ju-Young; Cho, Jae-Hyoung; Kim, Young-Bum; Youn, Byung-Soo; Sul, Hei Sook; Yoon, Kun-Ho

    2016-01-01

    The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes. PMID:27044861

  12. Generation of insulin-producing cells from gnotobiotic porcine skin-derived stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Ji Hoon; Lee, Sung Ho; Heo, Young Tae [Department of Bioscience and Biotechnology, Bio-Organ Research Center, Konkuk University, Seoul 143-701 (Korea, Republic of); Uhm, Sang Jun [Department of Animal Biotechnology, Bio-Organ Research Center, Konkuk University, Seoul 143-701 (Korea, Republic of); Lee, Hoon Taek, E-mail: htl3675@konkuk.ac.kr [Department of Animal Biotechnology, Bio-Organ Research Center, Konkuk University, Seoul 143-701 (Korea, Republic of)

    2010-07-09

    A major problem in the treatment of type 1 diabetes mellitus is the limited availability of alternative sources of insulin-producing cells for islet transplantation. In this study, we investigated the effect of bone morphogenetic protein 4 (BMP-4) treatments of gnotobiotic porcine skin-derived stem cells (gSDSCs) on their reprogramming and subsequent differentiation into insulin-producing cells (IPCs). We isolated SDSCs from the ear skin of a gnotobiotic pig. During the proliferation period, the cells expressed stem-cell markers Oct-4, Sox-2, and CD90; nestin expression also increased significantly. The cells could differentiate into IPCs after treatments with activin-A, glucagon-like peptide-1 (GLP-1), and nicotinamide. After 15 days in the differentiation medium, controlled gSDSCs began expressing endocrine progenitor genes and proteins (Ngn3, Neuro-D, PDX-1, NKX2.2, NKX6.1, and insulin). The IPCs showed increased insulin synthesis after glucose stimulation. The results indicate that stem cells derived from the skin of gnotobiotic pigs can differentiate into IPCs under the appropriate conditions in vitro. Our three-stage induction protocol could be applied without genetic modification to source IPCs from stem cells in the skin of patients with diabetes for autologous transplantation.

  13. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... Disease Organizations (PDF, 293 KB). Alternate Language URL Insulin Resistance and Prediabetes Page Content On this page: ... Nutrition Points to Remember Clinical Trials What is insulin? Insulin is a hormone made in the pancreas, ...

  14. Insulin Human Inhalation

    Science.gov (United States)

    ... is a short-acting, man-made version of human insulin. Insulin inhalation works by replacing the insulin ... and selegiline (Eldepryl, Emsam, Zelapar); niacin; oral contraceptives (birth control pills); oral medications for diabetes such as pioglitazone ( ...

  15. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

    Directory of Open Access Journals (Sweden)

    Morgan Kristen

    2011-01-01

    Full Text Available Abstract Background We and others have demonstrated previously that ghrelin receptor (GhrR knock out (KO mice fed a high fat diet (HFD have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG and hyperinsulinemic-euglycemic (HI-E clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Results Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd, and decreased hepatic glucose production (HGP. HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. Conclusions These results indicate that improved glucose homeostasis of GhrR KO mice is

  16. Polyphenol-rich extract of Syzygium cumini leaf dually improves peripheral insulin sensitivity and pancreatic islet function in monosodium L-glutamate-induced obese rats

    Directory of Open Access Journals (Sweden)

    Jonas Rodrigues Sanches

    2016-03-01

    Full Text Available Syzygium cumini (L. Skeels (Myrtaceae has been traditionally used to treat a number of illnesses. Ethnopharmacological studies have particularly addressed antidiabetic and metabolic-related effects of extracts prepared from its different parts, especially seed and pulp-fruit, however there is a lack of studies on phytochemical profile and biological properties of its leaf. As there is considerable interest in bioactive compounds to treat metabolic syndrome and its clustered risk factors, we sought to characterize the metabolic effects of hydroethanolic extract of S. cumini leaf (HESc on lean and monosodium L-glutamate (MSG-induced obese rats. HPLC-MS/MS characterization of the HESc polyphenolic profile, at 254 nm, identified 15 compounds pertaining to hydrolysable tannin and flavanol subclasses. At 60 days of age, both groups were randomly assigned to receive HESc (500 mg/kg or vehicle for 30 days. At the end of treatment, obese+HESc exhibited significantly lower body weight gain, body mass index, and white adipose tissue mass, compared to obese rats receiving vehicle. Obese rats treated with HESc showed a 2-fold increase in lipolytic activity in the periepididymal fat pad, as well as, brought triglyceride levels in serum, liver and skeletal muscle back to levels close those found in lean animals. Furthermore, HESc also improved hyperinsulinemia and insulin resistance in obese+HESc rats, which resulted in partial reversal of glucose intolerance, as compared to obese rats. HESc had no effect in lean rats. Assessment of ex vivo glucose-stimulated insulin secretion showed HESc potentiated pancreatic function in islets isolated from both lean and obese rats treated with HESc. In addition, HESc (10 – 1000 ug/mL increased glucose stimulated insulin secretion from both isolated rat islets and INS-1E beta cells. These data demonstrate that S. cumini leaf improved peripheral insulin sensitivity via stimulating/modulating beta cell insulin release

  17. Polyphenol-Rich Extract of Syzygium cumini Leaf Dually Improves Peripheral Insulin Sensitivity and Pancreatic Islet Function in Monosodium L-Glutamate-Induced Obese Rats.

    Science.gov (United States)

    Sanches, Jonas R; França, Lucas M; Chagas, Vinicyus T; Gaspar, Renato S; Dos Santos, Kayque A; Gonçalves, Luciana M; Sloboda, Deborah M; Holloway, Alison C; Dutra, Richard P; Carneiro, Everardo M; Cappelli, Ana Paula G; Paes, Antonio Marcus de A

    2016-01-01

    Syzygium cumini (L.) Skeels (Myrtaceae) has been traditionally used to treat a number of illnesses. Ethnopharmacological studies have particularly addressed antidiabetic and metabolic-related effects of extracts prepared from its different parts, especially seed, and pulp-fruit, however. there is a lack of studies on phytochemical profile and biological properties of its leaf. As there is considerable interest in bioactive compounds to treat metabolic syndrome and its clustered risk factors, we sought to characterize the metabolic effects of hydroethanolic extract of S. cumini leaf (HESc) on lean and monosodium L-glutamate (MSG)-induced obese rats. HPLC-MS/MS characterization of the HESc polyphenolic profile, at 254 nm, identified 15 compounds pertaining to hydrolysable tannin and flavanol subclasses. At 60 days of age, both groups were randomly assigned to receive HESc (500 mg/kg) or vehicle for 30 days. At the end of treatment, obese+HESc exhibited significantly lower body weight gain, body mass index, and white adipose tissue mass, compared to obese rats receiving vehicle. Obese rats treated with HESc showed a twofold increase in lipolytic activity in the periepididymal fat pad, as well as, brought triglyceride levels in serum, liver and skeletal muscle back to levels close those found in lean animals. Furthermore, HESc also improved hyperinsulinemia and insulin resistance in obese+HESc rats, which resulted in partial reversal of glucose intolerance, as compared to obese rats. HESc had no effect in lean rats. Assessment of ex vivo glucose-stimulated insulin secretion showed HESc potentiated pancreatic function in islets isolated from both lean and obese rats treated with HESc. In addition, HESc (10-1000 μg/mL) increased glucose stimulated insulin secretion from both isolated rat islets and INS-1E β-cells. These data demonstrate that S. cumini leaf improved peripheral insulin sensitivity via stimulating/modulating β-cell insulin release, which was associated

  18. β-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion.

    Science.gov (United States)

    Reynolds, Merrick S; Hancock, Chad R; Ray, Jason D; Kener, Kyle B; Draney, Carrie; Garland, Kevin; Hardman, Jeremy; Bikman, Benjamin T; Tessem, Jeffery S

    2016-07-01

    β-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study, we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here, we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16 mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose-stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP and ultimately inhibits glucose-stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for β-cell mitochondrial function and insulin secretion. PMID:27221116

  19. Concentrated insulins: the new basal insulins

    Directory of Open Access Journals (Sweden)

    Lamos EM

    2016-03-01

    Full Text Available Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Introduction: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered: This review highlights the published reports of the pharmacokinetic (PK and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion: Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration

  20. H2O2-Activated Mitochondrial Phospholipase iPLA2 gamma Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-Protein-Coupled Receptor GPR40, and Regulates Insulin Secretion in Pancreatic beta-Cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Jan; Dlasková, Andrea; Zelenka, Jaroslav; Jabůrek, Martin; Ježek, Petr

    2015-01-01

    Roč. 23, č. 12 (2015), s. 958-972. ISSN 1523-0864 R&D Projects: GA ČR(CZ) GPP303/11/P320; GA ČR(CZ) GA13-02033S; GA ČR(CZ) GA13-06666S; GA ČR GA15-02051S Institutional support: RVO:67985823 Keywords : mitochondrial phospholipase iPLA2 gamma * uncoupling protein UCP2 * G-protein coupled receptor - 40 * glucose -stimulated insulin secretion * pancreatic beta cells Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 7.407, year: 2014

  1. Glucose metabolism in non-diabetic and insulin-dependent diabetic subjects with end-stage renal failure.

    Science.gov (United States)

    Schmitz, O

    1991-02-01

    Chronic uremia is frequently associated with an impaired carbohydrate tolerance. During the past decade considerable progress have been made in characterizing and quantifying this biochemical abnormality in end-stage renal failure (ESRF). Primarily, this has been possible by means of the glucose clamp technique which basically makes it possible to evaluate insulin sensitivity and glucose-stimulated insulin secretion. Combined with the use of tracer dilution technique, hepatic vein catheterization technique, infusion of somatostatin, forearm or leg techniques and indirect calorimetry, insight into several other major parameters of glucose kinetics has been achieved; i.e. insulin-mediated glucose uptake (IMGU), glucose-induced glucose uptake (GIGU), hepatic glucose production (HGP) splanchnic glucose uptake and oxidative and nonoxidative glucose disposal. Of course, these extra facets make the clamp procedure less feasible to accomplish for technical reasons and demand an extensive knowledge of the limitations of these methods. One major factor behind the reduced glucose tolerance in uremia is an impaired sensitivity to insulin (insulin resistance) in peripheral tissues, mainly in skeletal muscle. In non-dialysed uremic patients the insulin dose-response curve is characterized by a decreased maximal response and by a rightward shift. In general, the insulin resistance is pronounced, but a few weeks on maintenance hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) are enough to improve insulin action significantly. Occasionally, IMGU has been found normal in patients on long-term HD. In contrast to insulin-stimulated glucose uptake, basal glucose turnover is normal in patients with ESRF. The ability of glucose to enhance its own uptake is difficult to measure in human studies, because even small amounts of insulin is able to modulate GIGU profoundly. At basal insulinemia, however, GIGU is markedly impaired in uremia. Recently, it has been suggested

  2. Inhibition of human insulin gene transcription by peroxisome proliferator-activated receptor γ and thiazolidinedione oral antidiabetic drugs

    Science.gov (United States)

    Schinner, S; Krätzner, R; Baun, D; Dickel, C; Blume, R; Oetjen, E

    2009-01-01

    Background and purpose: The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is essential for glucose homeostasis. PPARγ ligands reducing insulin levels in vivo are used as drugs to treat type 2 diabetes mellitus. Genes regulated by PPARγ have been found in several tissues including insulin-producing pancreatic islet β-cells. However, the role of PPARγ at the insulin gene was unknown. Therefore, the effect of PPARγ and PPARγ ligands like rosiglitazone on insulin gene transcription was investigated. Experimental approach: Reporter gene assays were used in the β-cell line HIT and in primary mature pancreatic islets of transgenic mice. Mapping studies and internal mutations were carried out to locate PPARγ-responsive promoter regions. Key results: Rosiglitazone caused a PPARγ-dependent inhibition of insulin gene transcription in a β-cell line. This inhibition was concentration-dependent and had an EC50 similar to that for the activation of a reporter gene under the control of multimerized PPAR binding sites. Also in normal primary pancreatic islets of transgenic mice, known to express high levels of PPARγ, rosiglitazone inhibited glucose-stimulated insulin gene transcription. Transactivation and mapping experiments suggest that, in contrast to the rat glucagon gene, the inhibition of the human insulin gene promoter by PPARγ/rosiglitazone does not depend on promoter-bound Pax6 and is attributable to the proximal insulin gene promoter region around the transcription start site from −56 to +18. Conclusions and implications: The human insulin gene represents a novel PPARγ target that may contribute to the action of thiazolidinediones in type 2 diabetes mellitus. PMID:19338578

  3. High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients

    DEFF Research Database (Denmark)

    Gjesing, Anette Marianne Prior; Hornbak, Malene; Allin, Kristine H.; Ekstrøm, Claus Thorn; Urhammer, Søren A.; Eiberg, Hans; Pedersen, Oluf; Hansen, Torben

    2014-01-01

    ∈±∈SE: 0.49∈±∈0.14) and beta cell responsiveness to glucose (h 2∈±∈SE: 0.66∈±∈0.12). Additionally, strong genetic correlations were found between measures of beta cell response after glucose and tolbutamide stimulation, with correlation coefficients ranging from 0.77 to 0.88. Furthermore, we identified......Aims/hypothesis: The aim of this study was to estimate the heritability of quantitative measures of glucose regulation obtained from a tolbutamide-modified frequently sampled IVGTT (t-FSIGT) and to correlate the heritability of the glucose-stimulated beta cell response to the tolbutamide...... after tolbutamide (DIT), insulin sensitivity (SI), glucose effectiveness (SG) and beta cell responsiveness to glucose were calculated. A polygenic variance component model was used to estimate heritability, genetic correlations and associations. Results: We found high heritabilities for acute insulin...

  4. Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats.

    Science.gov (United States)

    Miller, Desinia B; Snow, Samantha J; Henriquez, Andres; Schladweiler, Mette C; Ledbetter, Allen D; Richards, Judy E; Andrews, Debora L; Kodavanti, Urmila P

    2016-09-01

    Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25ppm or 1.00ppm ozone, 5h/day, 3 consecutive days/week (wk) for 13wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13wk or following a 1wk recovery period (13wk+1wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13wk, however, these responses were largely reversible following a 1wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. PMID:27368153

  5. NEWER STRATEGIES FOR INSULIN DELIVERY

    OpenAIRE

    Singh Nisha; Lokwani Priyanka; Kaushik Avinash Yogendraji; Sharma Ritu

    2011-01-01

    Insulin is a proteinaceous hormone produced in the islets of Langerhans in the pancreas and used as a treatment in the diabetes mellitus. Successful oral insulin delivery involves overcoming the enzymatic and physical barriers and taking steps to conserve bioactivity during formulation processing. Newer strategies for insulin delivery include insulin pen injector, Refillable insulin injection pen, Insulin Syringe, Transfersome and Implantable insulin pumps.

  6. Insulin Resistance and Hyperinsulinemia

    OpenAIRE

    Kim, Sun H.; Reaven, Gerald M

    2008-01-01

    OBJECTIVE—Recently, it has been suggested that insulin resistance and hyperinsulinemia can exist in isolation and have differential impacts on cardiovascular disease (CVD). To evaluate this suggestion, we assessed the degree of discordance between insulin sensitivity and insulin response in a healthy, nondiabetic population. RESEARCH DESIGN AND METHODS—Insulin sensitivity was quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 4...

  7. Autoantibodies against human insulin.

    OpenAIRE

    Wilkin, T J; Nicholson, S.

    1984-01-01

    Sera from 680 non-diabetic subjects with suspected autoimmune disease were screened for 13 different antibodies. Of the 582 sera found to contain these antibodies, nine bound insulin in an IgG specific enzyme linked immunosorbent assay (micro ELISA). Four of the sera bound human, porcine, and bovine insulins and five bound exclusively human insulin. "Cold" human, porcine, and bovine insulins each displaced, in a dose dependent manner, the four sera which bound all three insulins, but only hum...

  8. Decreased 11β-Hydroxysteroid Dehydrogenase 1 Level and Activity in Murine Pancreatic Islets Caused by Insulin-Like Growth Factor I Overexpression.

    Directory of Open Access Journals (Sweden)

    Subrata Chowdhury

    Full Text Available We have reported a high expression of IGF-I in pancreatic islet β-cells of transgenic mice under the metallothionein promoter. cDNA microarray analysis of the islets revealed that the expression of 82 genes was significantly altered compared to wild-type mice. Of these, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1, which is responsible for the conversion of inert cortisone (11-dehydrocorticosterone, DHC in rodents to active cortisol (corticosterone in the liver and adipose tissues, has not been identified previously as an IGF-I target in pancreatic islets. We characterized the changes in its protein level, enzyme activity and glucose-stimulated insulin secretion. In freshly isolated islets, the level of 11β-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11β-HSD1 was observed exclusively in glucagon-producing, islet α-cells but at a lower level in transgenic vs. wild-type animals. MT-IGF islets also exhibited reduced enzymatic activities. Dexamethasone (DEX and DHC inhibited glucose-stimulated insulin secretion from freshly isolated islets of wild-type mice. In the islets of MT-IGF mice, 48-h pre-incubation of DEX caused a significant decrease in insulin release, while the effect of DHC was largely blunted consistent with diminished 11β-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11β-HSD1 cDNA in MIN6 insulinoma cells, which together with DHC caused apoptosis and a significant decrease in proliferation. Both effects were abolished with the treatment of an 11β-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11β-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion.

  9. Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells.

    Science.gov (United States)

    Zuellig, Richard A; Hornemann, Thorsten; Othman, Alaa; Hehl, Adrian B; Bode, Heiko; Güntert, Tanja; Ogunshola, Omolara O; Saponara, Enrica; Grabliauskaite, Kamile; Jang, Jae-Hwi; Ungethuem, Udo; Wei, Yu; von Eckardstein, Arnold; Graf, Rolf; Sonda, Sabrina

    2014-04-01

    Irreversible failure of pancreatic β-cells is the main culprit in the pathophysiology of diabetes, a disease that is now a global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as a novel biomarker for the disease. In this study, we analyzed whether deoxysphingolipids directly compromise the functionality of insulin-producing Ins-1 cells and primary islets. Treatment with 1-deoxysphinganine induced dose-dependent cytotoxicity with senescent, necrotic, and apoptotic characteristics and compromised glucose-stimulated insulin secretion. In addition, 1-deoxysphinganine altered cytoskeleton dynamics, resulting in intracellular accumulation of filamentous actin and activation of the Rho family GTPase Rac1. Moreover, 1-deoxysphinganine selectively upregulated ceramide synthase 5 expression and was converted to 1-deoxy-dihydroceramides without altering normal ceramide levels. Inhibition of intracellular 1-deoxysphinganine trafficking and ceramide synthesis improved the viability of the cells, indicating that the intracellular metabolites of 1-deoxysphinganine contribute to its cytotoxicity. Analyses of signaling pathways identified Jun N-terminal kinase and p38 mitogen-activated protein kinase as antagonistic effectors of cellular senescence. The results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulin-producing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic β-cells. Thus, targeting deoxysphingolipid synthesis may complement the currently available therapies for diabetes. PMID:24379346

  10. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

    OpenAIRE

    RobertRoot-Bernstein

    2014-01-01

    Rationale: Insulin resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome and obesity. The mechanism by which insulin and estrogen interact is unknown. We hypothesize that estrogen binds directly to insulin and the insulin receptor producing insulin resistance. Objectives: To determine the binding constants of steroid hormones to insulin, the insulin recepto...

  11. Insulin pumps.

    Science.gov (United States)

    Pickup, J

    2011-02-01

    The last year has seen a continued uptake of insulin pump therapy in most countries. The USA is still a leader in pump use, with probably some 40% of type 1 diabetic patients on continuous subcutaneous insulin infusion (CSII), but the large variation in usage within Europe remains, with relatively high use (> 15%) in, for example, Norway, Austria, Germany and Sweden and low use (companies or funding from national health services, the availability of sufficient diabetes nurse educators and dietitians trained in pump procedures, and clear referral pathways for the pump candidate from general practitioner or general hospital to specialist pump centre. There are now several comprehensive national guidelines on CSII use (see ATTD Yearbook 2009) but more work needs to be done in unifying uptake and ensuring all those who can benefit do so. Technology developments recently include increasing use of pumps with continuous glucose monitoring (CGM) connectivity (see elsewhere in this volume) and the emergence of numerous manufacturers developing so-called 'patch pumps', often for the type 2 diabetes market. Interestingly, the evidence base for CSII in this group is not well established, and for this reason the selected papers on CSII in this section include several in this area. The use of CSII in diabetic pregnancy is a long-established practice, in spite of the lack of evidence that it is superior to multiple daily injections (MDI), and few randomised controlled trials have been done in recent years. Several papers in this field this year continue the debate about the usefulness of CSII in diabetic pregnancy and are reviewed here. It is pleasing to see more research on the psychosocial aspects of CSII during the year, both from the point of view of how psychological beliefs influence outcomes on CSII (is there a type of patient who does particularly well or poorly on CSII?) and how CSII affects psychological factors like mood, behaviour and quality of life. Quality of

  12. Long-term insulin-like growth factor-I expression in skeletal muscles attenuates the enhanced in vitro proliferation ability of the resident satellite cells in transgenic mice

    Science.gov (United States)

    Chakravarthy, M. V.; Fiorotto, M. L.; Schwartz, R. J.; Booth, F. W.

    2001-01-01

    Insulin-like growth factor-I (IGF-I) overexpression for 1-month in mouse skeletal muscle increases satellite cell proliferation potential. However, it is unknown whether this beneficial enhancement by IGF-I expression would persist over a longer-term duration in aged mice. This is an important issue to address if a prolonged course of IGF-I is to be used clinically in muscle-wasting conditions where satellite cells may become limiting. Using the IGF-I transgenic (IGF-I Tg) mouse that selectively expresses the IGF-I transgene in striated muscles, we found that 18-months of continuous IGF-I overexpression led to a loss in the enhanced in vitro proliferative capacity of satellite cells from Tg skeletal muscles. Also 18-month-old IGF-I Tg satellite cells lost the enhanced BrdU incorporation, greater pRb and Akt phosphorylations, and decreased p27(Kip1) levels initially observed in cells from 1-month-old IGF-I Tg mice. The levels of those biochemical markers reverted to similar values seen in the 18-months WT littermates. These findings, therefore, suggest that there is no further beneficial effect on enhancing satellite cell proliferation ability with persistent long-term expression of IGF-I in skeletal muscles of these transgenic mice.

  13. Intranasal insulin therapy

    DEFF Research Database (Denmark)

    Hilsted, J; Madsbad, S; Hvidberg, A;

    1995-01-01

    To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover...... randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more...... quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was...

  14. Generalised insulin oedema after intensification of treatment with insulin analogues

    OpenAIRE

    Adamo, Luigi; Thoelke, Mark

    2013-01-01

    We report a case of generalised insulin oedema after intensification of treatment with genetically modified insulin. This is the first case of generalised oedema in response to treatment with insulin analogues in a patient not insulin naive.

  15. Human insulin genome sequence map, biochemical structure of insulin for recombinant DNA insulin.

    Science.gov (United States)

    Chakraborty, Chiranjib; Mungantiwar, Ashish A

    2003-08-01

    Insulin is a essential molecule for type I diabetes that is marketed by very few companies. It is the first molecule, which was made by recombinant technology; but the commercialization process is very difficult. Knowledge about biochemical structure of insulin and human insulin genome sequence map is pivotal to large scale manufacturing of recombinant DNA Insulin. This paper reviews human insulin genome sequence map, the amino acid sequence of porcine insulin, crystal structure of porcine insulin, insulin monomer, aggregation surfaces of insulin, conformational variation in the insulin monomer, insulin X-ray structures for recombinant DNA technology in the synthesis of human insulin in Escherichia coli. PMID:12769691

  16. Effect of isologous and autologous insulin antibodies on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lou/M rats

    International Nuclear Information System (INIS)

    The in vivo bioavailability, distribution, and metabolic fate of 125I-labeled insulin complexed to isologous and autologous antibodies were studied in inbred Lou/M rats. There was an impaired bioavailability of the 125I-insulin bound to the isologous and autologous antibodies. Very little of the 125I-insulin in these immune complexes could bind to insulin receptors on hepatocytes or renal tubular cells and be degraded, because the amounts of 125I from degraded 125I-insulin in the blood or secreted into the stomach were markedly attenuated in both cases for at least 30 min after injection. There was a simultaneous accumulation of 125I-insulin immune complexes in the liver and the kidneys of Lou/M rats injected with 125I-insulin complexed with isologous antibodies or when insulin-immunized Lou/M rats were injected with 125I-insulin during the same interval. The impaired bioavailability of immune-complexed insulin and altered distribution of radioactivity due to the accumulation of immune complexes in the liver and kidney were also observed in previous experiments in which Lewis rats were injected with xenogenic guinea pig and homologous insulin antibodies. These observations are therefore submitted as evidence that the Lou/M rat is a valid model in which to study the bioavailability of insulin immune complexed to isologous, homologous, and xenogenic antibodies and the metabolic fate of the respective insulin-antibody immune complexes

  17. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    Energy Technology Data Exchange (ETDEWEB)

    Sekiya, Motohiro [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yagyu, Hiroaki [Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498 (Japan); Gotoda, Takanari [Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Nagai, Ryozo [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Shimano, Hitoshi; Yamada, Nobuhiro [Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaragi 305-8575 (Japan); and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  18. Cytoskeletal dependence of insulin granule movement dynamics in INS-1 beta-cells in response to glucose.

    Directory of Open Access Journals (Sweden)

    Aoife T Heaslip

    Full Text Available For pancreatic β-cells to secrete insulin in response to elevated blood glucose, insulin granules retained within the subplasmalemmal space must be transported to sites of secretion on the plasma membrane. Using a combination of super-resolution STORM imaging and live cell TIRF microscopy we investigate how the organization and dynamics of the actin and microtubule cytoskeletons in INS-1 β-cells contribute to this process. GFP-labeled insulin granules display 3 different modes of motion (stationary, diffusive-like, and directed. Diffusive-like motion dominates in basal, low glucose conditions. Upon glucose stimulation no gross rearrangement of the actin cytoskeleton is observed but there are increases in the 1 rate of microtubule polymerization; 2 rate of diffusive-like motion; and 3 proportion of granules undergoing microtubule-based directed motion. By pharmacologically perturbing the actin and microtubule cytoskeletons, we determine that microtubule-dependent granule transport occurs within the subplasmalemmal space and that the actin cytoskeleton limits this transport in basal conditions, when insulin secretion needs to be inhibited.

  19. Rotary antenna attenuator

    Science.gov (United States)

    Dickinson, R. M.; Hardy, J. C.

    1969-01-01

    Radio frequency attenuator, having negligible insertion loss at minimum attenuation, can be used for making precise antenna gain measurements. It is small in size compared to a rotary-vane attenuator.

  20. Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor

    International Nuclear Information System (INIS)

    Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. -- Highlights: → Mechanical stretch augments insulin-induced VSMC proliferation via IGF-1 receptor. → Src/EGFR-mediated ERK and Akt phosphorylation are augmented in stretched VSMCs. → Similar to in vitro experiment, IGF-1 receptor is increased in hypertensive rats. → Results provide possible mechanisms of vascular remodeling in hypertension with DM.

  1. Mechanical stretch augments insulin-induced vascular smooth muscle cell proliferation by insulin-like growth factor-1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Gang [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Hitomi, Hirofumi, E-mail: hitomi@kms.ac.jp [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Hosomi, Naohisa [Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa (Japan); Lei, Bai; Nakano, Daisuke [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Deguchi, Kazushi; Mori, Hirohito; Masaki, Tsutomu [Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa (Japan); Ma, Hong [Department of Anesthesiology, First Affiliated Hospital of China Medical University, Shenyang (China); Griendling, Kathy K. [Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (United States); Nishiyama, Akira [Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa (Japan)

    2011-10-15

    Insulin resistance and hypertension have been implicated in the pathogenesis of cardiovascular disease; however, little is known about the roles of insulin and mechanical force in vascular smooth muscle cell (VSMC) remodeling. We investigated the contribution of mechanical stretch to insulin-induced VSMC proliferation. Thymidine incorporation was stimulated by insulin in stretched VSMCs, but not in un-stretched VSMCs. Insulin increased 2-deoxy-glucose incorporation in both stretched and un-stretched VSMCs. Mechanical stretch augmented insulin-induced extracellular signal-regulated kinase (ERK) and Akt phosphorylation. Inhibitors of epidermal growth factor (EGF) receptor tyrosine kinase and Src attenuated insulin-induced ERK and Akt phosphorylation, as well as thymidine incorporation, whereas 2-deoxy-glucose incorporation was not affected by these inhibitors. Moreover, stretch augmented insulin-like growth factor (IGF)-1 receptor expression, although it did not alter the expression of insulin receptor and insulin receptor substrate-1. Insulin-induced ERK and Akt activation, and thymidine incorporation were inhibited by siRNA for the IGF-1 receptor. Mechanical stretch augments insulin-induced VSMC proliferation via upregulation of IGF-1 receptor, and downstream Src/EGF receptor-mediated ERK and Akt activation. Similar to in vitro experiment, IGF-1 receptor expression was also augmented in hypertensive rats. These results provide a basis for clarifying the molecular mechanisms of vascular remodeling in hypertensive patients with hyperinsulinemia. -- Highlights: {yields} Mechanical stretch augments insulin-induced VSMC proliferation via IGF-1 receptor. {yields} Src/EGFR-mediated ERK and Akt phosphorylation are augmented in stretched VSMCs. {yields} Similar to in vitro experiment, IGF-1 receptor is increased in hypertensive rats. {yields} Results provide possible mechanisms of vascular remodeling in hypertension with DM.

  2. Giving an insulin injection

    Science.gov (United States)

    ... medlineplus.gov/ency/patientinstructions/000660.htm Giving an insulin injection To use the sharing features on this ... and syringes. Filling the Syringe - One Type of Insulin Wash your hands with soap and water. Dry ...

  3. Insulin pump (image)

    Science.gov (United States)

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  4. Insulin Lispro Injection

    Science.gov (United States)

    ... not use any type of insulin after the expiration date printed on the bottle has passed.Insulin ... sweating weakness muscle cramps abnormal heartbeat shortness of breath large weight gain in a short period of ...

  5. The Insulin Pump

    OpenAIRE

    Toews, C. J.

    1985-01-01

    Subcutaneous continuous insulin infusion systems deliver insulin at a basal rate designed to keep blood glucose levels normal in the non-fed state. Additional insulin is delivered at meal time. Pumps can provide near optimal control of blood glucose concentrations in selected, highly motivated patients. The pump provides better diabetic control than once daily insulin injections, although several daily injections can provide comparable control. Optimal control with the pump causes some short-...

  6. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin;

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between and...

  7. Glycosphingolipids and insulin resistance

    NARCIS (Netherlands)

    M. Langeveld; J.F.M.G. Aerts

    2009-01-01

    Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple sphingol

  8. Exercise Protects against Diet-Induced Insulin Resistance through Downregulation of Protein Kinase Cβ in Mice

    OpenAIRE

    Xiaoquan Rao; Jixin Zhong; Xiaohua Xu; Brianna Jordan; Santosh Maurya; Zachary Braunstein; Tse-Yao Wang; Wei Huang; Sudha Aggarwal; Muthu Periasamy; Sanjay Rajagopalan; Kamal Mehta; Qinghua Sun

    2013-01-01

    Physical exercise is an important and effective therapy for diabetes. However, its underlying mechanism is not fully understood. Protein kinase Cβ (PKCβ) has been suggested to be involved in the pathogenesis of obesity and insulin resistance, but the role of PKCβ in exercise-induced improvements in insulin resistance is completely unknown. In this study, we evaluated the involvement of PKCβ in exercise-attenuated insulin resistance in high-fat diet (HFD)-fed mice. PKCβ(-/-) and wild-type mice...

  9. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  10. DC attenuation meter

    Science.gov (United States)

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  11. FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice.

    Science.gov (United States)

    Zhang, Ting; Kim, Dae Hyun; Xiao, Xiangwei; Lee, Sojin; Gong, Zhenwei; Muzumdar, Radhika; Calabuig-Navarro, Virtu; Yamauchi, Jun; Harashima, Hideyoshi; Wang, Rennian; Bottino, Rita; Alvarez-Perez, Juan Carlos; Garcia-Ocaña, Adolfo; Gittes, George; Dong, H Henry

    2016-03-01

    β-Cell compensation is an essential mechanism by which β-cells increase insulin secretion for overcoming insulin resistance to maintain euglycemia in obesity. Failure of β-cells to compensate for insulin resistance contributes to insulin insufficiency and overt diabetes. To understand the mechanism of β-cell compensation, we characterized the role of forkhead box O1 (FoxO1) in β-cell compensation in mice under physiological and pathological conditions. FoxO1 is a key transcription factor that serves as a nutrient sensor for integrating insulin signaling to cell metabolism, growth, and proliferation. We showed that FoxO1 improved β-cell compensation via 3 distinct mechanisms by increasing β-cell mass, enhancing β-cell glucose sensing, and augmenting β-cell antioxidative function. These effects accounted for increased glucose-stimulated insulin secretion and enhanced glucose tolerance in β-cell-specific FoxO1-transgenic mice. When fed a high-fat diet, β-cell-specific FoxO1-transgenic mice were protected from developing fat-induced glucose disorder. This effect was attributable to increased β-cell mass and function. Furthermore, we showed that FoxO1 activity was up-regulated in islets, correlating with the induction of physiological β-cell compensation in high-fat-induced obese C57BL/6J mice. These data characterize FoxO1 as a pivotal factor for orchestrating physiological adaptation of β-cell mass and function to overnutrition and obesity. PMID:26727107

  12. Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism

    Directory of Open Access Journals (Sweden)

    Jessica R. Gooding

    2015-10-01

    Full Text Available Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS from islet β cells, heralds the onset of type 2 diabetes (T2D. To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP and an increase in adenylosuccinate (S-AMP, suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS. Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1. S-AMP also overcomes the defect in glucose-induced exocytosis in β cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing β cell dysfunction in T2D.

  13. Characterization of the Insulin Reservoir in Rat Islets of Langerhans: Evaluation of Hormone Synthesis, Processing, Storage and Secretion.

    Science.gov (United States)

    Gishizky, Mikhail Lev

    1988-12-01

    It has been reported that acute glucose stimulation of islets results in the preferential release of newly synthesized insulin. This suggests that the large islet hormone reservoir may represent a heterogeneous pool. In these investigation we characterized the nature of the islet hormone reservoir and evaluated possible mechanisms responsible for its regulation. Our studies demonstrated that under stimulated secretory conditions normal pancreatic islets secreted newly synthesized insulin in preference to their large stored hormone content. The preferential release pattern was observed with all secretogogues tested and was not restricted to a specific subset of islets. Aided by computer model analysis, we proposed that the islet insulin reservoir represented a heterogeneous pool composed of at least two hypothetical compartments--labile and stable. Evaluation of the islet hormone reservoir under different in vivo and in vitro conditions demonstrated that in response to prolonged stimulation, the hypothetical labile compartment apparently decreased in size. This augmentation in the compartmental character was associated with (1) decreased amount of insulin secreted, (2) increased proportion of newly synthesized insulin secreted, and (3) an increased rate of prohormone conversion with no alteration in the rate of hormone synthesis. Thus parameters which defined the islet hormone reservoir represented a dynamic system that responded to the islets milieu. Preferential release of newly synthesized insulin was not an intrinsic property of insulin secreting cells. Furthermore, the mechanism responsible for the compartmentalization of the insulin reservoir did not discriminate between the two non-allelic murine insulins. Our studies indicated that differences in the amino acid structure of the two prohormones apparently resulted in proinsulin I being transported to the conversion compartment faster than proinsulin II. However, glucose regulation of the synthesis and

  14. Stress Hyperglycemia, Insulin Treatment, and Innate Immune Cells

    Directory of Open Access Journals (Sweden)

    Fangming Xiu

    2014-01-01

    Full Text Available Hyperglycemia (HG and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

  15. Suppression of insulin production and secretion by a decretin hormone.

    Science.gov (United States)

    Alfa, Ronald W; Park, Sangbin; Skelly, Kathleen-Rose; Poffenberger, Gregory; Jain, Nimit; Gu, Xueying; Kockel, Lutz; Wang, Jing; Liu, Yinghua; Powers, Alvin C; Kim, Seung K

    2015-02-01

    Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output. PMID:25651184

  16. Insulin resistance in different forms of hyperketonemia and in cows affected by puerperal metritis

    International Nuclear Information System (INIS)

    In dairy cows selected for high milk production the phenomenon of insulin resistance (IR) seems to play a pivotal role both in adaptation to the postpartum negative energy balance and in the aetiology of some periparturient metabolic disturbances. Perturbation of pancreatic insulin secretion and insulin sensitivity of peripheral tissues has been documented in the pathogenesis of abomasal displacement, cystic ovarian disease, excessive lipid accumulation in the liver and ketosis. In human population and in laboratory animal models pro-inflammatory cytokines like tumour necrosis factor-alpha (TNF-α) play an essential role in the development of IR that occurs in association with obesity, acute infections and endotoxaemia. A similar interaction between the intensive release of pro-inflammatory cytokines and IR has been recently explored also in ruminants. This trial was conducted in high-yielding dairy cows challenged with standard intravenous doses of glucose and insulin in different time intervals to parturition. The aim was to determine the grade and time-related changes of (i) glucose-stimulated insulin increase and (ii) insulin-induced glucose decline, furthermore (iii) the interrelation of these challenge tests with plasma levels of metabolites and metabolic hormones in cows showing various ketone pattern with and without puerperal metritis. 28 multiparous Holstein cows (previous 305 FCM day milk: 8331±192.8 L) were subjected to intravenous glucose tolerance test (IVGTT) on day -18, 7 and 70 around calving. Plasma βOH butyrate (BHB), non-esterified fatty acid (NEFA), glucose, insulin, insulin-like growth factor I (IGF-I) and leptin levels were measured regularly from -18 d before, till d 70 after calving. Cows were milked out twice a day. The course of postpartum uterine involution was checked regularly, and cows showing clinical signs of bacterial complications were treated with antibiotics combined with repeated administration of PGF2α. All cows showing

  17. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Tomoyuki [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Saotome, Masao, E-mail: msaotome@hama-med.ac.jp [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Funaki, Makoto [Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503 (Japan); Hayashi, Hideharu [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan)

    2014-05-01

    Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin

  18. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

    OpenAIRE

    Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu; Cao, Wenhong

    2011-01-01

    The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative s...

  19. Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues.

    OpenAIRE

    RADERMECKER, Régis; Scheen, André

    2007-01-01

    The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence but not completely suppressed the occurrence of insulin allergy manifestations. Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), and the use of insulin analogues, resulting from the alteration in the amino acid sequence of the native insulin molecule, may influence the immunogenicity and antigenic...

  20. Insulin analogs and cancer

    Directory of Open Access Journals (Sweden)

    Laura eSciacca

    2012-02-01

    Full Text Available Today, insulin analogs are used in millions of diabetic patients. Insulin analogs have been developed to achieve more physiological insulin replacement in terms of time course of the effect. Modifications in the amino acid sequence of the insulin molecule change the pharmacokinetics and pharmacodynamics of the analogs in respect to human insulin. However, these changes can also modify the molecular and biological effects of the analogs. The rapid-acting insulin analogs, lispro, aspart and glulisine, have a rapid onset and shorter duration of action. The long-acting insulin analogs glargine and detemir have a protracted duration of action and a relatively smooth serum concentration profile. Insulin and its analogs may function as growth factors and therefore have a theoretical potential to promote tumor proliferation. A major question is whether analogs have an increased mitogenic activity in respect to insulin. These ligands can promote cell proliferation through many mechanisms like the prolonged stimulation of the insulin receptor, stimulation of the IGF-1 receptor (IGF-1R, prevalent activation of the ERK rather than the AKT intracellular post-receptor pathways. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar to those of insulin. In contrast, long-acting analogs behave differently. Although not all data are homogeneous, both glargine and detemir have been found to have a decreased binding to IR but an increased binding to IGF-1R, a prevalent activation of the ERK pathway, and an increased mitogenic effect in respect to insulin. Recent retrospective epidemiological clinical studies have suggested that treatment with long-acting analogs (specifically glargine may increase the relative risk for cancer. Results are controversial and methodologically weak. Therefore prospective clinical studies are needed to evaluate the possible tumor growth-promoting effects of these insulin

  1. Rat liver insulin receptor

    International Nuclear Information System (INIS)

    Using insulin affinity chromatography, the authors have isolated highly purified insulin receptor from rat liver. When evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, the rat liver receptor contained the M/sub r/ 125,000 α-subunit, the M/sub r/ 90,000 β-subunit, and varying proportions of the M/sub r/ 45,000 β'-subunit. The specific insulin binding of the purified receptor was 25-30 μg of 125I-insulin/mg of protein, and the receptor underwent insulin-dependent autophosphorylation. Rat liver and human placental receptors differ from each other in several functional aspects: (1) the adsorption-desorption behavior from four insulin affinity columns indicated that the rat liver receptor binds less firmly to immobilized ligands; (2) the 125I-insulin binding affinity of the rat liver receptor is lower than that of the placental receptor; (3) partial reduction of the rat liver receptor with dithiothreitol increases its insulin binding affinity whereas the binding affinity of the placental receptor is unchanged; (4) at optimal insulin concentration, rat liver receptor autophosphorylation is stimulated 25-50-fold whereas the placental receptor is stimulated only 4-6-fold. Conversion of the β-subunit to β' by proteolysis is a major problem that occurs during exposure of the receptor to the pH 5.0 buffer used to elute the insulin affinity column. Proteolytic destruction and the accompanying loss of insulin-dependent autophosphorylation can be substantially reduced by proteolysis inhibitors. In summary, rat liver and human placental receptors differ functionally in both α- and β-subunits. Insulin binding to the α-subunit of the purified rat liver receptor communicates a signal that activates the β-subunit; however, major proteolytic destruction of the β-subunit does not affect insulin binding to the α-subunit

  2. Concentrated insulins: the new basal insulins

    OpenAIRE

    Lamos EM; Younk LM; Davis SN

    2016-01-01

    Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Introduction: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with in...

  3. Classifying insulin regimens

    DEFF Research Database (Denmark)

    Neu, A; Lange, K; Barrett, T;

    2015-01-01

    Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...... diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin...... variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the...

  4. Flexibility in insulin prescription

    Science.gov (United States)

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  5. Flexibility in insulin prescription.

    Science.gov (United States)

    Kalra, Sanjay; Gupta, Yashdeep; Unnikrishnan, Ambika Gopalakrishnan

    2016-01-01

    This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage. PMID:27186563

  6. Flexibility in insulin prescription

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2016-01-01

    Full Text Available This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage.

  7. Etiopathogenesis of insulin autoimmunity.

    OpenAIRE

    Åke Lenmark; Moustakas, Antonis K; Papadopoulos, George K; Norio Kanatsuna

    2012-01-01

    Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (pro)insulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and ...

  8. Insulin sensitivity and albuminuria

    DEFF Research Database (Denmark)

    Pilz, Stefan; Rutters, Femke; Nijpels, Giel;

    2014-01-01

    assessed by hyperinsulinemic-euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS...... albuminuria. This finding suggests that reduced insulin sensitivity either is simply related to or might causally contribute to the initial pathogenesis of albuminuria....

  9. AMPK and insulin action

    DEFF Research Database (Denmark)

    Frøsig, Christian; Jensen, Thomas Elbenhardt; Jeppesen, Jacob;

    2013-01-01

    and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action...

  10. Human ultralente insulin.

    OpenAIRE

    Holman, R R; Steemson, J; Darling, P; Reeves, W G; Turner, R.C.

    1984-01-01

    The greater solubility of human insulin and its possible faster action have led to doubts about whether a sufficiently long acting formulation could be produced to provide a basal supply for diabetics. In a double blind crossover study in 18 diabetics human ultralente insulin was as effective as beef ultralente insulin in controlling basal plasma glucose concentrations (median 5.7 mmol/l (103 mg/100 ml) with human and 6.3 mmol/l (114 mg/100 ml) with beef ultralente insulin respectively). Ther...

  11. Binding of insulin to rat pancreatic islets: comparison between pancreatic human insulin and biosynthetic human insulin

    Energy Technology Data Exchange (ETDEWEB)

    Verspohl, E.J.; Ammon, H.P.

    Human pancreatic insulin, biosynthetic human insulin (BHI), and pork insulin were compared in terms of their binding characteristics to insulin receptors on rat pancreatic islets. There was no difference in binding or on biologic effect, i.e., ability to inhibit insulin secretion.

  12. Hibiscus sabdariffa polyphenols alleviate insulin resistance and renal epithelial to mesenchymal transition: a novel action mechanism mediated by type 4 dipeptidyl peptidase.

    Science.gov (United States)

    Peng, Chiung-Huei; Yang, Yi-Sun; Chan, Kuei-Chuan; Wang, Chau-Jong; Chen, Mu-Lin; Huang, Chien-Ning

    2014-10-01

    The epithelial to mesenchymal transition (EMT) is important in renal fibrosis. Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1 (S307)) is a hallmark of insulin resistance. We report that polyphenol extracts of Hibiscus sabdariffa (HPE) ameliorate diabetic nephropathy and EMT. Recently it has been observed that type 4 dipeptidyl peptidase (DPP-4) inhibitor linagliptin is effective for treating type 2 diabetes and albuminuria. We investigated if DPP-4 and insulin resistance are involved in renal EMT and explored the role of HPE. In high glucose-stimulated tubular cells, HPE, like linagliptin, inhibited DPP-4 activation, thereby regulating vimentin (EMT marker) and IRS-1 (S307). IRS-1 knockdown revealed its essential role in mediating downstream EMT. In type 2 diabetic rats, pIRS-1 (S307) abundantly surrounds the tubular region, with increased vimentin in kidney. Both the expressions were reduced by HPE. In conclusion, HPE exerts effects similar to those of linagliptin, which improves insulin resistance and EMT, and could be an adjuvant to prevent diabetic nephropathy. PMID:25226384

  13. Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life

    DEFF Research Database (Denmark)

    Barbosa, Francisco B; Capito, Kirsten; Kofod, Hans; Thams, Peter

    2002-01-01

    , whereas the pancreatic insulin content was reduced by 30 % in the rats fed 8.7 % protein. In order to elucidate the mechanism responsible for the attenuation of insulin secretion, measurements were performed of the activity of several islet enzymes that had previously been supposed to be involved in the......Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.7% protein group was reduced 50%. The islet insulin and DNA content were similar...

  14. Anti-insulin antibody test

    Science.gov (United States)

    Insulin antibodies - serum; Insulin Ab test ... Normally, there are no antibodies against insulin in your blood. Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or ...

  15. Alternative Devices for Taking Insulin

    Science.gov (United States)

    ... KB). Alternate Language URL Alternative Devices for Taking Insulin Page Content On this page: What alternative devices ... the skin. [ Top ] What alternative devices for taking insulin are available? Insulin pens provide a convenient, easy- ...

  16. Pressure surge attenuator

    Science.gov (United States)

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  17. Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca(2+ Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity.

    Directory of Open Access Journals (Sweden)

    Yusaku Iwasaki

    Full Text Available Some of insulin's functions, including glucose/lipid metabolism, satiety and neuroprotection, involve the alteration of brain activities. Insulin could signal to the brain via penetrating through the blood-brain barrier and acting on the vagal afferents, while the latter remains unproved. This study aimed to clarify whether insulin directly regulates the nodose ganglion neurons (NGNs of vagal afferents in mice. NGs expressed insulin receptor (IR and insulin receptor substrate-2 (IRS2 mRNA, and some of NGNs were immunoreactive to IR. In patch-clamp and fura-2 microfluorometric studies, insulin (10(-12∼10(-6 M depolarized and increased cytosolic Ca(2+ concentration ([Ca(2+]i in single NGNs. The insulin-induced [Ca(2+]i increases were attenuated by L- and N-type Ca(2+ channel blockers, by phosphatidylinositol 3 kinase (PI3K inhibitor, and in NGNs from IRS2 knockout mice. Half of the insulin-responsive NGNs contained cocaine- and amphetamine-regulated transcript. Neuronal fibers expressing IRs were distributed in/around pancreatic islets. The NGNs innervating the pancreas, identified by injecting retrograde tracer into the pancreas, responded to insulin with much greater incidence than unlabeled NGNs. Insulin concentrations measured in pancreatic vein was 64-fold higher than that in circulation. Elevation of insulin to 10(-7 M recruited a remarkably greater population of NGNs to [Ca(2+]i increases. Systemic injection of glibenclamide rapidly released insulin and phosphorylated AKT in NGs. Furthermore, in IRS2 knockout mice, insulin action to suppress [Ca(2+]i in orexigenic ghrelin-responsive neurons in hypothalamic arcuate nucleus was intact while insulin action on NGN was markedly attenuated, suggesting a possible link between impaired insulin sensing by NGNs and hyperphagic obese phenotype in IRS2 knockout mice These data demonstrate that insulin directly activates NGNs via IR-IRS2-PI3K-AKT-cascade and depolarization-gated Ca(2+ influx. Pancreas

  18. Photonic Crystal Fiber Attenuator

    Institute of Scientific and Technical Information of China (English)

    Joo Beom Eom; Hokyung Kim; Jinchae Kim; Un-Chul Paek; Byeong Ha Lee

    2003-01-01

    We propose a novel fiber attenuator based on photonic crystal fibers. The difference in the modal field diameters of a conventional single mode fiber and a photonic crystal fiber was used. A variable optical attenuator was also achieved by applying macro-bending on the PCF part of the proposed attenuator

  19. Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis.

    Science.gov (United States)

    Cline, Gary W; Pongratz, Rebecca L; Zhao, Xiaojian; Papas, Klearchos K

    2011-11-11

    Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with (31)P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by (13)C NMR isotopomer analysis of the fate of [U-(13)C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM was found to be congruous with the correlation in KRB. Together, these results suggest that signaling mechanisms associated with both TCA cycle flux and with anaplerotic flux, but not ATP production, may be responsible for the enhanced rates of insulin secretion in more complex, and physiologically-relevant media. PMID:22008547

  20. Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion

    Directory of Open Access Journals (Sweden)

    Häring Hans-Ulrich

    2010-06-01

    Full Text Available Abstract Background Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance. Methods We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. Results The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07. Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: padditive model ≤ 0.009, effect sizes 8/8%, rs6232: pdominant model ≤ 0.01, effect sizes 10/21%. Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08. The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom ≤ 0.0047, 4.5% lower HOMAIR (pdom = 0.02 and 3.5% lower 120-min glucose (pdom = 0.0003 independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. Conclusions Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.

  1. Relationship of Insulin Sensitivity, Insulin Secretion, and Adiposity With Insulin Clearance in a Multiethnic Population

    OpenAIRE

    Lorenzo, Carlos; Hanley, Anthony J.G.; Wagenknecht, Lynne E; Rewers, Marian J.; Stefanovski, Darko; Goodarzi, Mark O.; Haffner, Steven M

    2012-01-01

    OBJECTIVE We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance. RESEARCH DESIGN AND METHODS We measured insulin sensitivity index (S I), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study. RESULTS MCRI was positive...

  2. Insulin Resistance of Puberty.

    Science.gov (United States)

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  3. Diabetes, insulin and exercise

    DEFF Research Database (Denmark)

    Richter, Erik; Galbo, H

    1986-01-01

    The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained...... by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so...... not be recommended as a means of improving metabolic control in insulin-dependent diabetes. However, our present knowledge and technology allows the well-informed and cooperative patient to exercise and even to reach the elite level. To achieve this, pre-exercise metabolic control should be optimal and knowledge...

  4. Insulin and the Lung

    DEFF Research Database (Denmark)

    Singh, Suchita; Prakash, Y S; Linneberg, Allan;

    2013-01-01

    , molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung......Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

  5. Is it dietary insulin?

    Science.gov (United States)

    Vaarala, Outi

    2006-10-01

    In humans the primary trigger of insulin-specific immunity is a modified self-antigen, that is, dietary bovine insulin, which breaks neonatal tolerance to self-insulin. The immune response induced by bovine insulin spreads to react with human insulin. This primary immune response induced in the gut immune system is regulated by the mechanisms of oral tolerance. Genetic factors and environmental factors, such as the gut microflora, breast milk-derived factors, and enteral infections, control the development of oral tolerance. The age of host modifies the immune response to oral antigens because the permeability of the gut decreases with age and mucosal immune response, such as IgA response, develops with age. The factors that control the function of the gut immune system may either be protective from autoimmunity by supporting tolerance, or they may induce autoimmunity by abating tolerance to dietary insulin. There is accumulating evidence that the intestinal immune system is aberrant in children with type 1 diabetes (T1D). Intestinal immune activation and increased gut permeability are associated with T1D. These aberrancies may be responsible for the impaired control of tolerance to dietary insulin. Later in life, factors that activate insulin-specific immune cells derived from the gut may switch the response toward cytotoxic immunity. Viruses, which infect beta cells, may release autoantigens and potentiate their presentation by an infection-associated "danger signal." This kind of secondary immunization may cause functional changes in the dietary insulin primed immune cells, and lead to the infiltration of insulin-reactive T cells to the pancreatic islets. PMID:17130578

  6. Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites

    International Nuclear Information System (INIS)

    Insulin degradation is an integral part of the cellular action of insulin. Recent evidence suggests that the enzyme insulin protease is involved in the degradation of insulin in mammalian tissues. Drosophila, which has insulin-like hormones and insulin receptor homologues, also expresses an insulin degrading enzyme with properties that are very similar to those of mammalian insulin protease. In the present study, the insulin cleavage products generated by the Drosophila insulin degrading enzyme were identified and compared with the products generated by the mammalian insulin protease. Both purified enzymes were incubated with porcine insulin specifically labeled with 125I on either the A19 or B26 position, and the degradation products were analyzed by HPLC before and after sulfitolysis. Isolation and sequencing of the cleavage products indicated that both enzymes cleave the A chain of intact insulin at identical sites between residues A13 and A14 and A14 and A15. These results demonstrate that all the insulin cleavage sites generated by the Drosopohila insulin degrading enzyme are shared in common with the mammalian insulin protease. These data support the hypothesis that there is evolutionary conservation of the insulin degrading enzyme and further suggest that this enzyme plays an important role in cellular function

  7. Insulin Resistance and Hypertension

    Institute of Scientific and Technical Information of China (English)

    张建华; 张春秀

    2002-01-01

    Summary: The insulin sensitivity in hypertensive patients with normal glucose tolerance (NGT),impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM) and the insulin resistance(IR) under the disorder of glucose metabolism and hypertension were studied. By glucose toler-ance test and insulin release test, insulin sensitivity index (ISI) and the ratio of area under glucosetolerance curve (AUCG) to area under insulin release curve (AUC1) were calculated and analyzed.The results showed that ISI was decreased to varying degrees in the patients with hypertension,the mildest in the group of NGT with hypertension, followed by the group of IGT without hyper-tension, the group of IGT with hypertension and DM (P=0). There was very significant differ-ence in the ratio of AUCG/AUC1 between the hypertensive patients with NGT and controls (P=0). It was concluded that a significant IR existed during the development of IGT both in hyperten-sion and nonhypertension. The increase of total insulin secretion (AUC1) was associated with non-hypertension simultaneously. IR of the hypertensive patients even existed in NGT and was wors-ened with the deterioration of glucose metabolism disorder, but the AUC1 in the HT groupchanged slightly. A relative deficiency of insulin secretion or dysfunction of β-cell of islet existed inIGT and DM of the hypertensive patients.

  8. A superactive insulin: [B10-aspartic acid]insulin(human).

    OpenAIRE

    Schwartz, G P; Burke, G. T.; Katsoyannis, P G

    1987-01-01

    The genetic basis for a case of familial hyperproinsulinemia has been elucidated recently. It involves a single point mutation in the proinsulin gene resulting in the substitution of aspartic acid for histidine-10 of the B chain of insulin. We have synthesized a human insulin analogue, [AspB10]insulin, corresponding to the mutant proinsulin and evaluated its biological activity. [AspB10]Insulin displayed a binding affinity to insulin receptors in rat liver plasma membranes that was 534 +/- 14...

  9. CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice.

    Science.gov (United States)

    Liu, Jun; Zhou, Ben; Yan, Menghong; Huang, Rui; Wang, Yuangao; He, Zhishui; Yang, Yonggang; Dai, Changgui; Wang, Yiqian; Zhang, Fang; Zhai, Qiwei

    2016-06-01

    Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of Clock(Δ19/Δ19) mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment. PMID:27035655

  10. Insulin glulisine: insulin receptor signaling characteristics in vivo.

    Science.gov (United States)

    Hennige, Anita M; Lehmann, Rainer; Weigert, Cora; Moeschel, Klaus; Schäuble, Myriam; Metzinger, Elisabeth; Lammers, Reiner; Häring, Hans-Ulrich

    2005-02-01

    In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. However, safety issues have been raised with these alternatives, as the alteration of the three-dimensional structure may alter the interaction with the insulin and/or IGF-I receptors and therefore lead to the activation of alternate metabolic as well as mitogenic signaling pathways. It is therefore essential to carefully study acute and long-term effects in a preclinical state, as insulin therapy is meant to be a lifelong treatment. In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. C57BL/6 mice were injected with insulin glulisine or regular insulin and Western blot analysis was performed for liver and muscle tissue. The extent and time course of insulin receptor phosphorylation and activation of downstream signaling elements after insulin glulisine treatment was similar to that of human regular insulin in vivo. Moreover, insulin signaling in hypothalamic tissue determined by PI 3-kinase activity was comparable. Therefore, insulin glulisine may be a useful tool for diabetes treatment. PMID:15677493

  11. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Samir Bhattacharya; Debleena Dey; Sib Sankar Roy

    2007-03-01

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, leading to a reduced amount of IR protein in insulin target cells. PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies. We provide an overview of this important area, emphasizing the current status.

  12. Insulin inhalation: NN 1998.

    Science.gov (United States)

    2004-01-01

    Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal

  13. Quercetin Stimulates Insulin Secretion and Reduces the Viability of Rat INS-1 Beta-Cells

    Directory of Open Access Journals (Sweden)

    Michael Kittl

    2016-06-01

    Full Text Available Background/Aims: Previously we described insulinotropic effects of Leonurus sibiricus L. plant extracts used for diabetes mellitus treatment in Traditional Mongolian Medicine. The flavonoid quercetin and its glycoside rutin, which exert anti-diabetic properties in vivo by interfering with insulin signaling in peripheral target tissues, are constituents of these extracts. This study was performed to better understand short- and long-term effects of quercetin and rutin on beta-cells. Methods: Cell viability, apoptosis, phospho-protein abundance and insulin release were determined using resazurin, annexin-V binding assays, Western blot and ELISA, respectively. Membrane potentials (Vmem, whole-cell Ca2+ (ICa- and ATP-sensitive K+ (IKATP currents were measured by patch clamp. Intracellular Ca2+ (Cai levels were measured by time-lapse imaging using the ratiometric Ca2+ indicator Fura-2. Results: Rutin, quercetin and the phosphoinositide-3-kinase (PI3K inhibitor LY294002 caused a dose-dependent reduction in cell viability with IC50 values of ∼75 µM, ∼25 µM and ∼3.5 µM, respectively. Quercetin (50 µM significantly increased the percentage of Annexin-V+ cells within 48 hrs. The mean cell volume (MCV of quercetin-treated cells was significantly lower. Within 2 hrs, quercetin significantly decreased basal- and insulin-stimulated Akt(T308 phosphorylation and increased Erk1/2 phosphorylation, without affecting P-Akt(S473 abundance. Basal- and glucose-stimulated insulin release were significantly stimulated by quercetin. Quercetin significantly depolarized Vmem by ∼25 mV which was prevented by the KATP-channel opener diazoxide, but not by the L-type ICa inhibitor nifedipine. Quercetin significantly stimulated ICa and caused a 50% inhibition of IKATP. The effects on Vmem, ICa and IKATP rapidly reached peak values and then gradually diminished to control values within ∼1 minute. With a similar time-response quercetin induced an elevation in Cai

  14. Variable laser attenuator

    Science.gov (United States)

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  15. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Zinman, Bernard; Philis-Tsimikas, Athena; Cariou, Bertrand;

    2012-01-01

    To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).......To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs)....

  16. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats.

    Science.gov (United States)

    Harriman, Geraldine; Greenwood, Jeremy; Bhat, Sathesh; Huang, Xinyi; Wang, Ruiying; Paul, Debamita; Tong, Liang; Saha, Asish K; Westlin, William F; Kapeller, Rosana; Harwood, H James

    2016-03-29

    Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease. PMID:26976583

  17. Peptide hormones in saliva. I. Insulin in saliva during the oral glucose tolerance test in female patients.

    Science.gov (United States)

    Simionescu, L; Aman, E; Muşeţeanu, P; Dinulescu, E; Giurcăneanu, M

    1985-01-01

    The radioimmunoassay (RIA) of insulin was performed in the serum and saliva of 27 female patients during the oral glucose tolerance test (OGTT). The patients were divided into two groups: 19 non-diabetic patients and 8 patients diagnosed as impaired glucose tolerance (IGT) disease. In one patient in each group, the OGTT was performed twice at intervals of 3-5 days. The results show that immunoreactive insulin (IRI) is present in saliva and its concentration increases during the glucose stimulation test from 6.48 +/- 1.13 microU/ml (means +/- SEM) in basal conditions at peak values of 45.46 +/- 10.14 microU/ml at 2 hrs after glucose intake. In patients with IGT salivary IRI increases from 5.18 +/- 1.39 microU/ml in basal conditions to peak values of 83.34 +/- 25.85 microU/ml at 3 hrs after glucose administration. Great response variations were observed either inter-individual or intraindividual in both groups of patients. Some patients had unusual high salivary IRI concentration especially in those with gastrointestinal troubles. Further, some hypotheses and experimental models, are advanced, considered useful for the explanation of the physiologic significance of the salivary IRI or of the IRI-like material. PMID:3901231

  18. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... use it for energy. Insulin's Role in Blood Glucose Control When blood glucose levels rise after a meal, ... also helps a person lose weight control blood glucose levels control blood pressure control cholesterol levels People in the ...

  19. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... Research Training & Career Development Grant programs for students, postdocs, and faculty Research at NIDDK Labs, faculty, and ... it for energy. Insulin's Role in Blood Glucose Control When blood glucose levels rise after a meal, ...

  20. Insulin allergy treated with human insulin (recombinant DNA).

    Science.gov (United States)

    De Leeuw, I; Delvigne, C; Bekaert, J

    1982-01-01

    Two insulin-dependent diabetic subjects treated with pork and beef insulin during a period of 6 mo developed severe local reactions. Both patients had an important allergic history (asthma, urticaria, drug reactions, rhinitis). Skin-testing revealed type I allergy to beef and pork insulin. Specific IgE-insulin binding was demonstrated with both insulins. After negative skin testing with NPH Lilly human insulin (recombinant DNA), treatment was started with this compound and remained successful during a period of 6-9 mo. In one patient a local reaction occurred when regular human insulin (recombinant DNA) was added to NPH in order to obtain better control. Skin testing with regular human insulin was positive, but not with NPH human insulin alone. The mechanism of this phenomenon remains unsolved. PMID:6765530

  1. Association of expression levels of pluripotency/stem cell markers with the differentiation outcome of Wharton's jelly mesenchymal stem cells into insulin producing cells.

    Science.gov (United States)

    Kassem, Dina H; Kamal, Mohamed M; El-Kholy, Abd El-Latif G; El-Mesallamy, Hala O

    2016-08-01

    Recently, there has been much attention towards generation of insulin producing cells (IPCs) from stem cells, especially from Wharton's jelly mesenchymal stem cells (WJ-MSCs). However, generation of mature IPCs remains a challenge. Assessment of generation of IPCs was usually done by examining β-cell markers, however, assessment of pluripotency/stem cell markers drew less attention. Therefore, the purpose of this study was to investigate the levels of pluripotency/stem cell markers during differentiation of WJ-MSCs into IPCs and the association of these levels with differentiation outcomes. WJ-MSCs were isolated, characterized then induced to differentiate into IPCs using three different protocols namely A, B and C. Differentiated IPCs were assessed by the expression of pluripotency/stem cell markers, together with β-cell markers using qRT-PCR, and functionally by measuring glucose stimulated insulin secretion. Differentiated cells from protocol A showed lowest expression of pluripotency/stem cell markers and relatively best GSIS. However, protocol B showed concomitant expression of pluripotency/stem cell and β-cell markers with relatively less insulin secretion as compared to protocol A. Protocol C failed to generate glucose-responsive IPCs. In conclusion, sustained expression of pluripotency/stem cell markers could be associated with the incomplete differentiation of WJ-MSCs into IPCs. A novel finding for which further investigations are warranted. PMID:27265786

  2. Etiopathogenesis of Insulin Autoimmunity

    Directory of Open Access Journals (Sweden)

    Norio Kanatsuna

    2012-01-01

    Full Text Available Autoimmunity against pancreatic islet beta cells is strongly associated with proinsulin, insulin, or both. The insulin autoreactivity is particularly pronounced in children with young age at onset of type 1 diabetes. Possible mechanisms for (proinsulin autoimmunity may involve beta-cell destruction resulting in proinsulin peptide presentation on HLA-DR-DQ Class II molecules in pancreatic draining lymphnodes. Recent data on proinsulin peptide binding to type 1 diabetes-associated HLA-DQ2 and -DQ8 is reviewed and illustrated by molecular modeling. The importance of the cellular immune reaction involving cytotoxic CD8-positive T cells to kill beta cells through Class I MHC is discussed along with speculations of the possible role of B lymphocytes in presenting the proinsulin autoantigen over and over again through insulin-carrying insulin autoantibodies. In contrast to autoantibodies against other islet autoantigens such as GAD65, IA-2, and ZnT8 transporters, it has not been possible yet to standardize the insulin autoantibody test. As islet autoantibodies predict type 1 diabetes, it is imperative to clarify the mechanisms of insulin autoimmunity.

  3. Conformational Dynamics of Insulin

    Directory of Open Access Journals (Sweden)

    Qing-xin eHua

    2011-10-01

    Full Text Available We have exploited a prandial insulin analogue (insulin lispro, the active component of Humalog®; Eli Lilly and Co. to elucidate the underlying structure and dynamics of insulin as a monomer in solution. Whereas NMR-based modeling recapitulates structural relationships of insulin crystals (T-state protomers, dynamic anomalies are revealed by amide-proton exchange kinetics in D2O. Surprisingly, the majority of hydrogen bonds observed in crystal structures are only transiently maintained in solution, including key T-state-specific inter-chain contacts. Long-lived hydrogen bonds (as defined by global exchange kinetics exist only at a subset of four -helical sites (two per chain flanking an internal disulfide bridge (cystine A20-B19; these sites map within the proposed folding nucleus of proinsulin. The anomalous flexibility of insulin otherwise spans its active surface and may facilitate receptor binding. Because conformational fluctuations promote the degradation of pharmaceutical formulations, we envisage that dynamic re-engineering of insulin may enable design of ultra-stable formulations for humanitarian use in the developing world.

  4. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

    OpenAIRE

    Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

    2015-01-01

    Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, i...

  5. Molecular biocoding of insulin

    Directory of Open Access Journals (Sweden)

    Lutvo Kuric

    2010-07-01

    Full Text Available Lutvo KuricNovi Travnik, Kalinska, Bosnia and Herzegovina Abstract: This paper discusses cyberinformation studies of the amino acid composition of insulin, in particular the identification of scientific terminology that could describe this phenomenon, ie, the study of genetic information, as well as the relationship between the genetic language of proteins and theoretical aspects of this system and cybernetics. The results of this research show that there is a matrix code for insulin. It also shows that the coding system within the amino acid language gives detailed information, not only on the amino acid “record”, but also on its structure, configuration, and various shapes. The issue of the existence of an insulin code and coding of the individual structural elements of this protein are discussed. Answers to the following questions are sought. Does the matrix mechanism for biosynthesis of this protein function within the law of the general theory of information systems, and what is the significance of this for understanding the genetic language of insulin? What is the essence of existence and functioning of this language? Is the genetic information characterized only by biochemical principles or it is also characterized by cyberinformation principles? The potential effects of physical and chemical, as well as cybernetic and information principles, on the biochemical basis of insulin are also investigated. This paper discusses new methods for developing genetic technologies, in particular more advanced digital technology based on programming, cybernetics, and informational laws and systems, and how this new technology could be useful in medicine, bioinformatics, genetics, biochemistry, and other natural sciences.Keywords: human insulin, insulin model, biocode, genetic code, amino acids

  6. Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb’s cycle flux independent of ATP synthesis

    International Nuclear Information System (INIS)

    Highlights: ► We studied media effects on mechanisms of insulin secretion of INS-1 cells. ► Insulin secretion was higher in DMEM than KRB despite identical ATP synthesis rates. ► Insulin secretion rates correlated with rates of anaplerosis and TCA cycle. ► Mitochondria metabolism and substrate cycles augment secretion signal of ATP. -- Abstract: Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with 31P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by 13C NMR isotopomer analysis of the fate of [U-13C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15 mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM was

  7. Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Cline, Gary W., E-mail: gary.cline@yale.edu [The Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 (United States); Department of Surgery, University of Minnesota-Twin Cities, Minneapolis, MN 55455 (United States); Pongratz, Rebecca L.; Zhao, Xiaojian [The Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 (United States); Papas, Klearchos K. [Department of Surgery, University of Minnesota-Twin Cities, Minneapolis, MN 55455 (United States)

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer We studied media effects on mechanisms of insulin secretion of INS-1 cells. Black-Right-Pointing-Pointer Insulin secretion was higher in DMEM than KRB despite identical ATP synthesis rates. Black-Right-Pointing-Pointer Insulin secretion rates correlated with rates of anaplerosis and TCA cycle. Black-Right-Pointing-Pointer Mitochondria metabolism and substrate cycles augment secretion signal of ATP. -- Abstract: Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with {sup 31}P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by {sup 13}C NMR isotopomer analysis of the fate of [U-{sup 13}C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15 mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found

  8. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

    International Nuclear Information System (INIS)

    Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [3H]glucose and 2-deoxy[14C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats

  9. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

    Energy Technology Data Exchange (ETDEWEB)

    Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao [Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Boston, MA 02114 (United States); Martyn, J.A. Jeevendra, E-mail: jmartyn@partners.org [Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Boston, MA 02114 (United States)

    2013-02-01

    Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [{sup 3}H]glucose and 2-deoxy[{sup 14}C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats.

  10. Landing gear noise attenuation

    Science.gov (United States)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  11. RADIO FREQUENCY ATTENUATOR

    Science.gov (United States)

    Giordano, S.

    1963-11-12

    A high peak power level r-f attenuator that is readily and easily insertable along a coaxial cable having an inner conductor and an outer annular conductor without breaking the ends thereof is presented. Spaced first and second flares in the outer conductor face each other with a slidable cylindrical outer conductor portion therebetween. Dielectric means, such as water, contact the cable between the flares to attenuate the radio-frequency energy received thereby. The cylindrical outer conductor portion is slidable to adjust the voltage standing wave ratio to a low level, and one of the flares is slidable to adjust the attenuation level. An integral dielectric container is also provided. (AFC)

  12. Generation of insulin-producing cells from the mouse liver using β cell-related gene transfer including Mafa and Mafb.

    Directory of Open Access Journals (Sweden)

    Haruka Nagasaki

    Full Text Available Recent studies on the large Maf transcription factors have shown that Mafb and Mafa have respective and distinctive roles in β-cell development and maturation. However, whether this difference in roles is due to the timing of the gene expression (roughly, expression of Mafb before birth and of Mafa after birth or to the specific function of each gene is unclear. Our aim was to examine the functional differences between these genes that are closely related to β cells by using an in vivo model of β-like cell generation. We monitored insulin gene transcription by measuring bioluminescence emitted from the liver of insulin promoter-luciferase transgenic (MIP-Luc-VU mice. Adenoviral gene transfers of Pdx1/Neurod/Mafa (PDA and Pdx1/Neurod/Mafb (PDB combinations generated intense luminescence from the liver that lasted for more than 1 week and peaked at 3 days after transduction. The peak signal intensities of PDA and PDB were comparable. However, PDA but not PDB transfer resulted in significant bioluminescence on day 10, suggesting that Mafa has a more sustainable role in insulin gene activation than does Mafb. Both PDA and PDB transfers ameliorated the glucose levels in a streptozotocin (STZ-induced diabetic model for up to 21 days and 7 days, respectively. Furthermore, PDA transfer induced several gene expressions necessary for glucose sensing and insulin secretion in the liver on day 9. However, a glucose tolerance test and liver perfusion experiment did not show glucose-stimulated insulin secretion from intrahepatic β-like cells. These results demonstrate that bioluminescence imaging in MIP-Luc-VU mice provides a noninvasive means of detecting β-like cells in the liver. They also show that Mafa has a markedly intense and sustained role in β-like cell production in comparison with Mafb.

  13. A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiated β-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Byoung-Seob Ko

    2016-01-01

    Full Text Available We investigated that the long-term consumption of the water (KME-W and 70% ethanol (KME-E mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also made β-cell mass greater than the control by increasing β-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γ activity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W.

  14. A 70% Ethanol Extract of Mistletoe Rich in Betulin, Betulinic Acid, and Oleanolic Acid Potentiated β-Cell Function and Mass and Enhanced Hepatic Insulin Sensitivity.

    Science.gov (United States)

    Ko, Byoung-Seob; Kang, Suna; Moon, Bo Reum; Ryuk, Jin Ah; Park, Sunmin

    2016-01-01

    We investigated that the long-term consumption of the water (KME-W) and 70% ethanol (KME-E) mistletoe extracts had antidiabetic activities in partial pancreatectomized (Px) rats. Px rats were provided with a high-fat diet containing 0.6% KME-E, 0.6% KME-W, and 0.6% dextrin (control) for 8 weeks. As normal-control, Sham-operated rats were provided with 0.6% dextrin. In cell-based studies, the effects of its main terpenoids (betulin, betulinic acid, and oleanolic acid) on glucose metabolism were measured. Both KME-W and KME-E decreased epididymal fat mass by increasing fat oxidation in diabetic rats. KME-E but not KME-W exhibited greater potentiation of first-phase insulin secretion than the Px-control in a hyperglycemic clamp. KME-E also made β-cell mass greater than the control by increasing β-cell proliferation and decreasing its apoptosis. In a euglycemic-hyperinsulinemic clamp, whole-body glucose infusion rate and hepatic glucose output increased with potentiating hepatic insulin signaling in the following order: Px-control, KME-W, KME-E, and normal-control. Betulin potentiated insulin-stimulated glucose uptake via increased PPAR-γ activity and insulin signaling in 3T3-L1 adipocytes, whereas oleanolic acid enhanced glucose-stimulated insulin secretion and cell proliferation in insulinoma cells. In conclusion, KME-E prevented the deterioration of glucose metabolism in diabetic rats more effectively than KME-W and KME-E can be a better therapeutic agent for type 2 diabetes than KME-W. PMID:26884795

  15. Ovarian tumors secreting insulin.

    Science.gov (United States)

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  16. Insulin and carbohydrate dysregulation.

    Science.gov (United States)

    Gelato, Marie C

    2003-04-01

    Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed. PMID:12652377

  17. Insulin C-peptide test

    Science.gov (United States)

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin produced by the body and insulin injected ...

  18. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice

    Science.gov (United States)

    Zhang, Yongli; Dai, Chun-ling; Chen, Yanxing; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2016-01-01

    Elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD). At present, there is no treatment that can prevent anesthesia-induced postoperative cognitive dysfunction. Here, we treated mice with daily intranasal administration of insulin (1.75 U/day) for one week before anesthesia induced by intraperitoneal injection of propofol and maintained by inhalation of sevoflurane for 1 hr. We found that the insulin treatment prevented anesthesia-induced deficit in spatial learning and memory, as measured by Morris water maze task during 1–5 days after exposure to anesthesia. The insulin treatment also attenuated anesthesia-induced hyperphosphorylation of tau and promoted the expression of synaptic proteins and insulin signaling in the brain. These findings show a therapeutic potential of intranasal administration of insulin before surgery to reduce the risk of anesthesia-induced cognitive decline and AD. PMID:26879001

  19. Effects of Portulaca Oleracea on Insulin Resistance in Rats with Type 2 Diabetes Mellitus

    Institute of Scientific and Technical Information of China (English)

    沈岚; 陆付耳

    2003-01-01

    Objective: To study the effects of Portulaca oleracea, a Chinese medicinal herb, on insulin resistance in rats with type 2 diabetes mellitus (T2DM). Methods: Experimental model of T2DM was established by injection of streptozotocin (25mg/kg) and feeding with high calorie forage. The effects of Portulaca oleracea on oral glucose tolerance, serum levels of insulin, triglyceride, total cholesterol, high-density lipoproteins-cholesterol and free fatty acids, and insulin sensitivity index were all observed. Results: Portulaca oleracea could reduce the body weight, improve the impaired glucose tolerance and lipid metabolism, decrease serum free fatty acids, attenuate hyperinsulinemia and elevate insulin sensitivity. Conclusion: Portulaca oleracea could improve insulin resistance in rats with T2DM, and the mechanism might be related to its actions in improving lipid metabolism and decreasing free fatty acids.

  20. Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cβ in mice.

    Directory of Open Access Journals (Sweden)

    Xiaoquan Rao

    Full Text Available Physical exercise is an important and effective therapy for diabetes. However, its underlying mechanism is not fully understood. Protein kinase Cβ (PKCβ has been suggested to be involved in the pathogenesis of obesity and insulin resistance, but the role of PKCβ in exercise-induced improvements in insulin resistance is completely unknown. In this study, we evaluated the involvement of PKCβ in exercise-attenuated insulin resistance in high-fat diet (HFD-fed mice. PKCβ(-/- and wild-type mice were fed a HFD with or without exercise training. PKC protein expression, body and tissue weight change, glucose and insulin tolerance, metabolic rate, mitochondria size and number, adipose inflammation, and AKT activation were determined to evaluate insulin sensitivity and metabolic changes after intervention. PKCβ expression decreased in both skeletal muscle and liver tissue after exercise. Exercise and PKCβ deficiency can alleviate HFD-induced insulin resistance, as evidenced by improved insulin tolerance. In addition, fat accumulation and mitochondrial dysfunction induced by HFD were also ameliorated by both exercise and PKCβ deficiency. On the other hand, exercise had little effect on PKCβ(-/- mice. Further, our data indicated improved activation of AKT, the downstream signal molecule of insulin, in skeletal muscle and liver of exercised mice, whereas PKCβ deficiency blunted the difference between sedentary and exercised mice. These results suggest that downregulation of PKCβ contributes to exercise-induced improvement of insulin resistance in HFD-fed mice.

  1. Adipokines and Hepatic Insulin Resistance

    OpenAIRE

    Yu Li; Lin Ding; Waseem Hassan; Daoud Abdelkader; Jing Shang

    2013-01-01

    Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarificatio...

  2. Expression of PPARα modifies fatty acid effects on insulin secretion in uncoupling protein-2 knockout mice

    Directory of Open Access Journals (Sweden)

    Chan Catherine B

    2007-03-01

    Full Text Available Abstract Aims/hypothesis In uncoupling protein-2 (UCP2 knockout (KO mice, protection of beta cells from fatty acid exposure is dependent upon transcriptional events mediated by peroxisome proliferator-activated receptor-α (PPARα. Methods PPARα expression was reduced in isolated islets from UCP2KO and wild-type (WT mice with siRNA for PPARα (siPPARα overnight. Some islets were also cultured with oleic or palmitic acid, then glucose stimulated insulin secretion (GSIS was measured. Expression of genes was examined by quantitative RT-PCR or immunoblotting. PPARα activation was assessed by oligonucleotide consensus sequence binding. Results siPPARα treatment reduced PPARα protein expression in KO and WT islets by >85%. In siPPARα-treated UCP2KO islets, PA but not OA treatment significantly decreased the insulin response to 16.5 mM glucose. In WT islets, siPPARα treatment did not modify GSIS in PA and OA exposed groups. In WT islets, PA treatment significantly increased UCP2 mRNA and protein expression. Both PA and OA treatment significantly increased PPARα expression in UCP2KO and WT islets but OA treatment augmented PPARα protein expression only in UCP2KO islets (p Conclusion These data show that the negative effect of saturated fatty acid on GSIS is mediated by PPARα/UCP2. Knockout of UCP2 protects beta-cells from PA exposure. However, in the absence of both UCP2 and PPARα even a short exposure (24 h to PA significantly impairs GSIS.

  3. Attenuator And Conditioner

    Science.gov (United States)

    Anderson, Gene R.; Armendariz, Marcelino G.; Carson, Richard F.; Bryan, Robert P.; Duckett, III, Edwin B.; Kemme, Shanalyn Adair; McCormick, Frederick B.; Peterson, David W.

    2006-04-04

    An apparatus and method of attenuating and/or conditioning optical energy for an optical transmitter, receiver or transceiver module is disclosed. An apparatus for attenuating the optical output of an optoelectronic connector including: a mounting surface; an array of optoelectronic devices having at least a first end; an array of optical elements having at least a first end; the first end of the array of optical elements optically aligned with the first end of the array of optoelectronic devices; an optical path extending from the first end of the array of optoelectronic devices and ending at a second end of the array of optical elements; and an attenuator in the optical path for attenuating the optical energy emitted from the array of optoelectronic devices. Alternatively, a conditioner may be adapted in the optical path for conditioning the optical energy emitted from the array of optoelectronic devices.

  4. Insulin-induced localized lipoatrophy:

    OpenAIRE

    Breznik, Vesna; Kokol, Rok; Luzar, Boštjan; Miljković, Jovan

    2013-01-01

    Insulin lipoatrophy is a rare immunologic cutaneous complication in diabetes mellitus that presents with localized subcutaneous fat atrophy at the insulin injection site. We report the case of a 62-year-old woman with type 2 diabetes mellitus that developed localized lipoatrophy on the abdomen after 6 years of therapy with the insulin analogues detemir and aspart.

  5. Cinnamon, glucose and insulin sensitivity

    Science.gov (United States)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  6. Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-Ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

    OpenAIRE

    Vasantharaju S. Gowdra; Mudgal, Jayesh; Bansal, Punit; Pawan G. Nayak; Manohara Reddy, Seethappa A.; Shenoy, Gautham G.; Valiathan, Manna; Mallikarjuna R. Chamallamudi; Nampurath, Gopalan K

    2014-01-01

    We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised...

  7. Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

    OpenAIRE

    Vasantharaju S. Gowdra; Mudgal, Jayesh; Bansal, Punit; Pawan G. Nayak; Manohara Reddy, Seethappa A.; Shenoy, Gautham G.; Valiathan, Manna; Mallikarjuna R. Chamallamudi; Nampurath, Gopalan K

    2014-01-01

    We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised...

  8. Cyanidin-3-O-β-Glucoside and Protocatechuic Acid Exert Insulin-Like Effects by Upregulating PPARγ Activity in Human Omental Adipocytes

    OpenAIRE

    Scazzocchio, Beatrice; Varì, Rosaria; Filesi, Carmelina; D’Archivio, Massimo; Santangelo, Carmela; Giovannini, Claudio; Iacovelli, Annunziata; Silecchia, Gianfranco; Volti, Giovanni Li; Galvano, Fabio; Masella, Roberta

    2011-01-01

    OBJECTIVE Insulin resistance (IR) represents an independent risk factor for metabolic, cardiovascular, and neoplastic disorders. Preventing/attenuating IR is a major objective to be reached to preserve population health. Because many insulin-sensitizing drugs have shown unwanted side effects, active harmless compounds are sought after. Dietary anthocyanins have been demonstrated to ameliorate hyperglycemia and insulin sensitivity. This study aimed at investigating whether cyanidin-3-O-β-gluco...

  9. Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?

    OpenAIRE

    Sami N. Nasrallah; L. Raymond Reynolds

    2012-01-01

    The advances in recombinant DNA technology have led to an improvement in the properties of currently available long-acting insulin analogs. Insulin degludec, a new generation ultra-long-acting basal insulin, currently in phase 3 clinical trials, has a promising future in clinical use. When compared to its rival basal insulin analogs, a longer duration of action and lower incidence of hypoglycemic events in both type 1 and type 2 diabetic patients has been demonstrated.1,2 Its unique mechanism...

  10. Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells: effects on cell metabolism and insulin secretion.

    Science.gov (United States)

    Rubí, Blanca; Antinozzi, Peter A; Herrero, Laura; Ishihara, Hisamitsu; Asins, Guillermina; Serra, Dolors; Wollheim, Claes B; Maechler, Pierre; Hegardt, Fausto G

    2002-01-01

    Lipid metabolism in the beta-cell is critical for the regulation of insulin secretion. Pancreatic beta-cells chronically exposed to fatty acids show higher carnitine palmitoyltransferase I (CPT I) protein levels, higher palmitate oxidation rates and an altered insulin response to glucose. We examined the effect of increasing CPT I levels on insulin secretion in cultured beta-cells. We prepared a recombinant adenovirus containing the cDNA for the rat liver isoform of CPT I. The overexpression of CPT I in INS1E cells caused a more than a 5-fold increase in the levels of CPT I protein (detected by Western blotting), a 6-fold increase in the CPT activity, and an increase in fatty acid oxidation at 2.5 mM glucose (1.7-fold) and 15 mM glucose (3.1-fold). Insulin secretion was stimulated in control cells by 15 mM glucose or 30 mM KCl. INS1E cells overexpressing CPT I showed lower insulin secretion on stimulation with 15 mM glucose (-40%; P<0.05). This decrease depended on CPT I activity, since the presence of etomoxir, a specific inhibitor of CPT I, in the preincubation medium normalized the CPT I activity, the fatty-acid oxidation rate and the insulin secretion in response to glucose. Exogenous palmitate (0.25 mM) rescued glucose-stimulated insulin secretion (GSIS) in CPT I-overexpressing cells, indicating that the mechanism of impaired GSIS was through the depletion of a critical lipid. Depolarizing the cells with KCl or intermediary glucose concentrations (7.5 mM) elicited similar insulin secretion in control cells and cells overexpressing CPT I. Glucose-induced ATP increase, glucose metabolism and the triacylglycerol content remained unchanged. These results provide further evidence that CPT I activity regulates insulin secretion in the beta-cell. They also indicate that up-regulation of CPT I contributes to the loss of response to high glucose in beta-cells exposed to fatty acids. PMID:11988095

  11. Insulin som trickster

    DEFF Research Database (Denmark)

    Lassen, Aske Juul

    2011-01-01

    grænser nedbrydes i en konstant penetrering af huden, når blodsukkeret måles eller insulinen indsprøjtes. Insulin analyseres som en tricksterfigur, der udøver et grænsearbejde på kroppen, leger med dens kategorier og vender forholdet mellem gift og medicin, frihed og ufrihed, kunstighed og naturlighed...

  12. Polyethyleneglycol RIA (radioimmunoassay) insulin

    International Nuclear Information System (INIS)

    Insulin is a polypeptide hormone of M.W. 6,000 composed of two peptide chains, A and B, jointed by two cross-linked disulphide bonds and synthesized by the beta-cells of the islets of Langerhans of the pancreas. Insulin influences most of the metabolic functions of the body. Its best known action is to lower the blood glucose concentration by increasing the rate at which glucose is converted to glycogen in the liver and muscles and to fat in adipose tissue, by stimulating the rate of glucose metabolism and by depressing gluconeogenesis. Insulin stimulates the synthesis of proteins, DNA and RNA in cells generally, and promotes the uptake of aminoacids and their incorporation into muscle protein. It increases the uptake of glucose in adipose tissue and its conversion into fat and inhibits lipolysis. Insulin primary action is on the cell membrane, where it probably facilitates the transport of glucose and aminoacids into the cells. At the same time it may activate intracellular enzymes such as glycogen synthetase, concerned with glycogen synthesis. (Author)

  13. Insulin signaling regulates mitochondrial function in pancreatic beta-cells.

    Directory of Open Access Journals (Sweden)

    Siming Liu

    Full Text Available Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in beta-cells that included glucokinase (GK, and the pro-apoptotic protein, BAD(S. Mitochondria isolated from beta-cells derived from beta-cell specific insulin receptor knockout (betaIRKO mice exhibited reduced BAD(S, GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in betaIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BAD(S. The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in betaIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for beta-cell dysfunction in type 2 diabetes.

  14. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

    Directory of Open Access Journals (Sweden)

    RobertRoot-Bernstein

    2014-07-01

    Methods: Ultraviolet spectroscopy, capillary electrophoresis and NMR demonstrated estrogen binding to insulin and its receptor. Horse-radish peroxidase-linked insulin was used in an ELISA-like procedure to measure the effect of estradiol on binding of insulin to its receptor. Measurements: Binding constants for estrogens to insulin and the insulin receptor were determined by concentration-dependent spectral shifts. The effect of estradiol on insulin-HRP binding to its receptor was determined by shifts in the insulin binding curve. Main Results: Estradiol bound to insulin with a Kd of 12 x 10-9 M and to the insulin receptor with a Kd of 24 x 10-9 M, while other hormones had significantly less affinity. 200 nM estradiol shifted the binding curve of insulin to its receptor 0.8 log units to the right. Conclusions: Estradiol concentrations in many hyperestrogenemic syndromes are sufficient to interfere with insulin binding to its receptor producing significant insulin resistance.

  15. Insulin gene mutations and diabetes

    OpenAIRE

    Nishi, Masahiro; Nanjo, Kishio

    2011-01-01

    Abstract Some mutations of the insulin gene cause hyperinsulinemia or hyperproinsulinemia. Replacement of biologically important amino acid leads to defective receptor binding, longer half‐life and hyperinsulinemia. Three mutant insulins have been identified: (i) insulin Chicago (F49L or PheB25Leu); (ii) insulin Los Angeles (F48S or PheB24Ser); (iii) and insulin Wakayama (V92L or ValA3Leu). Replacement of amino acid is necessary for proinsulin processing results in hyperproinsulinemia. Four t...

  16. Insulin Modifies Honeybee Worker Behavior

    Directory of Open Access Journals (Sweden)

    Christine M. Mott

    2012-10-01

    Full Text Available The insulin signaling pathway has been hypothesized to play a key role in regulation of worker social insect behavior. We tested whether insulin treatment has direct effects on worker honeybee behavior in two contexts, sucrose response thresholds in winter bees and the progression to foraging by summer nurse bees. Treatment of winter worker bees with bovine insulin, used as a proxy for honeybee insulin, increased the bees’ sucrose response threshold. Treatment of summer nurse bees with bovine insulin significantly decreased the age at which foraging was initiated. This work provides further insight into the role of endocrine controls in behavior of in honeybees and insects in general.

  17. Microcystin-LR induces dysfunction of insulin secretion in rat insulinoma (INS-1) cells: Implications for diabetes mellitus.

    Science.gov (United States)

    Zhao, Yanyan; Shi, Kun; Su, Xiaomei; Xie, Liqiang; Yan, Yunjun

    2016-08-15

    Microcystins (MCs) are the most frequent cyanobacterial toxins observed in freshwater systems. Accumulating evidence suggests that MCs pose a serious threat to public health. However, the contributions of the exposure of MCs to the occurrence of human diseases remain largely unknown. This study provides the evidence of the effects of MC-LR on pancreatic β-cell function through the exposure of rat insulinoma (INS-1) cells to 0, 10, 20, or 40μM MC-LR for 72h and explores the underlying molecular mechanisms. Our results demonstrate that exposure to MC-LR for 72h suppresses cell viability, disturbs glucose-stimulated insulin secretion (GSIS), and decreases the expression of insulin protein. Moreover, MC-LR disrupts the cell cycle distribution and increases cell apoptosis at 20 or 40μM for 72h, respectively, indicating that the β-cell mass would be decreased by MC-LR exposure. A transcriptomic analysis revealed several key genes (e.g., Pdx-1, Neurod1, and Abcc8) involved in insulin secretion are significantly differentially expressed in INS-1 cells in response to MC-LR exposure. In addition, several signal transduction pathways associated with diabetes (e.g., type 1 and 2 diabetes) were also identified compared with the control cells. We recommend that MC be considered as a new environmental factor that promotes diabetes development. The identified key genes or pathways may potentially contribute to the future therapies in the environmental contaminants induced β-cell damage. PMID:27107231

  18. Adipocyte lipolysis and insulin resistance.

    Science.gov (United States)

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. PMID:26542285

  19. Managing diabetes with inhaled insulin

    Directory of Open Access Journals (Sweden)

    Lucy D Mastrandrea

    2012-01-01

    Full Text Available The incidence of diabetes is increasing world-wide. Many individuals with diabetes require insulin to control their blood sugar and prevent both microvascular and macrovascular complications associated with this chronic disease. Current regimens involve delivery of subcutaneous insulin by injection or continuous insulin infusion. One area of research to advance diabetes care is aimed at developing alternate routes of insulin administration that will make daily management less invasive for patients. This review will focus on inhaled insulin, a novel formulation which takes advantage of drug delivery through the pulmonary system. The pharmacology, efficacy, and safety of inhaled insulin will be discussed. In addition, the status of inhaled insulin as a potential therapy for individuals with diabetes will be reviewed.

  20. Insulin degludec for diabetes mellitus.

    Science.gov (United States)

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  1. Insulin secretion enhancing activity of roselle calyx extract in normal and streptozotocin-induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Eamruthai Wisetmuen

    2013-01-01

    Full Text Available Background and Objective: Our recent study revealed the antihyperglycemic activity of an ethanolic extract of roselle calyxes (Hibiscus sabdariffa in diabetic rats. The present study had, therefore, an objective to investigate the mechanism underlying this activity. Materials and Methods: Male Sprague Dawley rats were induced to be diabetes by intraperitoneal injection of 45 mg/kg streptozotocin (STZ. Normal rats as well as diabetic rats were administered with the ethanolic extract of H. sabdariffa calyxes (HS-EE at 0.1 and 1.0 g/kg/day, respectively, for 6 weeks. Then, blood glucose and insulin levels, at basal and glucose-stimulated secretions, were measured. The pancreas was dissected to examine histologically. Results: HS-EE 1.0 g/kg/day significantly decreased the blood glucose level by 38 ± 12% in diabetic rats but not in normal rats. In normal rats, treatment with 1.0 g/kg HS-EE increased the basal insulin level significantly as compared with control normal rats (1.28 ± 0.25 and 0.55 ± 0.05 ng/ml, respectively. Interestingly, diabetic rats treated with 1.0 g/kg HS-EE also showed a significant increase in basal insulin level as compared with the control diabetic rats (0.30 ± 0.05 and 0.15 ± 0.01 ng/ml, respectively. Concerning microscopic histological examination, HS-EE 1.0 g/kg significantly increased the number of islets of Langerhans in both normal rats (1.2 ± 0.1 and 2.0 ± 0.1 islet number/10 low-power fields (LPF for control and HS-EE treated group, respectively and diabetic rats (1.0 ± 0.3 and 3.9 ± 0.6 islet number/10 LPF for control and HS-EE treated group, respectively. Conclusion: The antidiabetic activity of HS-EE may be partially mediated via the stimulating effect on insulin secretion.

  2. Insulin resistance and hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Manuel Romero-Gómez

    2006-01-01

    Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients.Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARy receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American.Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin.Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA ≤ 2 than patients with HOMA > 2. In experiments carried out on Huh-7cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance,steatosis and fibrosis progression.

  3. Superactive insulin: [B10-aspartic acid]insulin(human)

    International Nuclear Information System (INIS)

    The genetic basis for a case of familial hyperproinsulinemia has been elucidated recently. It involves a single point mutation in the proinsulin gene resulting in the substitution of aspartic acid for histidine-10 of the B chain of insulin. The authors have synthesized a human insulin analogue, [Asp/sup B10/] insulin, corresponding to the mutant proinsulin and evaluated its biological activity. [Asp/sup B10/] Insulin displayed a binding affinity to insulin receptors in rat liver plasma membranes that was 534 +- 146% relative to the natural hormone. In lipogenesis assays, the synthetic analogue exhibited a potency that was 435 +- 144% relative to insulin, which is statistically not different from its binding affinity. Reversed-phase HPLC indicated that the synthetic analogue is more apolar than natural insulin. They suggest that the observed properties reflect changes in the conformation of the analogue relative to natural insulin, which results in a stronger interaction with the insulin receptor. Thus, a single substitution of an amino acid residue of human insulin has resulted in a superactive hormone

  4. Superactive insulin: (B10-aspartic acid)insulin(human)

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, G.P.; Burke, G.T.; Katsoyannis, P.G.

    1987-09-01

    The genetic basis for a case of familial hyperproinsulinemia has been elucidated recently. It involves a single point mutation in the proinsulin gene resulting in the substitution of aspartic acid for histidine-10 of the B chain of insulin. The authors have synthesized a human insulin analogue, (Asp/sup B10/) insulin, corresponding to the mutant proinsulin and evaluated its biological activity. (Asp/sup B10/) Insulin displayed a binding affinity to insulin receptors in rat liver plasma membranes that was 534 +- 146% relative to the natural hormone. In lipogenesis assays, the synthetic analogue exhibited a potency that was 435 +- 144% relative to insulin, which is statistically not different from its binding affinity. Reversed-phase HPLC indicated that the synthetic analogue is more apolar than natural insulin. They suggest that the observed properties reflect changes in the conformation of the analogue relative to natural insulin, which results in a stronger interaction with the insulin receptor. Thus, a single substitution of an amino acid residue of human insulin has resulted in a superactive hormone.

  5. Treatment satisfaction and quality of life with insulin glargine plus insulin lispro compared with NPH insulin plus unmodified human insulin in people with Type 1 diabetes

    OpenAIRE

    Ashwell , SG; Stephens, JW; Witthaus, E; Home, PD; Bradley, Clare

    2008-01-01

    OBJECTIVE— The purpose of this study was to compare quality of life and treatment satisfaction using insulin glargine plus insulin lispro with that using NPH insulin plus unmodified human insulin in adults with type 1 diabetes managed with multiple injection regimens. RESEARCH DESIGN AND METHODS— As part of a 32-week, five-center, two-way crossover study in 56 individuals with type 1 diabetes randomized to evening insulin glargine plus mealtime insulin lispro or to NPH insulin (once or twi...

  6. The expression of the beta cell-derived autoimmune ligand for the killer receptor nkp46 is attenuated in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Chamutal Gur

    Full Text Available NK cells rapidly kill tumor cells, virus infected cells and even self cells. This is mediated via killer receptors, among which NKp46 (NCR1 in mice is prominent. We have recently demonstrated that in type 1 diabetes (T1D NK cells accumulate in the diseased pancreas and that they manifest a hyporesponsive phenotype. In addition, we found that NKp46 recognizes an unknown ligand expressed by beta cells derived from humans and mice and that blocking of NKp46 activity prevented diabetes development. Here we investigated the properties of the unknown NKp46 ligand. We show that the NKp46 ligand is mainly located in insulin granules and that it is constitutively secreted. Following glucose stimulation the NKp46 ligand translocates to the cell membrane and its secretion decreases. We further demonstrate by using several modalities that the unknown NKp46 ligand is not insulin. Finally, we studied the expression of the NKp46 ligand in type 2 diabetes (T2D using 3 different in vivo models and 2 species; mice and gerbils. We demonstrate that the expression of the NKp46 ligand is decreased in all models of T2D studied, suggesting that NKp46 is not involved in T2D.

  7. A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells.

    Science.gov (United States)

    Saxena, Pratik; Heng, Boon Chin; Bai, Peng; Folcher, Marc; Zulewski, Henryk; Fussenegger, Martin

    2016-01-01

    Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine. PMID:27063289

  8. Association of IDDM and attenuated response of 2',5'-oligoadenylate synthetase to yellow fever vaccine

    DEFF Research Database (Denmark)

    Bonnevie-Nielsen, V; Larsen, M L; Frifelt, J J;

    1989-01-01

    Basal and yellow fever vaccination-induced 2',5'-oligoadenylate synthetase (2',5'A) activity was determined in blood mononuclear cells (peripheral blood lymphocytes [PBLs]) from insulin-dependent diabetes mellitus (IDDM) and matched control subjects. The live attenuated yellow fever vaccine repre...

  9. Radiofrequency attenuator and method

    Science.gov (United States)

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-11-10

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3 C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  10. Insulin receptor in Drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Petruzzelli, L.; Herrera, R.; Rosen, O.

    1986-05-01

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound /sup 125/I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to /sup 125/I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to /sup 125/I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development.

  11. Insulin receptor in Drosophila melanogaster

    International Nuclear Information System (INIS)

    A specific, high affinity insulin receptor is present in both adult Drosophila and in Drosophila embryos. Wheat germ lectin-enriched extracts of detergent-solubilized membranes from embryos and adults bind insulin with a K/sub d/ of 15 nM. Binding is specific for insulin; micromolar concentrations of proinsulin, IGFI, and IGFII are required to displace bound 125I-insulin. Insulin-dependent protein tyrosine kinase activity appears during embryogenesis. It is evident between 6 and 12 hours of development, peaks between 12 and 18 hours and falls in the adult. During 0-6 hours of embryogenesis, and in the adult, a specific protein band (Mr = 135,000) is crosslinked to 125I-insulin. During 6-12 and 12-18 hours of embryogenesis stages in which insulin-dependent protein tyrosine kinase is high, an additional band (Mr = 100,000) becomes crosslinked to 125I-insulin. Isolation and DNA sequence analysis of genomic clones encoding the Drosophila insulin receptor will be presented as will the characterization of insulin receptor mRNA's during development

  12. The Axin/TNKS complex interacts with KIF3A and is required for insulin-stimulated GLUT4 translocation

    Institute of Scientific and Technical Information of China (English)

    Hui-Ling Guo; Zhiyun Ye; Shu-Yong Lin; Sheng-Cai Lin; Cixiong Zhang; Qi Liu; Qinxi Li; Guili Lian; Di Wu; Xuebin Li; Wei Zhang; Yuemao Shen

    2012-01-01

    Insulin-stimulated glucose uptake by the glucose transporter GLUT4 plays a central role in whole-body glucose homeostasis,dysregulation of which leads to type 2 diabetes.However,the molecular components and mechanisms regulating insulin-stimulated glucose uptake remain largely unclear.Here,we demonstrate that Axin interacts with the ADP-ribosylase tankyrase 2 (TNKS2) and the kinesin motor protein KIF3A,forming a ternary complex crucial for GLUT4 translocation in response to insulin.Specific knockdown of the individual components of the complex attenuated insulin-stimulated GLUT4 translocation to the plasma membrane.Importantly,TNKS2-/- mice exhibit reduced insulin sensitivity and higher blood glucose levels when re-fed after fasting.Mechanistically,we demonstrate that in the absence of insulin,Axin,TNKS and KIF3A are co-localized with GLUT4 on the trans-Golgi network.Insulin treatment suppresses the ADP-ribosylase activity of TNKS,leading to a reduction in ADP ribosylation and ubiquitination of both Axin and TNKS,and a concurrent stabilization of the complex.Inhibition of Akt,the major effector kinase of insulin signaling,abrogates the insulin-mediated complex stabilization.We have thus elucidated a new protein complex that is directly associated with the motor protein kinesin in insulin-stimulated GLUT4 translocation.

  13. Cinnamon extract improves insulin sensitivity in the brain and lowers liver fat in mouse models of obesity.

    Directory of Open Access Journals (Sweden)

    Tina Sartorius

    Full Text Available OBJECTIVES: Treatment of diabetic subjects with cinnamon demonstrated an improvement in blood glucose concentrations and insulin sensitivity but the underlying mechanisms remained unclear. This work intends to elucidate the impact of cinnamon effects on the brain by using isolated astrocytes, and an obese and diabetic mouse model. METHODS: Cinnamon components (eugenol, cinnamaldehyde were added to astrocytes and liver cells to measure insulin signaling and glycogen synthesis. Ob/ob mice were supplemented with extract from cinnamomum zeylanicum for 6 weeks and cortical brain activity, locomotion and energy expenditure were evaluated. Insulin action was determined in brain and liver tissues. RESULTS: Treatment of primary astrocytes with eugenol promoted glycogen synthesis, whereas the effect of cinnamaldehyde was attenuated. In terms of brain function in vivo, cinnamon extract improved insulin sensitivity and brain activity in ob/ob mice, and the insulin-stimulated locomotor activity was improved. In addition, fasting blood glucose levels and glucose tolerance were greatly improved in ob/ob mice due to cinnamon extracts, while insulin secretion was unaltered. This corresponded with lower triglyceride and increased liver glycogen content and improved insulin action in liver tissues. In vitro, Fao cells exposed to cinnamon exhibited no change in insulin action. CONCLUSIONS: Together, cinnamon extract improved insulin action in the brain as well as brain activity and locomotion. This specific effect may represent an important central feature of cinnamon in improving insulin action in the brain, and mediates metabolic alterations in the periphery to decrease liver fat and improve glucose homeostasis.

  14. Insulin and insulin mutants stimulate glucose uptake in rat adipocytes

    Institute of Scientific and Technical Information of China (English)

    姚矢音; 张新堂; 许英镐; 张信娜; 朱尚权

    1999-01-01

    A simple method to determine the in vitro biological activity of insulin by measuring glucose uptake in the rat adipocytes is presented here. In the presence of insulin, the glucose uptake is 5-6 times more than the basal control. And the uptake of D-[3-3H]-glucose is linear as the logarithm of insulin concentration from 0.2 μg/L to 1.0 μg/L. Glucose and 3-O-methyl-glucose inhibit D-[3-3H]-glucose uptake into adipocytes. By this method, the in vitro biological activity of [B2-Lys]-insulin and [B3-Lys]-insulin was measured to be 61.6% and 154% respectively, relative to that of insulin.

  15. "胰岛代理细胞"的构建:在HepG2细胞中获得胰岛素分泌%Construction of an "artificial beta cell":Modulation of glucose-stimulated insulin secretion from HepG2 cell

    Institute of Scientific and Technical Information of China (English)

    郑宏庭; 邓华聪; 兰丽珍; 方芳

    2004-01-01

    目的:利用转基因技术将HepG2细胞改建为具有生理性胰岛素分泌能力的"胰岛代理细胞".方法:以携葡萄糖激酶(glucokinase,gk)基因的逆转录病毒及携人胰岛素原基因突变体(mutant proinsulin gene,mpin)的逆转录病毒共同感染肝母细胞瘤细胞系HepG2,G418选择培养基挑选抗性细胞集落,放免法、SDSPAGE、Western-blot及反转录酶聚合酶链反应(RT-PCR)鉴定HepG2细胞中两个目的基因的转录及表达;选取联合表达葡萄糖激酶及成熟胰岛素的HepG2细胞进行葡萄糖反应性胰岛素分泌的检测,以单独表达成熟胰岛素的HepG2细胞作对照.结果:在G418选择培养基中3 wk获阳性细胞克隆,采用放免法、SDS-PAGE、Western-blot从20个细胞克隆中挑选出联合表达葡萄糖激酶及成熟胰岛素的HepG2细胞4株,其中1株2个目的基因表达均较强,命名为细胞克隆"β";经RT-PCR检测证实细胞"β"中已有两个目的基因的转录.在细胞"β"中,葡萄糖浓度为0.5 mmol/L和0.75 mmol/L时,胰岛素的分泌无显著性差异(P>0.05);葡萄糖浓度为2.0 mmol/L,3.0 mmol/L,4.0 mmol/L,5.0 mmol/L,及6.0 mmol/L时,胰岛素的分泌无显著性差异(P>0.05);其余葡萄糖浓度条件下,胰岛素的分泌差异均有显著性意义(P<0.05).在单独表达胰岛素的HepG2细胞中,各葡萄糖浓度条件下,胰岛素的分泌均无显著性差异(P>0.05).说明在细胞"β"中获得了葡萄糖反应性胰岛素分泌,葡萄糖浓度约1.75-2 mmol/L时出现胰岛素分泌高峰.结论:成功构建了具有生理性胰岛素分泌能力的"胰岛代理细胞"系.

  16. Expression Analysis of cPLA2 Alpha Interacting TIP60 in Diabetic KKAy and Non-Diabetic C57BL Wild-Type Mice: No Impact of Transient and Stable TIP60 Overexpression on Glucose-Stimulated Insulin Secretion in Pancreatic Beta-Cells

    DEFF Research Database (Denmark)

    Nordentoft, Iver; Jeppesen, Per B; Nielsen, Anders L;

    2007-01-01

    In the present study we investigate the expression levels of cytosolic phospholipase A2 alpha (cPLA2alpha) interacting histone acetyl transferase proteins TIP60alpha and TIP60beta in non-diabetic C57BL wild-type mice and obese type 2 diabetic KKAy model mice. The aim was to test our hypothesis that...

  17. Antioxidant rich flavonoids from Oreocnide integrifolia enhance glucose uptake and insulin secretion and protects pancreatic β-cells from streptozotocin insult

    Directory of Open Access Journals (Sweden)

    Ansarullah

    2011-12-01

    Full Text Available Abstract Background Insulin deficiency is the prime basis of all diabetic manifestations and agents that can bring about insulin secretion would be of pivotal significance for cure of diabetes. To test this hypothesis, we carried out bioactivity guided fractionation of Oreocnide integrifolia (Urticaceae; a folklore plant consumed for ameliorating diabetic symptoms using experimental models. Methods We carried out bioassay guided fractionation using RINmF and C2C12 cell line for glucose stimulated insulin secretion (GSIS and glucose uptake potential of fractions. Further, the bioactive fraction was challenged for its GSIS in cultured mouse islets with basal (4.5 mM and stimulated (16.7 mM levels of glucose concentrations. The Flavonoid rich fraction (FRF was exposed to 2 mM streptozotocin stress and the anti-ROS/RNS potential was evaluated. Additionally, the bioactive fraction was assessed for its antidiabetic and anti-apoptotic property in-vivo using multidose streptozotocin induced diabetes in BALB/c mice. Results The results suggested FRF to be the most active fraction as assessed by GSIS in RINm5F cells and its ability for glucose uptake in C2C12 cells. FRF displayed significant potential in terms of increasing intracellular calcium and cAMP levels even in presence of a phosphodiesterase inhibitor, IBMX in cultured pancreatic islets. FRF depicted a dose-dependent reversal of all the cytotoxic manifestations except peroxynitrite and NO formation when subjected in-vitro along with STZ. Further scrutinization of FRF for its in-vivo antidiabetic property demonstrated improved glycemic indices and decreased pancreatic β-cell apoptosis. Conclusions Overall, the flavonoid mixture has shown to have significant insulin secretogogue, insulinomimetic and cytoprotective effects and can be evaluated for clinical trials as a therapeutant in the management of diabetic manifestations.

  18. Binding of vanadium compounds perturbs conformation and aggregation state of insulin

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The interactions between zinc-free insulin and vanadium compounds, NaVO3, VO(acac)2 and VO(ma)2, have been investigated by fluorescence spectroscopy, circular dichroism (CD) and Fourier-transformed infrared (FT-IR) spectroscopy. The results showed that binding of vanadium compounds produced a static quenching of the intrinsic fluorescence of insulin. The apparent association constants were determined to be (0.17±0.01)×104 L*mol-1 for NaVO3, (2.8±0.2)×104 L*mol-1 for VO(acac)2, and (4.0±0.1)×104 L*mol-1 for VO(ma)2, respectively. The light scattering intensity of insulin decreased upon incubation with the vanadium compounds, suggesting the disaggregation of insulin. The attenuation of the band at 273 nm of insulin CD spectra also supported the disaggregation of insulin observed above. A new band at 1650~1653 cm-1 appeared in the FT-IR spectra of insulin upon incubation with the vanadium compounds, indicating the formation of an α-helix structure at B (9-19) motif. This α-helix structure suggests a structural change of insulin from an extended conformation (T state) to a helical conformation (R state), which is essential for binding of insulin to its receptor. In conclusion, binding of vanadium compounds results in conformational changes and disaggregation of insulin. These changes might account for the enhancement of binding affinity for insulin to its receptor in the presence of vanadium compounds.

  19. [Intensified insulin therapy and insulin micro-pumps during pregnancy].

    Science.gov (United States)

    Galuppi, V

    1994-06-01

    Before conception and during pregnancy in diabetic patients, every possible effort should be made in order to obtain a good, if not perfect, metabolic control and to warrant maternal and fetal health. Multiple daily injections are required to achieve a very strict glucose regulation in pregnant patients with insulin-dependent diabetes mellitus. The most usual intensive insulin administration patterns require 3 premeal doses of short-acting insulin and 1 (at bedtime) or 2 (one in the morning and one at bedtime) injections of intermediate or slow-acting insulin. As an alternative choice, insulin pumps allow a continuous subcutaneous infusion with short-acting insulin according to a basal rate which cover the insulin need during the night and between meals. Premeal and presnack surges of insulin are administrated by the patient herself. Home glucose monitoring must be used to adjust insulin doses. Target glucose levels every diabetic pregnant woman should try to achieve are lower than in non-pregnant women: fasting glycaemia should be below 100 mg/dl, 1 hour post-prandial value below 140 mg/dl and 2 hour post-prandial level below 120 mg/dl. The stricter the control and treatment goals are, the more frequently hypoglycaemia may occur. Hypoglycaemia may be harmful especially for patients with severe diabetic complications and may affect the fetus. Therefore, every pregnant diabetic woman should receive individualized treatment and glycaemic goals according to her clinical features, her compliance and her social and cultural background. PMID:7968932

  20. Interactions of short-acting, intermediate-acting and pre-mixed human insulins with free radicals--Comparative EPR examination.

    Science.gov (United States)

    Olczyk, Paweł; Komosinska-Vassev, Katarzyna; Ramos, Paweł; Mencner, Łukasz; Olczyk, Krystyna; Pilawa, Barbara

    2015-07-25

    Electron paramagnetic resonance (EPR) spectroscopy was used to examine insulins interactions with free radicals. Human recombinant DNA insulins of three groups were studied: short-acting insulin (Insuman Rapid); intermediate-acting insulins (Humulin N, Insuman Basal), and pre-mixed insulins (Humulin M3, Gensulin M50, Gensulin M40, Gensulin M30). The aim of an X-band (9.3GHz) study was comparative analysis of antioxidative properties of the three groups of human insulins. DPPH was used as a stable free radical model. Amplitudes of EPR lines of DPPH as the paramagnetic free radical reference, and DPPH interacting with the individual tested insulins were compared. For all the examined insulins kinetics of their interactions with free radicals up to 60 min were obtained. The strongest interactions with free radicals were observed for the short-acting insulin - Insuman Rapid. The lowest interactions with free radicals were characteristic for intermediate-acting insulin - Insuman Basal. The pre-mixed insulins i.e. Humulin M3 and Gensulin M50 revealed the fastest interactions with free radicals. The short acting, intermediate acting and premixed insulins have been found to be effective agents in reducing free radical formation in vitro and should be further considered as potential useful tools in attenuation of oxidative stress in diabetic patients. PMID:25975232

  1. Insulin Degludec, The New Generation Basal Insulin or Just another Basal Insulin?

    Science.gov (United States)

    Nasrallah, Sami N; Reynolds, L Raymond

    2012-01-01

    The advances in recombinant DNA technology have led to an improvement in the properties of currently available long-acting insulin analogs. Insulin degludec, a new generation ultra-long-acting basal insulin, currently in phase 3 clinical trials, has a promising future in clinical use. When compared to its rival basal insulin analogs, a longer duration of action and lower incidence of hypoglycemic events in both type 1 and type 2 diabetic patients has been demonstrated.1,2 Its unique mechanism of action is based on multihexamer formation after subcutaneous injection. This reportedly allows for less pharmacodynamic variability and within-subject variability than currently available insulin analogs, and a duration of action that is over 24 hours.3 The lack of proof of carcinogenicity with insulin degludec is yet another factor that would be taken into consideration when choosing the optimal basal insulin for a diabetic individual.4 A formulation of insulin degludec with insulin aspart, Insulin degludec 70%/aspart 30%, may permit improved flexibly of dosing without compromising glycemic control or safety.5. PMID:22879797

  2. Pressure surge attenuator

    International Nuclear Information System (INIS)

    A pressure surge attenuation arrangement comprises crushable metal foam disposed adjacent regions adapted to be expanded by a pressure surge. In a pipe system such region consists of a thin walled inner pipe surrounded by a housing with crushable metal foam disposed in the space between the housing and the inner pipe. (author)

  3. Tritium Attenuation by Distillation

    International Nuclear Information System (INIS)

    The objective of this study was to determine how a 100 Area distillation system could be used to reduce to a satisfactory low value the tritium content of the dilute moderator produced in the 100 Area stills, and whether such a tritium attenuator would have sufficient capacity to process all this material before it is sent to the 400 Area for reprocessing

  4. Natural attenuation of herbicides

    DEFF Research Database (Denmark)

    Tuxen, Nina; Højberg, Anker Lajer; Broholm, Mette Martina;

    2002-01-01

    A field injection experiment in a sandy, aerobic aquifer showed that two phenoxy acids MCPP (mecoprop) and dichlorprop were degraded within I in downgradient of the injection wells after an apparent lag period. The plume development and microbial measurements indicated that microbial growth gover...... observations may be important for application of natural attenuation as a remedy in field scale systems....

  5. Gestational Diabetes Mellitus: Insulinic Management

    OpenAIRE

    Magon, Navneet; Seshiah, Veerasamy

    2014-01-01

    Diabetic pregnancies have attendant risks. Adverse fetal, neonatal, and maternal outcomes in a diabetic pregnancy can be avoided by optimum glycemic control. Most pregnancies with GDM can be managed with non-insulinic management, which includes medical nutrition therapy. However, many necessitate concomitant insulinic management. The new insulin analogs present undoubted advantages in reducing the risk of hypoglycemia, mainly during the night, and in promoting a more physiologic glycemic prof...

  6. Protein Crystal Recombinant Human Insulin

    Science.gov (United States)

    1994-01-01

    The comparison of protein crystal, Recombiant Human Insulin; space-grown (left) and earth-grown (right). On STS-60, Spacehab II indicated that space-grown crystals are larger and of greater optical clarity than their earth-grown counterparts. Recombiant Human Insulin facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  7. Cell factories for insulin production

    OpenAIRE

    Baeshen, Nabih A.; Baeshen, Mohammed N; Sheikh, Abdullah; Bora, Roop S; Mohamed Morsi M. Ahmed; Ramadan, Hassan A I; Saini, Kulvinder Singh; Redwan, Elrashdy M.

    2014-01-01

    The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Manufacturing of therapeutic recombinant proteins require an appropriate host org...

  8. Nutritional Modulation of Insulin Resistance

    OpenAIRE

    Weickert, Martin O.

    2012-01-01

    Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM). Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss i...

  9. Alterations in whole-body insulin sensitivity resulting from repeated eccentric exercise of a single muscle group: a pilot investigation

    OpenAIRE

    Gonzalez, Javier; Barwood, Martin; Goodall, Stuart; Thomas, Kevin; Howatson, Glyn

    2015-01-01

    Unaccustomed eccentric exercise using large muscle groups elicits soreness, decrements in physical function and impairs markers of whole-body insulin sensitivity; although these effects are attenuated with a repeated exposure. Eccentric exercise of a small muscle group (elbow flexors) displays similar soreness and damage profiles in response to repeated exposure. However, it is unknown whether damage to small muscle groups impacts upon whole-body insulin sensitivity. This pilot investigation ...

  10. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    International Nuclear Information System (INIS)

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo

  11. Fumosorinone, a novel PTP1B inhibitor, activates insulin signaling in insulin-resistance HepG2 cells and shows anti-diabetic effect in diabetic KKAy mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Zhi-Qin [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Liu, Ting; Chen, Chuan [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China); Li, Ming-Yan; Wang, Zi-Yu; Chen, Ruo-song; Wei, Gui-xiang; Wang, Xiao-yi [College of Pharmaceutical Sciences, key laboratory of pharmaceutical quality control of Hebei province, Hebei University, Baoding 071002 (China); Luo, Du-Qiang, E-mail: duqiangluo999@126.com [College of Life Sciences, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002 (China)

    2015-05-15

    Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathways, and its increased activity and expression are implicated in the pathogenesis of insulin resistance. Therefore, the inhibition of PTP1B is anticipated to become a potential therapeutic strategy to treat T2DM. Fumosorinone (FU), a new natural product isolated from insect fungi Isaria fumosorosea, was found to inhibit PTP1B activity in our previous study. Herein, the effects of FU on insulin resistance and mechanism in vitro and in vivo were investigated. FU increased the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, and also reduced blood glucose and lipid levels of type 2 diabetic KKAy mice. FU decreased the expression of PTP1B both in insulin-resistant HepG2 cells and in liver tissues of diabetic KKAy mice. Furthermore, FU increased the phosphorylation of IRβ, IRS-2, Akt, GSK3β and Erk1/2 in insulin-resistant HepG2 cells, as well as the phosphorylation of IRβ, IRS-2, Akt in liver tissues of diabetic KKAy mice. These results showed that FU increased glucose uptake and improved insulin resistance by down-regulating the expression of PTP1B and activating the insulin signaling pathway, suggesting that it may possess antidiabetic properties. - Highlights: • Fumosorinone is a new PTP1B inhibitor isolated from insect pathogenic fungi. • Fumosorinone attenuated the insulin resistance both in vitro and in vivo. • Fumosorinone decreased the expression of PTP1B both in vitro and in vivo. • Fumosorinone activated the insulin signaling pathway both in vitro and in vivo.

  12. A compact rotary vane attenuator

    Science.gov (United States)

    Nixon, D. L.; Otosh, T. Y.; Stelzried, C. T.

    1969-01-01

    Rotary vane attenuator, when used as a front end attenuator, introduces an insertion loss that is proportional to the angle of rotation. New technique allows the construction of a shortened compact unit suitable for most installations.

  13. Photon attenuation by intensifying screens

    International Nuclear Information System (INIS)

    The photon attenuation by intensifying screens of different chemical composition has been determined. The attenuation of photons between 20 keV and 120 keV was measured by use of a multi-channel analyzer and a broad bremsstrahlung distribution. The attenuation by the intensifying screens was hereby determined simultaneously at many different monoenergetic photon energies. Experimentally determined attenuations were found to agree well with attenuation calculated from mass attenuation coefficients. The attenuation by the screens was also determined at various bremsstrahlung distributions, simulating those occurring behind the patient in various diagnostic X-ray examinations. The high attenuation in some of the intensifying screens form the basis for an analysis of the construction of asymmetric screen pairs. Single screen systems are suggested as a favourable alternative to thick screen pair systems. (Author)

  14. In vitro cultivation of human fetal pancreatic ductal stem cells and their differentiation into insulin-producing cells

    Institute of Scientific and Technical Information of China (English)

    Zhong-Xiang Yao; Mao-Lin Qin; Jian-Jun Liu; Xing-Shu Chen; De-Shan Zhou

    2004-01-01

    AIM: To isolate, culture and identify the human fetal pancreatic ductal stem cells in vitro, and to observe the potency of these multipotential cells differentiation into insulin-producing cells.METHODS: The human fetal pancreas was digested by 1 g/L collagease type Ⅳ and then 2.5 g/L trypsin was used to isolate the pancreatic ducta stem cells, followed by culture in serum-free, glucose-free DMEM media with some additional chemical substrates in vitro (according to the different Stage). The cells were induced by glucose-free (control),5 mmol/L, 17.8 mmol/L and 25 mmol/L glucose, respectively.The cell types of differentiated cells were identified using immunocytochemical staining.RESULTS: The shape of human fetal pancreatic ductal stem cells culturedin vitro was firstly fusiform in the first 2 wk,and became monolayer and cobblestone pattern after another 3 to 4 wk. After induced and differentiated by the glucose of different concentrations for another 1 to 2 wk,the cells formed the pancreatic islet-like structures. The identification and potency of these cells were then identified by using the pancreatic ductal stem cell marker, cytokeratin-19 (CK-19), pancreatic β cell marker, insulin and pancreatic α cell marker, glucagons with immunocytochemical staining.At the end of the second week, 95.2% of the cells were positive for CK-19 immunoreactivity. Up to 22.7% of the cells induced by glucose were positive for insulin immunoreactivity, and less than 3.8% of the cells were positive for glucagon immunoreactivity in pancreatic isletlike structures. The positive ratio of immunoreactive staining was dependent on the concentration of glucose, and it was observed that the 17.8 mmol/L glucose stimulated effectively to produce insulin- and glucagons-producing cells.CONCLUSION: The human fetal pancreatic ductal stem cells are capable of proliferation in vitro. These cells have multidifferentiation potential and can be induced by glucose and differentiated into insulin

  15. Interference with Akt signaling pathway contributes curcumin-induced adipocyte insulin resistance.

    Science.gov (United States)

    Zhang, Deling; Zhang, Yemin; Ye, Mao; Ding, Youming; Tang, Zhao; Li, Mingxin; Zhou, Yu; Wang, Changhua

    2016-07-01

    Previous study has shown that curcumin directly or indirectly suppresses insulin signaling in 3T3-L1 adipocytes. However, the underlying mechanism remains unclear. Here we experimentally demonstrate that curcumin inhibited the ubiquitin-proteasome system (UPS) function, activated autophagy, and reduced protein levels of protein kinase B (Akt) in a dose- and time-dependent manner in 3T3-L1 adipocytes, accompanied with attenuation of insulin-stimulated Akt phosphorylation, plasma membrane translocation of glucose transporter type 4 (GLUT4), and glucose uptake. These in vitro inhibitory effects of curcumin on Akt protein expression and insulin action were reversed by pharmacological and genetic inhibition of autophagy but not by inhibition of the UPS and caspases. In addition, Akt reduction in adipose tissues of mice treated with curcumin could be recovered by administration of autophagy inhibitor bafilomycin A1 (BFA). This new finding provides a novel mechanism by which curcumin induces insulin resistance in adipocytes. PMID:27113027

  16. Important role of heparan sulfate in postnatal islet growth and insulin secretion

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Iwao; Noguchi, Naoya [Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Nata, Koji [Department of Medical Biochemistry, Iwate Medical University School of Pharmacy, Yahaba-cho 028-3603 (Japan); Yamada, Shuhei; Kaneiwa, Tomoyuki; Mizumoto, Shuji [Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University Graduate School of Life Science, Sapporo 001-0021 (Japan); Ikeda, Takayuki [Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Sugihara, Kazushi; Asano, Masahide [Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640 (Japan); Yoshikawa, Takeo [Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Yamauchi, Akiyo [Department of Biochemistry, Nara Medical University, Kashihara 634-8521 (Japan); Shervani, Nausheen Jamal; Uruno, Akira [Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai 980-8575 (Japan); Kato, Ichiro [Department of Biochemistry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama 930-0194 (Japan); Unno, Michiaki [Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574 (Japan); Sugahara, Kazuyuki [Laboratory of Proteoglycan Signaling and Therapeutics, Hokkaido University Graduate School of Life Science, Sapporo 001-0021 (Japan); Takasawa, Shin [Department of Biochemistry, Nara Medical University, Kashihara 634-8521 (Japan); and others

    2009-05-22

    Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet {beta}-cells after 1 week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in {beta}-cells. These mice exhibited abnormal islet morphology with reduced {beta}-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion.

  17. Important role of heparan sulfate in postnatal islet growth and insulin secretion

    International Nuclear Information System (INIS)

    Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet β-cells after 1 week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in β-cells. These mice exhibited abnormal islet morphology with reduced β-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion.

  18. Human insulin prepared by recombinant DNA techniques and native human insulin interact identically with insulin receptors.

    OpenAIRE

    Keefer, L M; Piron, M A; DE MEYTS, P.

    1981-01-01

    Human insulin synthesized from A and B chains separately produced in Escherichia coli from cloned synthetic genes (prepared by the Eli Lilly Research Laboratories, Indianapolis, IN) was characterized by examining its interaction with human cultured lymphocytes, human circulating erythrocytes in vitro, and isolated rat fat cells. The binding behavior of the biosynthetic insulin with human cells was indistinguishable from that of native human or porcine insulins, with respect to affinity, assoc...

  19. SIRT2 regulates insulin sensitivity in insulin resistant neuronal cells.

    Science.gov (United States)

    Arora, Amita; Dey, Chinmoy Sankar

    2016-06-10

    Insulin resistance in brain is well-associated with pathophysiology of deficits in whole-body energy metabolism, neurodegenerative diseases etc. Among the seven sirtuins, SIRT2 is the major deacetylase expressed in brain. Inhibition of SIRT2 confers neuroprotection in case of Parkinson's disease (PD) and Huntington's disease (HD). However, the role of this sirtuin in neuronal insulin resistance is not known. In this study, we report the role of SIRT2 in regulating insulin-sensitivity in neuronal cells in vitro. Using approaches like pharmacological inhibition of SIRT2, siRNA mediated SIRT2 knockdown and over-expression of wild-type and catalytically-mutated SIRT2, we observed that downregulation of SIRT2 ameliorated the reduced activity of AKT and increased insulin-stimulated glucose uptake in insulin resistant neuro-2a cells. The data was supported by over expression of catalytically-inactive SIRT2 in insulin-resistant human SH-SY5Y neuronal cells. Data highlights a crucial role of SIRT2 in regulation of neuronal insulin sensitivity under insulin resistant condition. PMID:27163642

  20. Improved insulin sensitivity after exercise: focus on insulin signaling

    DEFF Research Database (Denmark)

    Frøsig, Christian; Richter, Erik

    2009-01-01

    After a single bout of exercise, the ability of insulin to stimulate glucose uptake is markedly improved locally in the previously active muscles. This makes exercise a potent stimulus counteracting insulin resistance characterizing type 2 diabetes (T2D). It is believed that at least part of the ...

  1. Monoclonal antibodies to the human insulin receptor block insulin binding and inhibit insulin action.

    OpenAIRE

    Roth, R A; Cassell, D J; Wong, K. Y.; Maddux, B A; Goldfine, I D

    1982-01-01

    Antibodies to the insulin receptor were prepared in BALB/c mice by immunization with IM-9 human lymphocytes, a cell type that has a large number of plasma membrane insulin receptors. The spleens of these mice were then removed, and their lymphocytes were fused to a mouse myeloma cell line, FO cells. After screening over 1,200 resulting hybrids, one stable hybrid was obtained that produced IgG1 antibodies directed towards the insulin receptor. This antibody blocked 125I-labeled insulin binding...

  2. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Dhindsa G

    2004-04-01

    Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

  3. [Medication of the month. Insulin glargine (Lantus)].

    Science.gov (United States)

    Scheen, A J

    2004-02-01

    Insulin glargine (Lantus) is a human insulin analogue produced by recombinant DNA technology and recently launched by Aventis. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue (pH > 7,4) from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant over 24 hours as compared to conventional human insulins, especially NPH. This allows once-daily injection as basal insulin therapy, at any moment of the clock time (but if possible at the same time from day to day). Reproducibility of plasma insulin levels is also improved with insulin glargine as compared to human NPH insulin. Insulin glargine administration should be combined to rapid insulin injections, before each meal in order to control postprandial hyperglycaemia, or with oral antidiabetic agents in type 2 diabetes. The pharmacokinetic properties of insulin glargine allow an easier titration of basal insulin dose, which should facilitate adequate blood glucose control while decreasing the risk of hypoglycaemia, especially during night time. Insulin glargine use is safe with no increased antigenicity, immunogenicity or mitogenicity reactions as compared to human insulin. Optimal use of this new insulin analogue should be integrated in a global management of the diabetic patient as well as in a new culture of insulin therapy. PMID:15112902

  4. Downhole pressure attenuation apparatus

    International Nuclear Information System (INIS)

    This patent describes a process for preventing damage to tool strings and other downhole equipment in a well caused by pressures produced during detonation of one or more downhole explosive devices. It comprises adding to a tool string at least one pressure attenuating apparatus for attenuating the peak pressure wave and quasi-static pressure pulse produced by the explosive devices, the pressure attenuating apparatus including an initially closed relief vent including tubing means supporting a plurality of charge port assemblies each including an explosive filled shaped charge and a prestressed disc, the shaped charges interconnected by a detonating cord, the amount of explosive in each shaped charge being sufficient to rupture its associated disc without damaging surrounding tubular bodies in the well, and a vent chamber defined by the tubing means and providing a liquid free volume, and opening the relief vent substantially contemporaneously with downhole explosive device detonation by detonating the shaped charges to rupture the discs of the charge port assemblies

  5. Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice

    Science.gov (United States)

    Weisberg, S; Leibel, R; Tortoriello, D V

    2016-01-01

    Background: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). Results: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. Conclusions: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance. PMID:27110686

  6. Control algorithms for dynamic attenuators

    Energy Technology Data Exchange (ETDEWEB)

    Hsieh, Scott S., E-mail: sshsieh@stanford.edu [Department of Radiology, Stanford University, Stanford, California 94305 and Department of Electrical Engineering, Stanford University, Stanford, California 94305 (United States); Pelc, Norbert J. [Department of Radiology, Stanford University, Stanford California 94305 and Department of Bioengineering, Stanford University, Stanford, California 94305 (United States)

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  7. Flexible graphene based microwave attenuators.

    Science.gov (United States)

    Byun, Kisik; Ju Park, Yong; Ahn, Jong-Hyun; Min, Byung-Wook

    2015-02-01

    We demonstrate flexible 3 dB and 6 dB microwave attenuators using multilayer graphene grown by the chemical vapor deposition method. On the basis of the characterized results of multilayer graphene and graphene-Au ohmic contacts, the graphene attenuators are designed and measured. The flexible graphene-based attenuators have 3 dB and 6 dB attenuation with a return loss of less than -15 dB at higher than 5 GHz. The devices have shown durability in a bending cycling test of 100 times. The circuit model of the attenuator based on the characterized results matches the experimental results well. PMID:25590144

  8. Flexible graphene based microwave attenuators

    International Nuclear Information System (INIS)

    We demonstrate flexible 3 dB and 6 dB microwave attenuators using multilayer graphene grown by the chemical vapor deposition method. On the basis of the characterized results of multilayer graphene and graphene–Au ohmic contacts, the graphene attenuators are designed and measured. The flexible graphene-based attenuators have 3 dB and 6 dB attenuation with a return loss of less than −15 dB at higher than 5 GHz. The devices have shown durability in a bending cycling test of 100 times. The circuit model of the attenuator based on the characterized results matches the experimental results well. (paper)

  9. Additional disulfide bonds in insulin

    DEFF Research Database (Denmark)

    Vinther, Tine N; Pettersson, Ingrid; Huus, Kasper;

    2015-01-01

    -chain is flexible and can adapt multiple conformations. We examined how well disulfide bond predictions algorithms could identify disulfide bonds in this region of insulin. In order to identify stable insulin analogues with additional disulfide bonds, which could be expressed, the Cβ cut-off distance had...... higher yields in comparison to analogues with additional disulfide bonds that were more difficult to predict. In contrast, addition of the fourth disulfide bond rendered all analogues resistant to fibrillation under stress conditions and all stable analogues bound to the insulin receptor with picomolar...... predicts four additional four disulfide insulin analogues which could be expressed. Although the location of the additional disulfide bonds is only slightly shifted, this shift impacts both stability and activity of the resulting insulin analogues....

  10. Cardiovascular effects of basal insulins

    Directory of Open Access Journals (Sweden)

    Mannucci E

    2015-07-01

    Full Text Available Edoardo Mannucci,1 Stefano Giannini,2 Ilaria Dicembrini1 1Diabetes Agency, Careggi Teaching Hospital, Florence, 2Section of Endocrinology, Department of Biomedical Clinical and Experimental Sciences, University of Florence and Careggi University Hospital, Florence, Italy Abstract: Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane and basal insulin analogs (glargine, detemir, and the more recent degludec differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with

  11. Studies on insulin receptor, 2

    International Nuclear Information System (INIS)

    The present study is to investigate an influence of starvation and high fat diet on insulin receptor of the plasma membrane by means of radioreceptor assay using 125I-labelled insulin. Male guinea pigs of Hartley strain were employed for the starvation study, and 125I-insulin binding capacity on the plasma membrane of the liver and kidney was determined at 24, 48 and 72 hours of the fast after the last meal. Male rats of Wistar strain were employed for the high fat study where the diet containing 35% of butter was fed ad libitum for 38 or 68 days. The animals were killed at the fast of 12 hours, and 125I-insulin binding capacity on the plasma membrane of the liver was determined. The results obtained are summarized as follows: 1) An increase in 125I-insulin binding capacity on the plasma membrane of the liver and kidney was observed by the starvation for 24 to 72 hours. 2) The mechanism of the increase by starvation was considered to be different by the organs; it was due to an increase in number of insulin receptor in the liver, and due to an increase in affinity of insulin receptor in the kidney. 3) In non-obese rats fed with high fat diet, the number of insulin receptor on the liver plasma membrane showed a decrease, and this observation clearly indicated that the decrease in number of the receptor did not depend on the obesity. 4) Obese rats also fed with high fat diet presented a decrease in number of insulin receptor without an elevation of insulin levels in the circulating blood. This indicated that at least in the obese rats fed with high fat diet, the decrease in number of the receptor was not due to hyperinsulinemia. (author)

  12. The Role of Insulin, Insulin Growth Factor, and Insulin-Degrading Enzyme in Brain Aging and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Claude Messier

    2005-01-01

    Full Text Available Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor-based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity-related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in aging and in some animal models of type 2 diabetes; brain insulin resistance may be present as well. Studies examining the effect of the hyperinsulinic clamp or intranasal insulin on cognitive function have found a small but consistent improvement in memory and changes in brain neuroelectric parameters in evoked brain potentials consistent with improved attention or memory processing. These effects appear to be due to raised brain insulin levels. Peripheral levels of Insulin Growth Factor-I (IGF-I are associated with glucose regulation and influence glucose disposal. There is some indication that reduced sensitivity to insulin or IGF-I in the brain, as observed in aging, obesity, and diabetes, decreases the clearance of Aβ amyloid. Such a decrease involves the insulin receptor cascade and can also increase amyloid toxicity. Insulin and IGF-I may modulate brain levels of insulin degrading enzyme, which would also lead to an accumulation of Aβ amyloid.

  13. 21 CFR 522.1160 - Insulin.

    Science.gov (United States)

    2010-04-01

    ...) of insulin. (2) Each mL of protamine zinc recombinant human insulin suspension contains 40 IU of... control has been attained. (B) Protamine zinc recombinant human insulin. Administer an initial dose of 0.1... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Insulin. 522.1160 Section 522.1160 Food and...

  14. Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics.

    OpenAIRE

    Gray, R S; Cowan, P.; Di Mario, U.; Elton, R A; Clarke, B F; Duncan, L J

    1985-01-01

    Sixteen insulin dependent diabetics of long standing, with undetectable fasting plasma C peptide concentrations, and eight non-diabetic controls were each infused intravenously with biosynthetic human and highly purified beef insulin (1 mU/kg/min) while euglycaemia was maintained by a Biostator. No difference was observed between the two insulins in respect of insulin pharmacokinetics or biological action. The diabetics showed appreciable insulin resistance, manifested by a 40% reduction in t...

  15. Alternative routes of insulin delivery

    Institute of Scientific and Technical Information of China (English)

    Ranjith K. Krishnankutty; Aju Mathew; Saikiran K. Sedimbi; Shrikumar Suryanarayan; Carani B. Sanjeevi

    2009-01-01

    Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications. Patient compliance has really been a major concern for this route of administration. Several alternative routes of administration are under consideration for effective glycemic control, including oral, inhaled, buccal, nasal, and patch routes. One of the approaches involving inhaled insulin has now reached the market. Several other candidates may reach the market in the near future, the promising one being oral insulin.

  16. Cutaneous allergy to human (recombinant DNA) insulin.

    Science.gov (United States)

    Grammer, L C; Metzger, B E; Patterson, R

    1984-03-16

    p6 report two cases of cutaneous allergy to human (recombinant DNA) insulin. Each patient had a history of systemic allergic reactions to porcine insulin and was at least as reactive to human as to porcine insulin by end-point cutaneous titration. Both patients' insulin allergy was managed with animal insulins and both have done well. Our experience with these two patients indicates that human insulin (rDNA) should not be expected to be efficacious in all patients with systemic allergy to insulin. PMID:6366262

  17. Prevention of beta cell dysfunction and apoptosis by adenoviral gene transfer of rat insulin-like growth factor 1

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhi-hong; LI Tang; CHEN Zong-bo; LUO Bing; SUN Ruo-peng

    2009-01-01

    Background Islet β-cells are almost completely destroyed when patients with type 1 diabete are diagnosed. To date, insulin substitute therapy is still one of the main treatments. The cure of type 1 diabetes requires β-cell regeneration from islet cell precursors and prevention of recurring autoimmunity, Therefore, β-cell regeneration and proliferation emerge as a new research focus on therapy for type 1 diabetes. Islet β-cell regeneration and development are controlled by many growth factors, especially insulin-like growth factor-1 (IGF-1).Methods Recombinant adenovirus encoding rat IGF-1 (rlGF-1) was constructed and transduced into rat β-cells, RINm5F cells. Western blotting analysis and ELISA were used to detect rlGF-1 protein. Streptozotocin (STZ) was used to induce RINm5F cell destruction. The level of nitric oxide (NO) was detected in cell culture supernatants by the Griess reaction. Islet cell function was evaluated by glucose-stimulated insulin production. Flow cytometry analysis was further used to investigate the apoptosis of RINm5F cells. Thiaoollyl blue viability assay was applied to determine cell viability.Results The recombined adenovirus-rlGF-1 was successfully constructed and the titer was 4.0×108pfu/ml. The rlGF-1 protein was effectively expressed in the RINm5F cells and cell culture supernatants, rlGF-1 expression remarkably inhibited STZ-induced islet cell apoptosis and significantly decreased the level of NO. Furthermore, IGF-1 expression also significantly protected insulin secretion and cell proliferation in a time-dependent manner.Conclusions Our study suggests that locally produced rlGF-1 from RINm5F cells may be beneficial in maintaining β-cell function, protecting β-cells from the destruction of apoptosis factors and promoting β-cell survival and proliferation. IGF-1 might be considered as a candidate gene in gene therapy for type 1 diabetes. In addition, it appears that the apoptosis induced by STZ may be NO-dependent.

  18. New ways of insulin delivery.

    Science.gov (United States)

    Heinemann, L

    2010-02-01

    When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can

  19. Control of Insulin Secretion by Production of Reactive Oxygen Species: Study Performed in Pancreatic Islets from Fed and 48-Hour Fasted Wistar Rats

    Science.gov (United States)

    Riva, Patrícia; Simões, Daniel; Curi, Rui; Carpinelli, Angelo Rafael

    2016-01-01

    Mitochondria and NADPH oxidase are important sources of reactive oxygen species in particular the superoxide radical (ROS) in pancreatic islets. These molecules derived from molecular oxygen are involved in pancreatic β-cells signaling and control of insulin secretion. We examined the involvement of ROS produced through NADPH oxidase in the leucine- and/or glucose-induced insulin secretion by pancreatic islets from fed or 48-hour fasted rats. Glucose-stimulated insulin secretion (GSIS) in isolated islets was evaluated at low (2.8 mM) or high (16.7 mM) glucose concentrations in the presence or absence of leucine (20 mM) and/or NADPH oxidase inhibitors (VAS2870–20 μM or diphenylene iodonium—DPI—5 μM). ROS production was determined in islets treated with dihydroethidium (DHE) or MitoSOX Red reagent for 20 min and dispersed for fluorescence measurement by flow cytometry. NADPH content variation was examined in INS-1E cells (an insulin secreting cell line) after incubation in the presence of glucose (2.8 or 16.7 mM) and leucine (20 mM). At 2.8 mM glucose, VAS2870 and DPI reduced net ROS production (by 30%) and increased GSIS (by 70%) in a negative correlation manner (r = -0.93). At 16.7 mM glucose or 20 mM leucine, both NADPH oxidase inhibitors did not alter insulin secretion neither net ROS production. Pentose phosphate pathway inhibition by treatment with DHEA (75 μM) at low glucose led to an increase in net ROS production in pancreatic islets from fed rats (by 40%) and induced a marked increase (by 144%) in islets from 48-hour fasted rats. The NADPH/NADP+ ratio was increased when INS-1E cells were exposed to high glucose (by 4.3-fold) or leucine (by 3-fold). In conclusion, increased ROS production through NADPH oxidase prevents the occurrence of hypoglycemia in fasting conditions, however, in the presence of high glucose or high leucine levels, the increased production of NADPH and the consequent enhancement of the activity of the antioxidant defenses

  20. Redox Regulation of Insulin Degradation by Insulin-Degrading Enzyme

    OpenAIRE

    Cordes, Crystal M.; Bennett, Robert G.; Siford, Gerri L.; Hamel, Frederick G.

    2011-01-01

    Insulin-degrading enzyme (IDE) is a thiol sensitive peptidase that degrades insulin and amyloid β, and has been linked to type 2 diabetes mellitus and Alzheimer's disease. We examined the thiol sensitivity of IDE using S-nitrosoglutathione, reduced glutathione, and oxidized glutathione to distinguish the effects of nitric oxide from that of the redox state. The in vitro activity of IDE was studied using either partially purified cytosolic enzyme from male Sprague-Dawley rats, or purified rat ...

  1. Inhaled insulin: overview of a novel route of insulin administration

    OpenAIRE

    Lucy D Mastrandrea

    2010-01-01

    Lucy D MastrandreaDepartment of Pediatrics, School of Medicine and Biochemical Sciences, University at Buffalo, Buffalo, NY, USAAbstract: Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular disease, both of which are affected by optimal diabetes control. Many individuals with diabetes rely on subcutaneous insulin administration by injection or continuous infusion to contro...

  2. Lipocalin-2 inhibits autophagy and induces insulin resistance in H9c2 cells.

    Science.gov (United States)

    Chan, Yee Kwan; Sung, Hye Kyoung; Jahng, James Won Suk; Kim, Grace Ha Eun; Han, Meng; Sweeney, Gary

    2016-07-15

    Lipocalin-2 (Lcn2; also known as neutrophil gelatinase associated lipocalin, NGAL) levels are increased in obesity and diabetes and associate with insulin resistance. Correlations exist between Lcn2 levels and various forms or stages of heart failure. Insulin resistance and autophagy both play well-established roles in cardiomyopathy. However, little is known about the impact of Lcn2 on insulin signaling in cardiomyocytes. In this study, we treated H9c2 cells with recombinant Lcn2 for 1 h followed by dose- and time-dependent insulin treatment and found that Lcn2 attenuated insulin signaling assessed via phosphorylation of Akt and p70S6K. We used multiple assays to demonstrate that Lcn2 reduced autophagic flux. First, Lcn2 reduced pULK1 S555, increased pULK1 S757 and reduced LC3-II levels determined by Western blotting. We validated the use of DQ-BSA to assess autolysosomal protein degradation and this together with MagicRed cathepsin B assay indicated that Lcn2 reduced lysosomal degradative activity. Furthermore, we generated H9c2 cells stably expressing tandem fluorescent RFP/GFP-LC3 and this approach verified that Lcn2 decreased autophagic flux. We also created an autophagy-deficient H9c2 cell model by overexpressing a dominant-negative Atg5 mutant and found that reduced autophagy levels also induced insulin resistance. Adding rapamycin after Lcn2 could stimulate autophagy and recover insulin sensitivity. In conclusion, our study indicated that acute Lcn2 treatment caused insulin resistance and use of gain and loss of function approaches elucidated a causative link between autophagy inhibition and regulation of insulin sensitivity by Lcn2. PMID:27090568

  3. Current european regulatory perspectives on insulin analogues

    OpenAIRE

    Enzmann Harald G; Weise Martina

    2011-01-01

    Abstract Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing aut...

  4. Insulin resistance and Alzheimer’s disease

    OpenAIRE

    de la Monte, Suzanne M.

    2009-01-01

    Emerging data demonstrate pivotal roles for brain insulin resistance and insulin deficiency as mediators of cognitive impairment and neurodegeneration, particularly Alzheimer’s disease (AD). Insulin and insulin-like growth factors (IGFs) regulate neuronal survival, energy metabolism, and plasticity, which are required for learning and memory. Hence, endogenous brain-specific impairments in insulin and IGF signaling account for the majority of AD-associated abnormalities. However, a second maj...

  5. Ultrasonic Attenuation in Zircaloy-4

    International Nuclear Information System (INIS)

    In this work the relationship between Zircaloy-4 grain size and ultrasonic attenuation behavior was studied for longitudinal waves in the frequency range of 10-90 MHz. The attenuation was analyzed as a function of frequency for samples with different mechanical and heat treatments having recrystallized and Widmanstatten structures with different grain size. The attenuation behavior was analyzed by different scattering models, depending on grain size, wavelength and frequency

  6. Chopping-Wheel Optical Attenuator

    Science.gov (United States)

    Leviton, Douglas B.

    1988-01-01

    Star-shaped rotating chopping wheel provides adjustable time-averaged attenuation of narrow beam of light without changing length of optical path or spectral distribution of light. Duty cycle or attenuation factor of chopped beam controlled by adjusting radius at which beam intersects wheel. Attenuation factor independent of wavelength. Useful in systems in which chopping frequency above frequency-response limits of photodetectors receiving chopped light. Used in systems using synchronous detection with lock-in amplifiers.

  7. Oligomannuronate-Chromium (Ⅲ) Complex Ameliorates Insulin Resistance in C57BL/KsJ-db/db Mice

    Institute of Scientific and Technical Information of China (English)

    HAO Cui; HAO Jiejie; WANG Wei; LI Guangsheng; ZENG Yangyang; WANG Peipei; ZHAO Xia; YU Guangli

    2011-01-01

    Diabetes mellitus is the most common metabolic disease and its prevalence is increasing in many countries year by year.More than 90% of diabetes patients are type 2 diabetes,which is caused by insulin resistance and beta-cell dysfunction.In this paper,the oligomannuronate-chromium (Ⅲ) complex (OM2) was prepared and its effect and mechanism on attenuating insulin resistance in diabetic C57BL/KsJ-db/db mice were studied.The results indicated that oral intake of OM2 (50mgkg1d-1) for 42d decreased blood glucose and lipid concentration,which was associated with the reduced serum insulin concentration and insulin resistance.According to western blot assay,OM2 could activate AMPK pathway to regulate glycogen synthesis,gluconeogenesis and lipid metabolism in the liver,and attenuate the hyperglycemic symptom in db/db mice.The effects of OM2 on attenuating insulin resistance were comparable to that of the established antidiabetic drug metformin,and OM2 showed less adverse effect than metformin in vivo.Based on the effectiveness and low toxicity,OM2 may potentially be used for prevention and treatment of type 2 diabetes mellitus.

  8. LINE-ABOVE-GROUND ATTENUATOR

    Science.gov (United States)

    Wilds, R.B.; Ames, J.R.

    1957-09-24

    The line-above-ground attenuator provides a continuously variable microwave attenuator for a coaxial line that is capable of high attenuation and low insertion loss. The device consists of a short section of the line-above- ground plane type transmission lime, a pair of identical rectangular slabs of lossy material like polytron, whose longitudinal axes are parallel to and indentically spaced away from either side of the line, and a geared mechanism to adjust amd maintain this spaced relationship. This device permits optimum fineness and accuracy of attenuator control which heretofore has been difficult to achieve.

  9. Insulin delivery methods: Past, present and future.

    Science.gov (United States)

    Shah, Rima B; Patel, Manhar; Maahs, David M; Shah, Viral N

    2016-01-01

    Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. PMID:27014614

  10. Cardiovascular effects of basal insulins.

    Science.gov (United States)

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  11. A retrospective database analysis of insulin use patterns in insulin-naïve patients with type 2 diabetes initiating basal insulin or mixtures

    OpenAIRE

    Bonafede, Machaon MK; Kalsekar, Anupama; Pawaskar, Manjiri; Ruiz, Kimberly M; Torres, Amelito M; Kelly, Karen R.; Curkendall, Suellen M

    2010-01-01

    Objective: To describe insulin persistence among patients with type 2 diabetes initiating insulin therapy with basal insulin or insulin mixtures and determine factors associated with nonpersistence. Research design and methods: The Thomson Reuters MarketScan® databases were used to retrospectively analyze insulin-naïve patients with type 2 diabetes by initiating insulin therapy. Insulin use was described using a variety of measures. The persistence to insulin was described using both a gap-ba...

  12. Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.

    OpenAIRE

    Nanjo, K; Sanke, T; Miyano, M; Okai, K.; Sowa, R; Kondo, M.; Nishimura, S; Iwo, K; Miyamura, K; Given, B D

    1986-01-01

    We have identified a non-insulin-dependent diabetic patient with fasting hyperinsulinemia (90 microU/ml), an elevated insulin:C-peptide molar ratio (1.68; normal, 0.05-0.20), normal insulin counterregulatory hormone levels, and an adequate response to exogenously administered insulin. Insulin-binding antibodies were absent from serum, erythrocyte insulin receptor binding was normal, and greater than 90% of circulating immunoreactive insulin coeluted with 125I-labeled insulin on gel filtration...

  13. Diabetes, insulin and cancer risk

    Directory of Open Access Journals (Sweden)

    Xi-Lin Yang

    2012-01-01

    Full Text Available There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown. On the other hand, there are ongoing debates about the risk association of insulin use with cancer. We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer, as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth. Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence, we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMP-activated protein kinase pathway due to reduced insulin action and insulin resistance, the insulin-like growth factor-1 (IGF-1-cholesterol synthesis pathway and renin-angiotensin system, presumably due to reduced insulin secretion and hyperglycemia, may play causal roles in the increased risk of cancer in diabetes. Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.

  14. Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells: relevant to the pathogenesis of diabetes.

    Directory of Open Access Journals (Sweden)

    Hung-Chih Hsu

    Full Text Available It has been postulated that folic acid (folate deficiency (FD may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet β cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-κB-dependent iNOS-mediated overproduction of nitric oxide (NO. The latter compound could then trigger depletion of endoplasmic reticulum (ER calcium (Ca(2+ store leading to cytosolic Ca(2+ overload and caused ER stress as evidence by the activation of CHOP expression. Furthermore, FD-induced apoptosis of RINm5F cells was found to be correlated with a time-dependent depletion of intracellular glutathione (GSH and a severe down-regulation of Bcl-2 expression. Along the same vein, we also demonstrated that FD could severely impede RINm5F cells to synthesize insulin and their abilities to secret insulin in response to glucose stimulation were appreciably hampered. Even more importantly, we found that folate replenishment could not restore the ability of RINm5F cells to resynthesize insulin. Taken together, our data provide strong evidence to support the hypothesis that FD is a legitimate risk factor for the pathogenesis of diabetes.

  15. Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Thorsby, P; Kjems, L;

    2000-01-01

    The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual...... that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients....

  16. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice

    OpenAIRE

    Wojtaszewski, Jørgen F. P.; Higaki, Yasuki; Hirshman, Michael F.; Michael, M. Dodson; Dufresne, Scott D.; Kahn, C. Ronald; Goodyear, Laurie J.

    1999-01-01

    Physical exercise promotes glucose uptake into skeletal muscle and makes the working muscles more sensitive to insulin. To understand the role of insulin receptor (IR) signaling in these responses, we studied the effects of exercise and insulin on skeletal muscle glucose metabolism and insulin signaling in mice lacking insulin receptors specifically in muscle. Muscle-specific insulin receptor knockout (MIRKO) mice had normal resting 2-deoxy-glucose (2DG) uptake in soleus muscles but had no si...

  17. Oral salmon calcitonin enhances insulin action and glucose metabolism in diet-induced obese streptozotocin-diabetic rats

    DEFF Research Database (Denmark)

    Feigh, Michael; Hjuler, Sara T; Andreassen, Kim V;

    2014-01-01

    study we hypothesized that oral sCT as pharmacological intervention 1) exerted anti-hyperglycemic efficacy, and 2) enhanced insulin action in DIO-streptozotocin (DIO-STZ) diabetic rats. Diabetic hyperglycemia was induced in male selectively bred DIO rats by a single low dose (30mg/kg) injection of STZ......We previously reported that oral delivery of salmon calcitonin (sCT) improved energy and glucose homeostasis and attenuated diabetic progression in animal models of diet-induced obesity (DIO) and type 2 diabetes, although the glucoregulatory mode of action was not fully elucidated. In the present...... food intake and attenuated weight loss, albeit sustained glycemic control by reducing fasting blood glucose and HbA1c levels compared to those of vehicle-treated rats at the end of study. Notably, plasma levels of insulin, glucagon, leptin and adiponectin were unaltered, albeit insulin action was...

  18. Fiber optic attenuator

    Science.gov (United States)

    Buzzetti, Mike F. (Inventor)

    1994-01-01

    A fiber optic attenuator of the invention is a mandrel structure through which a bundle of optical fibers is wrapped around in a complete circle. The mandrel structure includes a flexible cylindrical sheath through which the bundle passes. A set screw on the mandrel structure impacts one side of the sheath against two posts on the opposite side of the sheath. By rotating the screw, the sheath is deformed to extend partially between the two posts, bending the fiber optic bundle to a small radius controlled by rotating the set screw. Bending the fiber optic bundle to a small radius causes light in each optical fiber to be lost in the cladding, the amount depending upon the radius about which the bundle is bent.

  19. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects.

    Science.gov (United States)

    Andreasen, Anne Sofie; Larsen, Nadja; Pedersen-Skovsgaard, Theis; Berg, Ronan M G; Møller, Kirsten; Svendsen, Kira Dynnes; Jakobsen, Mogens; Pedersen, Bente Klarlund

    2010-12-01

    According to animal studies, intake of probiotic bacteria may improve glucose homeostasis. We hypothesised that probiotic bacteria improve insulin sensitivity by attenuating systemic inflammation. Therefore, the effects of oral supplementation with the probiotic bacterium Lactobacillus acidophilus NCFM on insulin sensitivity and the inflammatory response were investigated in subjects with normal or impaired insulin sensitivity. In a double-blinded, randomised fashion, forty-five males with type 2 diabetes, impaired or normal glucose tolerance were enrolled and allocated to a 4-week treatment course with either L. acidophilus NCFM or placebo. L. acidophilus was detected in stool samples by denaturating gradient gel electrophoresis and real-time PCR. Separated by the 4-week intervention period, two hyperinsulinaemic-euglycaemic clamps were performed to estimate insulin sensitivity. Furthermore, the systemic inflammatory response was evaluated by subjecting the participants to Escherichia coli lipopolysaccharide injection (0·3 ng/kg) before and after the treatment course. L. acidophilus NCFM was detected in 75 % of the faecal samples after treatment with the probiotic bacterium. Insulin sensitivity was preserved among volunteers in the L. acidophilus NCFM group, whereas it decreased in the placebo group. Both baseline inflammatory markers and the systemic inflammatory response were, however, unaffected by the intervention. In conclusion, intake of L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo, but did not affect the systemic inflammatory response. PMID:20815975

  20. The regulation of body fat distribution and the modulation of insulin action.

    Science.gov (United States)

    Cases, J A; Barzilai, N

    2000-11-01

    Body fat distribution may determine insulin resistance and its metabolic syndrome in humans, independent of obesity. Surgical removal of visceral fat (VF) in obese rats was associated with decreased leptin plasma levels and its gene expression in subcutaneous fat (SC). Chronic leptin treatment to rats decreased VF specifically supporting the role of leptin in determining fat distribution. Surgical removal of selected VF provided direct evidence of improved in vivo insulin action on hepatic glucose production (HGP) by over 2-fold vs sham-operated control. The impact of decreased VF on improved in vivo insulin action was further supported by obtaining similar decreases in VF by treating rats with leptin (Lep), beta3-aderenoreceptor agonist, or by severe caloric restriction (CR). All these three interventions improved insulin action on the modulation of HGP and were mostly attributed to preservation of hepatic glycogen stores. Because free fatty acids (FFA) plasma levels were unchanged, this effect may not be mediated portally by substrates. Improved peripheral insulin sensitivity and glycogen synthesis was demonstrated only in Lep. These data suggest that VF is a major determinant of hepatic insulin action. In obese rats, the ability of leptin to prevent visceral adiposity and its own expression is attenuated. Thus, the failure of leptin to regulate fat distribution and its own secretion suggest that 'leptin resistance' may be a pathologic feature in obesity. PMID:11126245

  1. Celastrol Protects against Antimycin A-Induced Insulin Resistance in Human Skeletal Muscle Cells

    Directory of Open Access Journals (Sweden)

    Mohamad Hafizi Abu Bakar

    2015-05-01

    Full Text Available Mitochondrial dysfunction and inflammation are widely accepted as key hallmarks of obesity-induced skeletal muscle insulin resistance. The aim of the present study was to evaluate the functional roles of an anti-inflammatory compound, celastrol, in mitochondrial dysfunction and insulin resistance induced by antimycin A (AMA in human skeletal muscle cells. We found that celastrol treatment improved insulin-stimulated glucose uptake activity of AMA-treated cells, apparently via PI3K/Akt pathways, with significant enhancement of mitochondrial activities. Furthermore, celastrol prevented increased levels of cellular oxidative damage where the production of several pro-inflammatory cytokines in cultures cells was greatly reduced. Celastrol significantly increased protein phosphorylation of insulin signaling cascades with amplified expression of AMPK protein and attenuated NF-κB and PKC θ activation in human skeletal muscle treated with AMA. The improvement of insulin signaling pathways by celastrol was also accompanied by augmented GLUT4 protein expression. Taken together, these results suggest that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction-induced insulin resistance in human skeletal muscle cells.

  2. Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Yoshinori Watanabe

    Full Text Available Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2 inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity.Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF rats.In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity.Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

  3. Characterization of polyhormonal insulin-producing cells derived in vitro from human embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Jennifer E. Bruin

    2014-01-01

    lack of GLUT1, may explain the absence of glucose-stimulated insulin secretion.

  4. Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin-resistant humans.

    OpenAIRE

    Kida, Y; Nyomba, B L; Bogardus, C; Mott, D M

    1991-01-01

    Insulin-stimulated glycogen synthase activity in human muscle correlates with insulin-mediated glucose disposal and is reduced in insulin-resistant subjects. Inhibition of the cyclic AMP-dependent protein kinase (A-kinase) is considered as a possible mechanism of insulin action for glycogen synthase activation. In this study, we investigated the time course of insulin action on human muscle A-kinase activity during a 2-h insulin infusion in 13 insulin-sensitive (group S) and 7 insulin-resista...

  5. Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization

    DEFF Research Database (Denmark)

    Vinther, Tine N.; Norrman, Mathias; Strauss, Holger M.;

    2012-01-01

    An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers in...... oligomerization and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further...

  6. Human insulin and porcine insulin in the treatment of diabetic children: comparison of metabolic control and insulin antibody production.

    OpenAIRE

    Mann, N P; Johnston, D I; Reeves, W G; Murphy, M A

    1983-01-01

    Semisynthetic human insulin and highly purified porcine insulin were compared in a double blind crossover study in 21 diabetic children. Glycosylated haemoglobin values at the end of four month treatment periods were higher after treatment with human insulin than after treatment with porcine insulin (mean 15.7% (SD 2.3%) v 14.2% (2.3%); p less than 0.01). Higher fasting blood glucose concentrations occurred during treatment with human insulin than with porcine insulin (mean 12.0 (SD 2.1) v 11...

  7. Protein engineering of insulin: Two novel fast-acting insulins [B16Ala]insulin and [B26Ala]insulin

    Institute of Scientific and Technical Information of China (English)

    ZHANG; Zhou; (张舟); TANG; Yuehua; (唐月华); YAO; Shiyin; (姚矢音); ZHU; Shangquan; (朱尚权); FENG; Youmin; (冯佑民)

    2003-01-01

    Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fast- acting insulin. Single-chain precursor of [B16Ala]insulin and [B26Ala]insulin is [B16Ala]PIP and [B26Ala]PIP, respectively, which are suitable for gene expression. Secretory expression level of the precursors in methylotrophic yeast Pichia pastoris was quite high, 650 mg/L and 130 mg/L, respectively. In vivo biological assay showed that the two fast-acting insulins have full or nearly full biological activity. So both [B16Ala]insulin and [B26Ala]insulin can be well developed as fast-acting insulin for clinic use.

  8. Treatment of insulin resistance in uremia.

    Science.gov (United States)

    Stefanović, V; Nesić, V; Stojimirović, B

    2003-02-01

    Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms. PMID:12653342

  9. Human insulin: DNA technology's first drug.

    Science.gov (United States)

    The, M J

    1989-11-01

    The history, biologic activity, and immunogenicity of human insulin are described. Recombinant human insulin first entered clinical trials in humans in 1980. At that time, the A and B chains of the insulin molecule were produced separately and then combined by chemical techniques. Since 1986, a different recombinant process has been used. The human genetic coding for proinsulin is inserted into Escherichia coli cells, which are then grown by fermentation to produce proinsulin. The connecting peptide is cleaved enzymatically from proinsulin to produce human insulin. Studies indicate that there are no important differences between pork insulin and human insulin in terms of therapeutic efficacy and disposition after intravenous administration. Recombinant human insulin has a faster onset of action and lower immunogenicity than pork or beef insulin. Diabetic patients may have an improvement in glucose concentrations when their therapy is switched from animal-source insulin to human insulin. Such a change usually requires a dosage adjustment, which must be determined by a physician. Pharmacists are responsible for educating patients concerning all insulin products and for preventing patients from interchanging insulin products. The availability of human insulin as the first pharmaceutical product manufactured through recombinant DNA technology, however, has had little effect on the pharmacist's role in the care of such patients. The production of human insulin through recombinant DNA technology represents an important advance in the treatment of patients with diabetes. PMID:2690608

  10. Adjustable Optical-Fiber Attenuator

    Science.gov (United States)

    Buzzetti, Mike F.

    1994-01-01

    Adjustable fiber-optic attenuator utilizes bending loss to reduce strength of light transmitted along it. Attenuator functions without introducing measurable back-reflection or insertion loss. Relatively insensitive to vibration and changes in temperature. Potential applications include cable television, telephone networks, other signal-distribution networks, and laboratory instrumentation.

  11. Beef Fat Enriched with Polyunsaturated Fatty Acid Biohydrogenation Products Improves Insulin Sensitivity Without Altering Dyslipidemia in Insulin Resistant JCR:LA-cp Rats.

    Science.gov (United States)

    Diane, Abdoulaye; Borthwick, Faye; Mapiye, Cletos; Vahmani, Payam; David, Rolland C; Vine, Donna F; Dugan, Michael E R; Proctor, Spencer D

    2016-07-01

    The main dietary sources of trans fatty acids are partially hydrogenated vegetable oils (PHVO), and products derived from polyunsaturated fatty acid biohydrogenation (PUFA-BHP) in ruminants. Trans fatty acid intake has historically been associated with negative effects on health, generating an anti-trans fat campaign to reduce their consumption. The profiles and effects on health of PHVO and PUFA-BHP can, however, be quite different. Dairy products naturally enriched with vaccenic and rumenic acids have many purported health benefits, but the putative benefits of beef fat naturally enriched with PUFA-BHP have not been investigated. The objective of the present experiment was to determine the effects of beef peri-renal fat (PRF) with differing enrichments of PUFA-BHP on lipid and insulin metabolism in a rodent model of dyslipidemia and insulin resistance (JCR:LA-cp rat). The results showed that 6 weeks of diet supplementation with beef PRF naturally enriched due to flaxseed (FS-PRF) or sunflower-seed (SS-PRF) feeding to cattle significantly improved plasma fasting insulin levels and insulin sensitivity, postprandial insulin levels (only in the FS-PRF) without altering dyslipidemia. Moreover, FS-PRF but not SS-PRF attenuated adipose tissue accumulation. Therefore, enhancing levels of PUFA-BHP in beef PRF with FS feeding may be a useful approach to maximize the health-conferring value of beef-derived fats. PMID:27072368

  12. Grape pomace and grape pomace extract improve insulin signaling in high-fat-fructose fed rat-induced metabolic syndrome.

    Science.gov (United States)

    Rodriguez Lanzi, Cecilia; Perdicaro, Diahann Jeanette; Antoniolli, Andrea; Fontana, Ariel Ramón; Miatello, Roberto Miguel; Bottini, Rubén; Vazquez Prieto, Marcela Alejandra

    2016-03-01

    In this study the effect of diet supplementation with grape pomace (GP) and grape pomace extract (GPE) on insulin sensitive tissues (adipose, liver and muscle) was evaluated in an experimental model of metabolic syndrome (MetS). MetS was developed by giving a high-fat-fructose (HFF) diet to Wistar rats. Six weeks of HFF diet induced weight gain, which was partially attenuated by GP (1 g per kg per day) and GPE (300 mg per kg per day) supplementation. HFF diet increased systolic blood pressure, triglycerides, insulin resistance (HOMA:IR) and inflammation (c-reactive protein (CRP)). Supplementation with GP prevented SBP, triglycerides and CRP increased and partially attenuated insulin resistance. On the other hand, GPE partially reduced SBP and triglycerides and significantly prevented insulin resistance and inflammation. Also, HFF diet induced higher triglycerides content and enhanced NADPH oxidase activity in the liver. Also, HFF diet increased the epididymal adipose tissue weight, enlarged adipocyte size, and c-jun N-terminal kinase (JNK) activation, probably contributing to a pro-inflammatory cytokine pattern (higher resistin) and lower adiponectin protein expression. These alterations may result in an impairment of insulin signaling cascade observed in adipose, liver and muscle tissue (IRS1, Akt, and extracellular signal-regulated kinases (ERK1/2)) from HFF rats. Supplementation with GP and to a greater extent GPE attenuated liver triglyceride content and adiposity and restored adipose, liver and muscle response to insulin. These findings show that supplementation with GP and GPE to a greater extent can counteract adiposity, inflammation, liver damage and impaired insulin signaling associated to MetS, supporting the utilization of winemaking residues in food industry/human health due to their high amount of bioactive compounds. PMID:26901521

  13. Insulin secretion: mechanisms of regulation

    Directory of Open Access Journals (Sweden)

    Radosavljević Tatjana

    2004-01-01

    Full Text Available Regulation of insulin secretion Beta cells are unique endocrine cells. They respond positively, in terms of insulin secretion, not only to changes in the extracellular glucose concentration, but also to activators of the phospholipase C (cholecystokinin or acetylcholine, and to activators of adenylate cyclase (glucagon, glucagon-like peptide-1, or gastric inhibitory polypeptide. Major messengers which mediate glucose action for insulin release are Ca2%, adenosine triphosphate (ATP and diacylglycerol (DAG. Major pathways of insulin release stimulation There are four major pathways involved in stimulation of insulin release. The first pathway is KATP channel-dependent pathway in which increased blood glucose concentrations and increased b-cell metabolism result in a change in intracellular ATP/ADP ratio. This is a contributory factor in closure of ATP-dependent K% channels, depolarization of b-cell membrane, in increased voltage-dependent L-type Ca2%channel activity. Increased Ca2% influx results in increased intracellular Ca2% and stimulated insulin release. KATP channel-independent pathway augments Ca2%-stimulated insulun secretion of KATP channel-dependent pathway. Major potentiation of release results from hormonal and peptidergic activation of receptors linked to adenylyl cyclase. Adenylyl cyclase activity is stimulated by hormones such as vasoactive intestinal peptide (VIP, glucagon-like peptide-1 (GLP-1, and so on. These hormones, acting via G protein, stimulate adenylyl cyclase, thus causing a rise in cyclic adenosine monophosphate (cAMP and activation of protein kinase A (PKA. Increased activity of PKA results in potentiation of insulin secretion.

  14. Regulation of recombinant human insulin-induced maturational events in Clarias batrachus (L.) oocytes in vitro.

    Science.gov (United States)

    Hajra, Sudip; Das, Debabrata; Ghosh, Pritha; Pal, Soumojit; Nath, Poulomi; Maitra, Sudipta

    2016-04-01

    Regulation of insulin-mediated resumption of meiotic maturation in catfish oocytes was investigated. Insulin stimulation of post-vitellogenic oocytes promotes the synthesis of cyclin B, histone H1 kinase activation and a germinal vesicle breakdown (GVBD) response in a dose-dependent and duration-dependent manner. The PI3K inhibitor wortmannin abrogates recombinant human (rh)-insulin action on histone H1 kinase activation and meiotic G2-M1 transition in denuded and follicle-enclosed oocytes in vitro. While the translational inhibitor cycloheximide attenuates rh-insulin action, priming with transcriptional blocker actinomycin D prevents insulin-stimulated maturational response appreciably, albeit in low amounts. Compared with rh-insulin, human chorionic gonadotrophin (hCG) stimulation of follicle-enclosed oocytes in vitro triggers a sharp increase in 17α,20β-dihydroxy-4-pregnen-3-one (17α,20β-DHP) secreted in the incubation medium at 12 h. Interestingly, the insulin, but not the hCG-induced, maturational response shows less susceptibility to steroidogenesis inhibitors, trilostane or dl-aminoglutethimide. In addition, priming with phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) or cell-permeable dbcAMP or adenylyl cyclase activator forskolin reverses the action of insulin on meiotic G2-M1 transition. Conversely, the adenylyl cyclase inhibitor, SQ 22536, or PKA inhibitor H89 promotes the resumption of meiosis alone and further potentiates the GVBD response in the presence of rh-insulin. Furthermore, insulin-mediated meiotic maturation involves the down-regulation of endogenous protein kinase A (PKA) activity in a manner sensitive to PI3K activation, suggesting potential involvement of a cross-talk between cAMP/PKA and insulin-mediated signalling cascade in catfish oocytes in vitro. Taken together, these results suggest that rh-insulin regulation of the maturational response in C. batrachus oocytes involves down-regulation of PKA, synthesis of cyclin

  15. Insulin resistance: β-arrestin development

    Institute of Scientific and Technical Information of China (English)

    Joseph T Rodgers; Pere Puigserver

    2009-01-01

    @@ Insulin resistance is simply the in-ability of insulin to elicit a physiologic response. While insulin resistance is most commonly associated with the pathogenesis of metabolic disorders such as type II diabetes and obesity, it is also a predisposing factor to a number of other diseases such as cancer and car-diovascular disease . There are just as many theories as to the cause of insulin resistance as there are insulin signal-ing molecules and it is very unclear as to which are the actual molecular mechanisms of insulin resistance in diseased states.

  16. Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes.

    Science.gov (United States)

    Lin, Yi; Sun, Zhongjie

    2015-12-01

    Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL(+/-)) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell-specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell-specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis. PMID:26340932

  17. Dietary glycemic index, glycemic load, fiber, simple sugars, and insulin resistance - The Inter99 study

    DEFF Research Database (Denmark)

    Lau, Cathrine; Pedersen, Oluf; Færch, Kristine; Carstensen, Bendix; Glumer, Charlotte; Jørgensen, Torben; Tetens, Inge; Borch-Johnsen, Knut

    2005-01-01

    high glycemic load or diets with a high content of total carbohydrate including simple sugars was not associated with the probability of having insulin resistance. Furthermore, intake of dietary fiber was inversely associated with the probability of having insulin resistance.......OBJECTIVE - To examine the relationship between daily glycemic index daily glycemic, load, simple sugars, dietary fiber, and the prevalence of a measure of insulin resistance in 30- to 60-year-old nondiabetic Danish men and women. RESEARCH DESIGN AND METHODS - The inter99 study is a.......05). Intake of dietary fiber explained the associations with daily glycemic load and total carbohydrate and attenuated the association with fruit and vegetables. No significant associations were observed for daily glycemic index or sucrose. CONCLUSIONS - Habitual intake of diets with a high glycemic index and...

  18. Insulin and insulin-like growth factor receptors and responses

    International Nuclear Information System (INIS)

    Insulin is a member of a family of structurally related hormones with diverse physiological functions. In humans, the best-characterized members of this family include insulin, insulin-like growth factor (IGF)-I, and IGF-II. Each of these three polypeptide hormones has its own distinct receptor. The structures of each of these receptors have now been deduced from analyses of isolated cDNA clones. To study further the responses mediated through these three different receptors, the authors have been studying cells expressing the proteins encoded by these three cDNAs. The isolated cDNAs have been transfected into Chinese hamster ovary (CHO) cells, and the resulting transfected cell lines have been characterized as to the ligand-binding activities and signal-transducing activities of the expressed proteins

  19. Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

    Directory of Open Access Journals (Sweden)

    Min He

    Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

  20. Patient Perspectives on Biosimilar Insulin.

    Science.gov (United States)

    Wilkins, Alasdair R; Venkat, Manu V; Brown, Adam S; Dong, Jessica P; Ran, Nina A; Hirsch, James S; Close, Kelly L

    2014-01-01

    Given that a new wave of biosimilar insulins will likely enter the market in coming years, it is important to understand patient perspectives on these biosimilars. A survey (N = 3214) conducted by the market research company dQ&A, which maintains a 10 000-patient panel of people with type 1 or type 2 diabetes in roughly equal measure, investigated these perspectives. The survey asked whether patients would switch to a hypothetical less expensive biosimilar insulin that was approved by their provider. Approximately 66% of respondents reported that they would "definitely" or "likely" use a biosimilar insulin, while 17% reported that they were "unlikely" to use or would "definitely not use" such a product. Type 2 diabetes patients demonstrated slightly more willingness to use biosimilars than type 1 diabetes patients. Common patient concerns included whether biosimilars would be as effective as reference products (~650 respondents), whether side effect profiles would deviate from those of reference products (~220 respondents), and the design of the delivery device (~50 respondents). While cost savings associated with biosimilar insulins could increase patient uptake, especially among patients without health insurance (some recent estimates suggest that biosimilars will come at a substantial discount), patients may still need assurance that a cheaper price tag is not necessarily associated with substandard quality. Overall, the dQ&A survey indicates that the majority of patients are willing to consider biosimilar insulins, but manufacturers will need to work proactively to address and assuage patient concerns regarding efficacy, safety, drug administration, and other factors. PMID:24876533

  1. How to achieve a predictable basal insulin?

    Science.gov (United States)

    Kurtzhals, P

    2005-09-01

    The development of insulin analogues over the last two decades have aimed at optimising the pharmacokinetic profile of subcutaneously injected insulin for therapeutic use in diabetes mellitus. Rapid acting analogues were successfully engineered and marketed in the late 1990's. In engineering long-acting analogues it has been a particular challenge to obtain action profiles that would be predictable from day to day in the same person. The most recent approach has been to acylate the insulin molecule with a fatty acid which provides the insulin molecule with a specific affinity for albumin. The first clinically available agent of this type is insulin detemir. Pharmacological studies have shown that reversible albumin binding will protract absorption following subcutaneous injection but still allow the insulin molecule to be recognised by the insulin receptor following dissociation from the carrier protein. Moreover, the molecular features of insulin detemir are attractive in that the molecule can be formulated as a neutral aqueous solution and does not precipitate after injection. Together with an important buffering mechanism effected by plasma albumin binding, this explains a highly significant reduction of within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. No safety considerations have been identified in using albumin as an insulin carrier to protract and buffer insulin action. In assessing the clinical attractiveness of insulin analogues, it is furthermore critically important to consider how the molecular modifications impact efficacy and safety. A number of pharmacological studies have shown that insulin detemir overall retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Taken together, insulin detemir provides an attractive novel approach for

  2. Insulin receptors in the mammary gland

    International Nuclear Information System (INIS)

    Insulin binding studies were conducted using mammary membrane preparations to further the authors understanding of insulin's role in regulating mammary metabolism, particularly ruminant mammary metabolism. Specific objectives were to: (1) characterize insulin binding to bovine mammary microsomes and determine if the specificity and kinetics of binding indicate the presence of insulin receptors in bovine mammary gland; (2) examine and compare insulin binding by liver and mammary microsomes of the pig and dairy cow; (3) examine insulin binding to bovine milk fat globule membranes (MFGM) and evaluate this model's usefulness in assessing insulin receptor regulation in the mammary gland of the cow; (4) examine the effect of dietary fat in insulin binding by rat mammary and liver microsomes. The specificity and kinetics of 125I-insulin binding of bovine mammary microsomes indicated the presence of insulin receptors in bovine mammary gland. Bovine liver and mammary microsomes specifically bound less 125I-insulin than did the corresponding porcine microsomes, and mammary microsomes, regardless of species, specifically bound less 125I-insulin than did liver microsomes. These differences in binding suggest differences in insulin responsiveness between pigs and cattle, as well as between the liver and mammary glands

  3. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

    OpenAIRE

    Vaag, A.; Henriksen, J E; Madsbad, S; Holm, N; Beck-Nielsen, H.

    1995-01-01

    12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes ...

  4. Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Rodbard, H W; Cariou, B; Zinman, B;

    2013-01-01

    The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes.......The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes....

  5. Molecular Characterisation of Long-Acting Insulin Analogues in Comparison with Human Insulin, IGF-1 and Insulin X10

    OpenAIRE

    Bo F Hansen; Glendorf, Tine; Hegelund, Anne C.; Lundby, Anders; Lützen, Anne; Slaaby, Rita; Stidsen, Carsten Enggaard

    2012-01-01

    Aims/Hypothesis There is controversy with respect to molecular characteristics of insulin analogues. We report a series of experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparison with human insulin, IGF-1, and the super-mitogenic insulin, X10. Methods We measured binding of ligands to membrane-bound and solubilised receptors, receptor activation and mitogenicity in a number of cell types. Results Detemir and glargine each ...

  6. Seismic attenuation in fractured media

    International Nuclear Information System (INIS)

    The prime objective of this paper is to quantitatively estimate seismic attenuation caused by fractures with different physical parameters. In seismic wave simulation, the fractured media are treated as the anisotropic media and fractures are represented by frequency-dependent elastic constants. Based on numerical experiments with three different parameters, namely viscosity, porosity and the Lamé parameters, this paper has the following observations. First, seismic attenuation is not affected by the viscosity within fractures, although it increases with the increase of porosity and decreases with the increase of the Lamé parameters within fractures. Among the latter two parameters, seismic attenuation is more sensitive to the Lamé parameters than to the porosity. Second, for the attenuation anisotropy, low frequencies have more anisotropic effect than high frequencies. For example, a 50 Hz wavefield has the strongest anisotropy effect if compared to 100 and 150 Hz wavefields. The attenuation anisotropy for low frequency (say 50 Hz) is more sensitive to the viscosity than the porosity and the Lamé parameters have the weakest effect among these three parameters. These observations suggest that low-frequency seismic attenuation, and especially the attenuation anisotropy in low frequency, would have great potential for fluid discrimination within fractured media. (paper)

  7. Inhibition of human insulin gene transcription and MafA transcriptional activity by the dual leucine zipper kinase.

    Science.gov (United States)

    Stahnke, Marie-Jeannette; Dickel, Corinna; Schröder, Sabine; Kaiser, Diana; Blume, Roland; Stein, Roland; Pouponnot, Celio; Oetjen, Elke

    2014-09-01

    Insulin biosynthesis is an essential β-cell function and inappropriate insulin secretion and biosynthesis contribute to the pathogenesis of diabetes mellitus type 2. Previous studies showed that the dual leucine zipper kinase (DLK) induces β-cell apoptosis. Since β-cell dysfunction precedes β-cell loss, in the present study the effect of DLK on insulin gene transcription was investigated in the HIT-T15 β-cell line. Downregulation of endogenous DLK increased whereas overexpression of DLK decreased human insulin gene transcription. 5'- and 3'-deletion human insulin promoter analyses resulted in the identification of a DLK responsive element that mapped to the DNA binding-site for the β-cell specific transcription factor MafA. Overexpression of DLK wild-type but not its kinase-dead mutant inhibited MafA transcriptional activity conferred by its transactivation domain. Furthermore, in the non-β-cell line JEG DLK inhibited MafA overexpression-induced human insulin promoter activity. Overexpression of MafA and DLK or its kinase-dead mutant into JEG cells revealed that DLK but not its mutant reduced MafA protein content. Inhibition of the down-stream DLK kinase c-Jun N-terminal kinase (JNK) by SP600125 attenuated DLK-induced MafA loss. Furthermore, mutation of the serine 65 to alanine, shown to confer MafA protein stability, increased MafA-dependent insulin gene transcription and prevented DLK-induced MafA loss in JEG cells. These data suggest that DLK by activating JNK triggers the phosphorylation and degradation of MafA thereby attenuating insulin gene transcription. Given the importance of MafA for β-cell function, the inhibition of DLK might preserve β-cell function and ultimately retard the development of diabetes mellitus type 2. PMID:24726898

  8. Pursuit of a perfect insulin.

    Science.gov (United States)

    Zaykov, Alexander N; Mayer, John P; DiMarchi, Richard D

    2016-06-01

    Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. PMID:26988411

  9. Insulin poisoning with suicidal intent

    Directory of Open Access Journals (Sweden)

    Abhay Gundgurthi

    2012-01-01

    Full Text Available We report a 27-year-old paramedical lady with no known comorbidities, who presented with rapid-onset coma with hypoglycemia (plasma glucose at admission was 35 mg/dL. Clinical alertness suspected and confirmed the diagnosis of exogenous insulin administration probably with suicidal intent. During the course of her ICU stay, she developed bradycardia and hypotension which required ionotropic support. She remained in coma for 90 hours. A total of 470 g of dextrose was infused until she regained consciousness. No other complications of insulin overdose were observed during her stay in the hospital. Recovery was complete without any residual neurological deficits. Insulin administration should be kept in differential diagnosis when any case presents with coma and hypoglycemia, especially in paramedical personnel.

  10. Microvascular Recruitment in Insulin Resistance

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker

    hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...... the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...

  11. Insulin utilizes the PI 3-kinase pathway to inhibit SP-A gene expression in lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Snyder Jeanne M

    2002-10-01

    Full Text Available Abstract Background It has been proposed that high insulin levels may cause delayed lung development in the fetuses of diabetic mothers. A key event in lung development is the production of adequate amounts of pulmonary surfactant. Insulin inhibits the expression of surfactant protein A (SP-A, the major surfactant-associated protein, in lung epithelial cells. In the present study, we investigated the signal transduction pathways involved in insulin inhibition of SP-A gene expression. Methods H441 cells, a human lung adenocarcinoma cell line, or human fetal lung explants were incubated with or without insulin. Transcription run-on assays were used to determine SP-A gene transcription rates. Northern blot analysis was used to examine the effect of various signal transduction inhibitors on SP-A gene expression. Immunoblot analysis was used to evaluate the levels and phosphorylation states of signal transduction protein kinases. Results Insulin decreased SP-A gene transcription in human lung epithelial cells within 1 hour. Insulin did not affect p44/42 mitogen-activated protein kinase (MAPK phosphorylation and the insulin inhibition of SP-A mRNA levels was not affected by PD98059, an inhibitor of the p44/42 MAPK pathway. In contrast, insulin increased p70 S6 kinase Thr389 phosphorylation within 15 minutes. Wortmannin or LY294002, both inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase, or rapamycin, an inhibitor of the activation of p70 S6 kinase, a downstream effector in the PI 3-kinase pathway, abolished or attenuated the insulin-induced inhibition of SP-A mRNA levels. Conclusion Insulin inhibition of SP-A gene expression in lung epithelial cells probably occurs via the rapamycin-sensitive PI 3-kinase signaling pathway.

  12. Increased skeletal muscle capillarization enhances insulin sensitivity

    DEFF Research Database (Denmark)

    Åkerström, Thorbjörn; Laub, Lasse; Vedel, Kenneth;

    2014-01-01

    Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. We therefore investigated whether increased skeletal muscle capillarization increases insulin sensitivity. S...

  13. Quantification of adipose tissue insulin sensitivity

    DEFF Research Database (Denmark)

    Søndergaard, Esben; Jensen, Michael D

    2016-01-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute...... to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible...... quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and...

  14. Quantification of adipose tissue insulin sensitivity.

    Science.gov (United States)

    Søndergaard, Esben; Jensen, Michael D

    2016-06-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses. PMID:27073214

  15. Insulin Aspart (rDNA Origin) Injection

    Science.gov (United States)

    ... not use any type of insulin after the expiration date printed on the bottle has passed.Insulin ... or itching over the whole body shortness of breath wheezing dizziness blurred vision fast heartbeat sweating weakness ...

  16. The impact of calcineurin inhibitors on insulin sensitivity and insulin secretion

    DEFF Research Database (Denmark)

    Øzbay, Aygen; Møller, N; Juhl, C;

    2012-01-01

    pulsatile insulin secretion were not significantly affected by the drugs. CONCLUSION: In conclusion, 8-10 days of treatment with cyclosporine and tacrolimus impairs insulin sensitivity to a similar degree in haemodialysis patients, while acute insulin responses and pulsatile insulin secretion remain...

  17. Hypersensitivity Reaction to Insulin Glargine and Insulin Detemir in a Pediatric Patient: A Case Report.

    Science.gov (United States)

    Badik, Jennifer; Chen, Jimmy; Letvak, Kira; So, Tsz-Yin

    2016-01-01

    Allergy to human insulin or its analogs is rare, but it is still a significant issue in current diabetes care. Allergic reactions can range from localized injection site reactions to generalized anaphylaxis, and they can be caused by excipients or the insulin molecules themselves. We presented a case of a 14-year-old male patient with generalized allergic reactions to insulin glargine and insulin detemir. The patient was successfully managed by being switched to a continuous subcutaneous insulin infusion with insulin aspart. Allergic reactions to insulin detemir and insulin glargine have both been well described, with insulin detemir allergy appearing to be more common. There are several potential mechanisms for insulin allergy, and immunologic characteristics vary among different insulin analogs. After confirming insulin allergy in practice, management involves treating symptoms and switching insulin preparations. This is the first documented case of allergies to both insulin glargine and insulin detemir in a pediatric patient. Exact mechanism of insulin allergy is unknown, and management strategies must be individualized for each patient. PMID:26997933

  18. Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population

    Directory of Open Access Journals (Sweden)

    Sudha S. Shankar, MD

    2015-12-01

    Conclusions: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

  19. Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Almind, K; Bjørbaek, C; Vestergaard, H;

    1993-01-01

    Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate g...

  20. Comparison of metformin and insulin versus insulin alone for type 2 diabetes

    DEFF Research Database (Denmark)

    Hemmingsen, Bianca; Christensen, Louise Lundby; Wetterslev, Jørn;

    2012-01-01

    To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.......To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes....

  1. Serum Insulin, Proinsulin and Proinsulin/Insulin Ratio in Type 2 Diabetic Patients: As an Index of β-Cell Function or Insulin Resistance

    OpenAIRE

    Kim, Nan Hee; Kim, Dong Lim; Choi, Kyung Mook; Baik, Sei Hyun; Choi, Dong Seop

    2000-01-01

    Background Although insulin resistance and decreased insulin secretion are characteristics of established type 2 DM, which of these metabolic abnormalities is the primary determinant of type 2 DM is controversial. It is also not well known how insulin resistance and beta cell dysfunction influence serum insulin, proinsulin, proinsulin/insulin ratio in type 2 DM. Methods We compared serum insulin, proinsulin and proinsulin/insulin ratio in type 2 diabetic patients and control subjects. We also...

  2. SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking in adipocytes.

    Science.gov (United States)

    Bruno, Joanne; Brumfield, Alexandria; Chaudhary, Natasha; Iaea, David; McGraw, Timothy E

    2016-07-01

    RAB10 is a regulator of insulin-stimulated translocation of the GLUT4 glucose transporter to the plasma membrane (PM) of adipocytes, which is essential for whole-body glucose homeostasis. We establish SEC16A as a novel RAB10 effector in this process. Colocalization of SEC16A with RAB10 is augmented by insulin stimulation, and SEC16A knockdown attenuates insulin-induced GLUT4 translocation, phenocopying RAB10 knockdown. We show that SEC16A and RAB10 promote insulin-stimulated mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment. We propose RAB10-SEC16A functions to accelerate formation of the vesicles that ferry GLUT4 to the PM during insulin stimulation. Because GLUT4 continually cycles between the PM and intracellular compartments, the maintenance of elevated cell-surface GLUT4 in the presence of insulin requires accelerated biogenesis of the specialized GLUT4 transport vesicles. The function of SEC16A in GLUT4 trafficking is independent of its previously characterized activity in ER exit site formation and therefore independent of canonical COPII-coated vesicle function. However, our data support a role for SEC23A, but not the other COPII components SEC13, SEC23B, and SEC31, in the insulin stimulation of GLUT4 trafficking, suggesting that vesicles derived from subcomplexes of COPII coat proteins have a role in the specialized trafficking of GLUT4. PMID:27354378

  3. Insulin Pump Safety Meeting: Summary Report

    OpenAIRE

    Klonoff, David C; Reyes, Juliet S.

    2009-01-01

    Diabetes Technology Society convened a panel of insulin pump experts in Bethesda, Maryland, on November 12, 2008, at the request of the Food and Drug Administration. The group consisted of physicians, nurses, diabetes educators, and engineers from across the United States. The panel members (1) discussed safety features of insulin pump therapy and (2) recommended adjustments to current insulin pump design and use to enhance overall safety. Software and hardware features of insulin pumps were ...

  4. Role of Mitochondrial Dysfunction in Insulin Resistance

    OpenAIRE

    Kim, Jeong-a; Wei, Yongzhong; Sowers, James R.

    2008-01-01

    Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the patho...

  5. Safety and Efficacy of Modern Insulin Analogues

    OpenAIRE

    Hye Jin Yoo; Keun Yong Park; Kang Seo Park; Kyu Jeung Ahn; Kyung Wan Min; Jeong Hyun Park; Sang Ah Chang; Bong Soo Cha; Dong-Jun Kim; Yong Seong Kim; Tae Keun Oh; Suk Chon; Il Seong Nam-Goong; Mi Jin Kim; Hye-Soon Kim

    2013-01-01

    Background A1chieve® was a noninterventional study evaluating the clinical safety and efficacy of biphasic insulin aspart 30, insulin detemir, and insulin aspart. Methods Korean type 2 diabetes patients who have not been treated with the study insulin or have started it within 4 weeks before enrollment were eligible for the study. The patient selection and the choice of regimen were at the discretion of the physician. The safety and efficacy information was collected from the subjects at base...

  6. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine.

    Science.gov (United States)

    Belhekar, Mahesh N; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  7. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine

    Directory of Open Access Journals (Sweden)

    Mahesh N Belhekar

    2015-01-01

    Full Text Available Insulin is an important agent for the treatment of diabetes mellitus (DM. Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1 hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control.

  8. Modulation of pancreatic MIN6 insulin secretion and proliferation and extrapancreatic glucose absorption with Achillea santolina, Eryngium creticum and Pistacia atlantica extracts: in vitro evaluation

    Directory of Open Access Journals (Sweden)

    Lara Majdalawi

    2012-06-01

    Full Text Available Objective: The present in vitro studies aimed to investigate the pancreatic and extrapancreatic effects of crude aqueous extracts (AE of Achillea santolina L, Eryngium creticum Lam, and Pistacia atlantica Desf utilized in Jordan diabetes ethnomedicine. Methods: Bioassays of β-cell proliferation and insulin secretion as well as glucose diffusion as possible modes of action were recruited. Results: Similar to L-alanine insulinotropic efficacy in MIN6 β-cell, glucose-stimulated Ca2+ regulated- insulin secretion was potentiated by AEs of E.creticum (0.01 mg/ml and P.atlantica (0.01, 0.1 and 0.5 mg/ml. A.santolina AE, however, was found ineffective. Comparable to glucagon-like peptid-1-enhanced β-cell proliferation in 2-day treatment wells, a dose dependent augmentation of bromodeoxyuridine incorporation was obtained with the A.santolina AE (0.05-1 mg/ml, and E.creticum AE (0.1, 0.5 and 1 mg/ml. P.atlantica concentrations lacked pancreatic proliferative capacity. While A.santolina and E.creticum AEs proved inactive, P.atlantica inhibited dose dependently overnight glucose movement in vitro, as effectively as guar gum diffusional hindrance in a simple glucose dialysis model. Conclusion: Current findings signify the in vitro diverse therapeutic antidiabetes properties of the selected medicinal plants. Future directives may assess the use of A.santolina, E.creticum and P.atlantica as new potential sources of functional foods or nutraceuticals or active leads into diabetes type 2 pharmacotherapy. [J Exp Integr Med 2012; 2(3.000: 245-254

  9. Insulin degludec/insulin aspart is the first co-formulation of basal and prandial insulin analogues

    Directory of Open Access Journals (Sweden)

    Ivan Ivanovich Dedov

    2014-12-01

    Full Text Available Achievement of glycemic control is the major therapeutic aim to prevent or delay the onset and progression of diabetes related complications. Insulin therapy represents a cornerstone in the treatment of diabetes and has been used widely for achieving glycemic goals. The aim for insulin therapy is to mimic the physiological profile of insulin secretion seen in nondiabetic patients. Development of the insulin analogs has offered new opportunities in the diabetes management to achieve greater safety and tolerability of diabetes treatment. Insulin degludec/insulin aspart(IDegAsp (Ryzodeg®, Novo Nordisk, Denmark is the first soluble co-formulation of 70% ultra-long acting insulin degludec and 30% rapid-acting prandial insulin aspart, providing both basal insulin coverage and a prandial insulin bolus in a single injection. This review discusses data regarding the efficacy, safety, tolerability and clinical benefits of IDegAsp. According to the clinical development program IDegAspprovides an achievement of similar glycemic control with superiority in lowering FPG with using less number of injections and lower daily insulin dose, and also associated with numerically lower rates of confirmed and nocturnal confirmed hypoglycaemia in comparison with premixed or basal insulin analogues, as well as a basal component for basal–bolus therapy with supplementary mealtime insulin aspart.Trial results suggest that IDegAspQD or BID maybe an appropriate and reasonable option for initiating insulin therapy in type 1 and type 2 diabetic patients inadequately controlled on maximal doses of oral antidiabetic drugs,and also a simple alternative to basal–bolus treatment in patients who require intensification of insulin therapy, especially when adherence to more complex regimens is challenging.

  10. Redox regulation of insulin degradation by insulin-degrading enzyme.

    Directory of Open Access Journals (Sweden)

    Crystal M Cordes

    Full Text Available Insulin-degrading enzyme (IDE is a thiol sensitive peptidase that degrades insulin and amyloid β, and has been linked to type 2 diabetes mellitus and Alzheimer's disease. We examined the thiol sensitivity of IDE using S-nitrosoglutathione, reduced glutathione, and oxidized glutathione to distinguish the effects of nitric oxide from that of the redox state. The in vitro activity of IDE was studied using either partially purified cytosolic enzyme from male Sprague-Dawley rats, or purified rat recombinant enzyme. We confirm that nitric oxide inhibits the degrading activity of IDE, and that it affects proteasome activity through this interaction with IDE, but does not affect the proteasome directly. Oxidized glutathione inhibits IDE through glutathionylation, which was reversible by dithiothreitol but not by ascorbic acid. Reduced glutathione had no effect on IDE, but reacted with partially degraded insulin to disrupt its disulfide bonds and accelerate its breakdown to trichloroacetic acid soluble fragments. Our results demonstrate the sensitivity of insulin degradation by IDE to the redox environment and suggest another mechanism by which the cell's oxidation state may contribute to the development of, and the link between, type 2 diabetes and Alzheimer's disease.

  11. Thermal dissociation and unfolding of insulin

    DEFF Research Database (Denmark)

    Huus, Kasper; Havelund, Svend; Olsen, Helle B;

    2005-01-01

    The thermal stability of human insulin was studied by differential scanning microcalorimetry and near-UV circular dichroism as a function of zinc/protein ratio, to elucidate the dissociation and unfolding processes of insulin in different association states. Zinc-free insulin, which is primarily...

  12. Insulin sensitivity : modulation by the brain

    NARCIS (Netherlands)

    Coomans, Claudia Pascalle

    2012-01-01

    The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated gluc

  13. Bioavailability and variability of biphasic insulin mixtures

    DEFF Research Database (Denmark)

    Søeborg, Tue; Rasmussen, Christian Hove; Mosekilde, Erik; Colding-Jørgensen, Morten

    2012-01-01

    insulin degradation. Soluble insulins are assumed to be degraded enzymatically in the subcutaneous tissue. Suspended insulin crystals form condensed heaps that are assumed to be degraded from their surface by invading macrophages. It is demonstrated how the shape of the heaps affects the absorption...

  14. Interstitial insulin concentrations determine glucose uptake rates but not insulin resistance in lean and obese men.

    OpenAIRE

    Castillo, C.; Bogardus, C; Bergman, R.; Thuillez, P; Lillioja, S

    1994-01-01

    Insulin action and obesity are both correlated with the density of muscle capillary supply in humans. Since the altered muscle anatomy in the obese might affect interstitial insulin concentrations and reduce insulin action, we have cannulated peripheral lymphatic vessels in lean and obese males, and compared peripheral lymph insulin concentrations with whole body glucose uptake during a euglycemic, hyperinsulinemic clamp. Lymph insulin concentrations in the lower limb averaged only 34% of art...

  15. Clinical application of insulin pumps in the management of insulin dependent diabetes.

    OpenAIRE

    Greene, S.A.; Smith, M. A.; Baum, J D

    1983-01-01

    Seven volunteers aged 12.0 to 17.9 years participated in a trial to compare conventional insulin treatment with continuous open loop (pump) insulin infusion. After 6 weeks of conventional treatment followed by 6 weeks of insulin pump treatment, 4 children chose to manage their diabetes permanently by means of the insulin pump. The mean blood glucose concentration (based on home blood glucose monitoring) while on conventional insulin treatment showed no appreciable change during the 6 weeks' t...

  16. Subetta increases phosphorylation of insulin receptor β-subunit alone and in the presence of insulin

    OpenAIRE

    Gorbunov, E A; Nicoll, J; Kachaeva, E. V.; Tarasov, S A; Epstein, O. I.

    2015-01-01

    It has been previously shown that Subetta (a drug containing released-active forms of antibodies to the insulin receptor β-subunit and antibodies to endothelial nitric oxide synthase) stimulated insulin-induced adiponectin production by mature human adipocytes in the absence of insulin. Therefore, it was assumed that Subetta could activate the insulin receptor. To confirm this hypothesis, the capacity of Subetta to activate the insulin receptor in mature human adipocytes in the absence or pre...

  17. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine

    OpenAIRE

    Belhekar, Mahesh N; Sarayu Pai; Parimal Tayade; Pradip Dalwadi; Renuka Munshi; Prema Varthakavi

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutane...

  18. Insulin signal transduction in skeletal muscle : special consideration for insulin resistance and diabetes

    OpenAIRE

    Song, Xiao Mei

    2000-01-01

    This dissertation work is focused on the insulin-signal-transduction pathways to glucose transport in skeletal muscle from animal models of NIDDM. The overall objective is to determine the effectiveness of different pharmacological treatments to improve insulin action in skeletal muscle. Muscle-fiber-type-specific differences in insulin signal transduction was first considered. We noted increased insulin action on insulin signaling events including; IR, IRS- 1, IRS-2, PI...

  19. Insulin requirements in patients with diabetes and declining kidney function: differences between insulin analogues and human insulin?

    Science.gov (United States)

    Kulozik, Felix

    2013-01-01

    Objectives: In diabetic nephropathy the decline of renal function causes modifications of the insulin and carbohydrate metabolism resulting in changed insulin requirements. The aim of the present study was to identify potential differences in the requirements of human insulin and various insulin analogues in patients with type 1 diabetes mellitus and renal dysfunction. Methods: The insulin requirements of 346 patients with type 1 diabetes mellitus under everyday life circumstances were assessed in an observational study. Simultaneously, laboratory parameters were measured and the estimated glomerular filtration rate (eGFR) was calculated using the formula by Cockcroft–Gault. Medical history and concomitant medication were recorded. The insulin requirements of long- and short-acting insulin were tested for a relationship with the eGFR and laboratory parameters. Results: The dosage of long-acting human insulin did not show any relation to eGFR. In contrast, a strong positive relation between dosage and renal function was found for insulin glargine and insulin detemir. After classification according to renal function, the insulin dosage at eGFR less than 60 ml/min was 29.7% lower in glargine-treated and 27.3% lower in detemir-treated patients compared with eGFR greater than 90 ml/min. Considering the whole range of eGFR, short-acting human insulin did not show a relation with renal function. Only after classification according to renal function was a dose reduction found for human insulin at eGFR less than 60 ml/min. In contrast, requirements of insulin lispro were significantly related to eGFR over the whole range of eGFR. At eGFR less than 60 ml/min the insulin dosage was 32.6% lower than at eGFR greater than 90 ml/min. The requirements of insulin aspart did not show any association with the eGFR. Conclusions: Patients with type 1 diabetes mellitus show different insulin requirements according to the renal function depending on the applied insulin. This finding is

  20. Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy

    Directory of Open Access Journals (Sweden)

    Pešić Milica

    2007-01-01

    Full Text Available Background/Aim. Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin for basal insulin supply in patients with type 1 diabetes. Methods. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IIT were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15; 2. NPH insulin twice daily (n = 15; 3. insulin glargine once daily (n = 18. Meal time insulin aspart was continued in all groups. Results. Fasting blood glucose (FBG was lower in the glargine group (7.30±0.98 mmol/l than in the twice daily NPH group (7.47±1.06 mmol/l, but without significant difference. FBG was significantly higher in the once daily NPH group (8.44±0.85 mmol/l; p < 0.05. HbA1c after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72±0.86% to 6.87±0.50%, as well as in the twice daily NPH group (from 7.80±0.83% to 7.01±0.63%. Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56±2.09 than in both NPH groups (9.0±1.65 in twice daily NPH group and 8.13±1.30 in other NPH group (episodes/patients-month, p < 0.05. Conclusion. Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbA1c and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

  1. High fasting serum insulin level due to autoantibody interference in insulin immunoassay discloses autoimmune insulin syndrome: a case report.

    Science.gov (United States)

    Lamy, Pierre-Jean; Sault, Corinne; Renard, Eric

    2016-08-01

    Insulin-antibodies are a cause of misleading results in insulin immunoassays. They may also mediate deleterious blood glucose variations. A patient presented with overtiredness, recurrent episodes of sweating, dizziness and fainting fits. A fasting serum insulin assay performed on a Modular platform (Modular analytic E170, Roche Diagnostic, Meylan, France) showed a highly elevated value of 194.7 mIU/L, whereas on the same sample glucose and C-peptide levels were normal. Other immunometric insulin assays were performed, as well as antibodies anti-insulin radiobinding assay (RBA) and gel filtration chromatography (GFC). While complementary insulin assays yielded closer to normal fasting levels, the free insulin concentration assessed after PEG precipitation was 14.0 mIU/L and the RBA was positive. GFC revealed that most of the insulin was complexed with a 150 kDa molecule, corresponding to an immunoglobulin G (IgG). A high fasting serum insulin level in a patient with neuroglucopenic symptoms was related to a high insulin-antibody level, suggesting an insulin autoimmune syndrome. PMID:27492703

  2. In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R;

    2005-01-01

    In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy....... insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant...

  3. Nutritional Modulation of Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Martin O. Weickert

    2012-01-01

    Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

  4. Mitochondrial efficiency and insulin resistance.

    Science.gov (United States)

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  5. Insulin therapy for pre-hyperglycemic beta-cell endoplasmic reticulum crowding.

    Directory of Open Access Journals (Sweden)

    Afaf Absood

    Full Text Available Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing evidence indicates that in early stages of type-2 diabetes and some types of monogenic diabetes linked with malfunctioning endoplasmic-reticulum (ER, the β-cell ER fails to process sufficient proinsulin once it becomes overloaded. These changes manifest with ER distention (ER-crowding and deficiency of secretory granules. We hypothesize that insulin therapy may improves β-cell function by alleviating ER-crowding. To support this hypothesis, we investigated pre-diabetic β-cell changes in hProC(A7Y-CpepGFP transgenic mice that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding. We attenuated the β-cell ER proinsulin synthesis with a treat-to-target insulin therapy while avoiding hypoglycemia and weight gain. Alleviation of ER-crowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tolerance. Our observations suggest that alleviation of pre-diabetic ER-crowding using a treat-to-target insulin therapy may improve β-cell function and may prevent further metabolic deterioration.

  6. Le medicament du mois. Insuline glargine (Lantus).

    OpenAIRE

    Scheen, André

    2004-01-01

    Insulin glargine (Lantus) is a human insulin analogue produced by recombinant DNA technology and recently launched by Aventis. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue (pH > 7,4) from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glar...

  7. Isoliquiritigenin impairs insulin signaling and adipocyte differentiation through the inhibition of protein-tyrosine phosphatase 1B oxidation in 3T3-L1 preadipocytes.

    Science.gov (United States)

    Park, Sun-Ji; Choe, Young-Geun; Kim, Jung-Hak; Chang, Kyu-Tae; Lee, Hyun-Shik; Lee, Dong-Seok

    2016-07-01

    Isoliquritigenin (ISL) is an abundant dietary flavonoid with a chalcone structure, which is an important constituent in Glycyrrhizae Radix (GR). ISL exhibits anti-oxidant activity, and this activity has been shown to play a beneficial role in various health conditions. However, it is unclear whether the anti-oxidant activity of ISL affects insulin signaling pathway and lipid accumulation of adipocytes. We sought to investigate the effects and molecular mechanisms of ISL on insulin-stimulated adipogenesis in 3T3-L1 cells. We investigated whether ISL attenuates insulin-induced Reactive Oxygen Species (ROS) generation, and whether ISL inhibits the lipid accumulation and the expression of adipogenic-genes during the differentiation of 3T3-L1 cells. ISL blocked the ROS generation, suppressed the lipid accumulation and the expression of adipocyte-specific proteins, which are increased in response to insulin stimulation during adipocyte differentiation of 3T3-L1 cells. We also investigated whether the anti-oxidant capacity of ISL is involved in regulating the molecular events of insulin-signaling cascade in 3T3-L1 adipocytes. ISL restores PTP1B activity by inhibiting PTP1B oxidation and IR/PI3K/AKT phosphorylation during the early stages of insulin-induced adipogenesis. Our findings show that the anti-oxidant capacity of ISL attenuated insulin IR/PI3K/AKT signaling through inhibition of PTP1B oxidation, and ultimately attenuated insulin-induced adipocyte differentiation of 3T3-L1 cells. PMID:27117918

  8. Glycogen overload by postexercise insulin administration abolished the exercise-induced increase in GLUT4 protein.

    Science.gov (United States)

    Chou, Chia-Hau; Tsai, Yin-Lan; Hou, Chien-Wen; Lee, Hsing-Hao; Chang, Wei-Hsiang; Lin, Tzi-Wen; Hsu, Tung-Hsiung; Huang, Yi-Jen; Kuo, Chia-Hua

    2005-12-01

    To elucidate the role of muscle glycogen storage on regulation of GLUT4 protein expression and whole-body glucose tolerance, muscle glycogen level was manipulated by exercise and insulin administration. Sixty Sprague-Dawley rats were evenly separated into three groups: control (CON), immediately after exercise (EX0), and 16 h after exercise (EX16). Rats from each group were further divided into two groups: saline- and insulin-injected. The 2-day exercise protocol consisted of 2 bouts of 3-h swimming with 45-min rest for each day, which effectively depleted glycogen in both red gastrocnemius (RG) and plantaris muscles. EX0 rats were sacrificed immediately after the last bout of exercise on second day. CON and EX16 rats were intubated with 1 g/kg glucose solution following exercise and recovery for 16 h before muscle tissue collection. Insulin (0.5 microU/kg) or saline was injected daily at the time when glucose was intubated. Insulin injection elevated muscle glycogen levels substantially in both muscles above saline-injected group at CON and EX16. With previous day insulin injection, EX0 preserved greater amount of postexercise glycogen above their saline-injected control. In the saline-injected rats, EX16 significantly increased GLUT4 protein level above CON, concurrent with muscle glycogen supercompensation. Insulin injection for EX16 rats significantly enhanced muscle glycogen level above their saline-injected control, but the increases in muscle GLUT4 protein and whole-body glucose tolerance were attenuated. In conclusion, the new finding of the study was that glycogen overload by postexercise insulin administration significantly abolished the exercise-induced increases in GLUT4 protein and glucose tolerance. PMID:16319996

  9. Associations between insulin action and integrity of brain microstructure differ with familial longevity and with age

    Directory of Open Access Journals (Sweden)

    Abimbola A. Akintola

    2015-05-01

    Full Text Available Impaired glucose metabolism and type 2 diabetes have been associated with cognitive decline, dementia, and with structural and functional brain features. However, it is unclear whether these associations differ in individuals that differ in familial longevity or age. Here, we investigated the association between parameters of glucose metabolism and microstructural brain integrity in offspring of long-lived families (offspring and controls; and age categories thereof. From the Leiden Longevity Study, 132 participants underwent oral glucose tolerance test to assess glycemia (fasted glucose and glucose area-under-the-curve (AUC, insulin resistance (fasted insulin, AUCinsulin, and homeostatic model assessment of insulin resistance (HOMA-IR, and pancreatic Beta cell secretory capacity (insulinogenic index. 3Tesla MRI and Magnetization Transfer (MT imaging MT-ratio peak-height was used to quantify differences in microstructural brain parenchymal tissue homogeneity that remain invisible on conventional MRI. Analyses were performed in offspring and age-matched controls, with and without stratification for age.In the full offspring group only, reduced peak-height in grey and white matter was inversely associated with AUCinsulin, fasted insulin, HOMA-IR and insulinogenic-index (all p65 years: in younger controls, significantly stronger inverse associations were observed between peak-height and fasted glucose, AUCglucose, fasted insulin, AUCinsulin and HOMA-IR in grey matter; and for AUCglucose, fasted insulin and HOMA-IR in white matter (all P-interaction<0.05. Although the strength of the associations tended to attenuate with age in the offspring group, the difference between age groups was not statistically significant. Thus, associations between impaired insulin action and reduced microstructural brain parenchymal tissue homogeneity were stronger in offspring compared to controls, and seemed to diminish with age.

  10. Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

    Science.gov (United States)

    Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Tsuda, Masaya; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki

    2016-05-15

    Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. PMID:26988296

  11. Leptin therapy, insulin sensitivity, and glucose homeostasis

    Directory of Open Access Journals (Sweden)

    Gilberto Paz-Filho

    2012-01-01

    Full Text Available Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insulinemia and insulin resistance. The understanding of the effects of leptin on the glucose-insulin homeostasis will lead to the development of leptin-based therapies against diabetes and other insulin resistance syndromes. In these review, we summarize the interactions between leptin and insulin, and their effects on the glucose metabolism.

  12. Pathogenesis of Insulin Resistance in Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Muhammad A. Abdul-Ghani

    2010-01-01

    Full Text Available Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

  13. Poly(lactic-co-glycolic) acid loaded nano-insulin has greater potentials of combating arsenic induced hyperglycemia in mice: Some novel findings

    Energy Technology Data Exchange (ETDEWEB)

    Samadder, Asmita; Das, Jayeeta; Das, Sreemanti; De, Arnab; Saha, Santu Kumar; Bhattacharyya, Soumya Sundar; Khuda-Bukhsh, Anisur Rahman, E-mail: prof_arkb@yahoo.co.in

    2013-02-15

    attenuates arsenic-induced diabetes in mice. ► Encapsulated insulin acts effectively at nearly 10 fold lesser dose than insulin. ► Injection route is more effective than oral administration route. ► Nano-insulin can cross blood–brain barrier with added physiological implications. ► Nano-insulin acts mainly through regulation of mitochondrial signaling cascade.

  14. Estimation of Water Vapour Attenuation And Rain Attenuation

    Directory of Open Access Journals (Sweden)

    K.Kalyana Srinivas

    2015-04-01

    Full Text Available Attenuation due to and water vapour and rain can severely degrade the radio wave propagation at centimeter or millimeter wavelengths. It restricts the path length of radio communication systems and limits the use of higher frequencies for line-of-sight microwave links and satellite communications. The attenuation will pose a greater problem to communication as the frequency of occurrence of heavy rain increases.In a tropical region, like Malaysia, where excessive rainfall is a common phenomenon throughout the year, the knowledge of the rain attenuation at the frequency of operation is extremely required for the design of a reliable terrestrial and earth space communication link at a particular location.

  15. Insulin-like growth factors decrease oxygen-regulated erythropoietin production by human hepatoma cells (Hep G2)

    OpenAIRE

    Scholz, H; Baier, W.; Ratcliffe, P.; Eckardt, K.; Zapf, J.; Kurtz, Armin; Bauer, C

    1992-01-01

    We examined the effects of insulin-like growth factors (IGFs) and insulin on erythropoietin (EPO) production by human hepatoma cells (Hep G2). Compared with normoxia (20% O2), EPO production by Hep G2 cells during a 72-h incubation was stimulated fivefold by exposure to low oxygen tension (1% O2) and nearly threefold by exposure to cobalt chloride (100 microM). IGF-I caused a concentration-dependent attenuation of EPO formation under normoxic conditions and inhibited (maximally 50%) EPO produ...

  16. B22 Glu Des-B30 Insulin: A Novel Monomeric Insulin

    Institute of Scientific and Technical Information of China (English)

    Hai-Juan DU; Jia-Hao SHI; Da-Fu CUI; You-Shang ZHANG

    2006-01-01

    Studies on monomeric insulin with reduced self-association are important in the development of insulin pharmaceutical preparations with rapid hypoglycemic action on patients with diabetes. Here we report a novel monomeric insulin, B22 Glu des-B30 insulin, prepared from a single chain insulin precursor with B22 Arg mutated to Glu, which was expressed in Pichia pastoris and converted to B22 Glu des-B30 insulin by tryptic digestion. It still retains 50% of the in vivo biological activity of porcine insulin and does not form a dimer even at a concentration of 10 mg/ml, showing that B22 Glu plays a key role in reducing the selfassociation of the insulin molecule without greatly reducing its biological activity. This novel monomeric insulin might have potential applications in the clinic.

  17. Pancreatic insulin-producing cells differentiated from human embryonic stem cells correct hyperglycemia in SCID/NOD mice, an animal model of diabetes.

    Directory of Open Access Journals (Sweden)

    Xiu-feng Hua

    Full Text Available Human pancreatic islet transplantation is a prospective curative treatment for diabetes. However, the lack of donor pancreases greatly limits this approach. One approach to overcome the limited supply of donor pancreases is to generate functional islets from human embryonic stem cells (hESCs, a cell line with unlimited proliferative capacity, through rapid directed differentiation. This study investigated whether pancreatic insulin-producing cells (IPCs differentiated from hESCs could correct hyperglycemia in severe combined immunodeficient (SCID/non-obese diabetic (NOD mice, an animal model of diabetes.We generated pancreatic IPCs from two hESC lines, YT1 and YT2, using an optimized four-stage differentiation protocol in a chemically defined culture system. Then, about 5-7 × 10(6 differentiated cells were transplanted into the epididymal fat pad of SCID/NOD mice (n = 20. The control group were transplanted with undifferentiated hESCs (n = 6. Graft survival and function were assessed using immunohistochemistry, and measuring serum human C-peptide and blood glucose levels.The pancreatic IPCs were generated by the four-stage differentiation protocol using hESCs. About 17.1% of differentiated cells expressed insulin, as determined by flow cytometry. These cells secreted insulin/C-peptide following glucose stimulation, similarly to adult human islets. Most of these IPCs co-expressed mature β cell-specific markers, including human C-peptide, GLUT2, PDX1, insulin, and glucagon. After implantation into the epididymal fat pad of SCID/NOD mice, the hESC-derived pancreatic IPCs corrected hyperglycemia for ≥ 8 weeks. None of the animals transplanted with pancreatic IPCs developed tumors during the time. The mean survival of recipients was increased by implanted IPCs as compared to implanted undifferentiated hESCs (P<0.0001.The results of this study confirmed that human terminally differentiated pancreatic IPCs derived from hESCs can correct

  18. Mathematical modeling and analysis of insulin clearance in vivo

    OpenAIRE

    Koschorreck, Markus; Gilles, Ernst Dieter

    2008-01-01

    Background Analyzing the dynamics of insulin concentration in the blood is necessary for a comprehensive understanding of the effects of insulin in vivo. Insulin removal from the blood has been addressed in many studies. The results are highly variable with respect to insulin clearance and the relative contributions of hepatic and renal insulin degradation. Results We present a dynamic mathematical model of insulin concentration in the blood and of insulin receptor activation in hepatocytes. ...

  19. Mathematical modeling and analysis of insulin clearance in vivo

    OpenAIRE

    Koschorreck, M.; Gilles, E. D.

    2008-01-01

    Background: Analyzing the dynamics of insulin concentration in the blood is necessary for a comprehensive understanding of the effects of insulin in vivo. Insulin removal from the blood has been addressed in many studies. The results are highly variable with respect to insulin clearance and the relative contributions of hepatic and renal insulin degradation. Results: We present a dynamic mathematical model of insulin concentration in the blood and of insulin receptor acti...

  20. Mathematical modeling and analysis of insulin clearance in vivo

    OpenAIRE

    Koschorreck, M.; Gilles, E.

    2008-01-01

    Background: Analyzing the dynamics of insulin concentration in the blood is necessary for a comprehensive understanding of the effects of insulin in vivo. Insulin removal from the blood has been addressed in many studies. The results are highly variable with respect to insulin clearance and the relative contributions of hepatic and renal insulin degradation. Results: We present a dynamic mathematical model of insulin concentration in the blood and of insulin receptor activation in hepatocytes...

  1. A clinical comparison of purified bovine and purified porcine insulins.

    OpenAIRE

    Olczak, S A; Greenwood, R H

    1985-01-01

    Twenty four patients with established insulin dependent diabetes treated with twice daily soluble and isophane bovine insulins were changed to equivalent doses of either purified bovine Neusulin and Neuphane (Wellcome) or purified porcine Actrapid and Monotard (Novo) insulins. After 6 months treatment the porcine group showed a 35% fall in insulin binding antibodies and a 14% reduction in insulin dosage. The group changed to purified bovine insulins showed no significant change in insulin bin...

  2. The attenuation and the attenuators: strategies and tactics

    Directory of Open Access Journals (Sweden)

    Antonio Briz

    2013-12-01

    Full Text Available This work is inscribed in a research project (ES.POR.ATENUAÇÃO that seeks to analyze and explain the attenuator activity in different regional varieties of Spanish and Portuguese, in order to perform, subsequently, different contrastive intralinguistic and interlinguistic studies. In this article, we explain some of the theoretical and methodological principles on which are based the qualitative and quantitative analysis. And especially, we will refer to the concept of attenuation (Briz 1995, 2002, 2003, 2005, 2007a, 2012.

  3. Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlate with salt sensitivity in normal subjects

    NARCIS (Netherlands)

    ter Maaten, JC; Bakker, SJL; Serne, EH; ter Wee, PM; Gans, ROB

    1999-01-01

    Background. Insulin induces increasing distal tubular sodium reabsorption. Opposite effects of insulin to offset insulin-induced sodium retention are supposedly increases in glomerular filtration rate (GFR) and decreases in proximal tubular sodium reabsorption. Defects in these opposing effects coul

  4. Curcumin prevents inflammatory response, oxidative stress and insulin resistance in high fructose fed male Wistar rats: Potential role of serine kinases.

    Science.gov (United States)

    Maithilikarpagaselvi, Nachimuthu; Sridhar, Magadi Gopalakrishna; Swaminathan, Rathinam Palamalai; Zachariah, Bobby

    2016-01-25

    Emerging evidence suggests that high fructose consumption may be a potentially important factor responsible for the rising incidence of insulin resistance and diabetes worldwide. The present study investigated the preventive effect of curcumin on inflammation, oxidative stress and insulin resistance in high fructose fed male Wistar rats at the molecular level. Fructose feeding for 10 weeks caused oxidative stress, inflammation and insulin resistance. Curcumin treatment attenuated the insulin resistance by decreasing IRS-1 serine phosphorylation and increasing IRS-1 tyrosine phosphorylation in the skeletal muscle of high fructose fed rats. It also attenuated hyperinsulinemia, glucose intolerance and HOMA-IR level. Curcumin administration lowered tumor necrosis factor alpha (TNF-α), C reactive protein (CRP) levels and downregulated the protein expression of cyclo-oxygenase 2 (COX-2), protein kinase theta (PKCθ). In addition, inhibitor κB alpha (IκBα) degradation was prevented by curcumin supplementation. Treatment with curcumin inhibited the rise of malondialdehyde (MDA), total oxidant status (TOS) and suppressed the protein expression of extracellular kinase ½ (ERK ½), p38 in the skeletal muscle of fructose fed rats. Further, it enhanced Glutathione Peroxidase (GPx) activity in the muscle of fructose fed rats. At the molecular level, curcumin inhibited the activation of stress sensitive kinases and inflammatory cascades. Our findings conclude that curcumin attenuated glucose intolerance and insulin resistance through its antioxidant and anti-inflammatory effects. Thus, we suggest the use of curcumin as a therapeutic adjuvant in the management of diabetes, obesity and their associated complications. PMID:26713546

  5. Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes.

    Science.gov (United States)

    Wang, Chih-Hao; Wang, Ching-Chu; Huang, Hsin-Chang; Wei, Yau-Huei

    2013-02-01

    Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome. PMID:23253816

  6. Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects

    OpenAIRE

    Shafqat, J.; Melles, E.; Sigmundsson, K.; Johansson, B.-L.; Ekberg, K; Alvelius, G.; Henriksson, M; Johansson, J; Wahren, J; Jörnvall, H

    2006-01-01

    Abstract. Using surface plasmon resonance (SPR) and electrospray mass spectrometry (ESI-MS), proinsulin C-peptide was found to influence insulin-insulin interactions. In SPR with chip-bound insulin, C-peptide mixed with analyte insulin increased the binding, while alone C-peptide did not. A control peptide with the same residues in random sequence had little effect. In ESI-MS, C-peptide lowered the presence of insulin hexamer. The data suggest that C-peptide promotes insulin disaggregation. I...

  7. Sound attenuation in magnetorheological fluids

    Science.gov (United States)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  8. Insulin degludec. Uncertainty over cardiovascular harms.

    Science.gov (United States)

    2014-06-01

    Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms

  9. Associations of age with serum insulin, proinsulin and the proinsulin-to-insulin ratio : a crosssectional study

    OpenAIRE

    Arnesen Egil; Bryhni Bente; Jenssen Trond G

    2010-01-01

    Abstract Background Insulin responses and insulin levels seem to decline with age. However, the question of beta cell impairment attributable to ageing has been sparsely addressed in population-based studies. Non-fasting insulin levels are determined by the ambient degree of insulin resistance together with the capacity of beta cells to compensate by insulin secretion to prevent hyperglycaemia. A raised proinsulin-to-insulin ratio (proinsulin/insulin) due to impaired processing of proinsulin ...

  10. Acute knockdown of the insulin receptor or its substrates Irs1 and 2 in 3T3-L1 adipocytes suppresses adiponectin production

    Science.gov (United States)

    Groeneveld, Matthijs P.; Brierley, Gemma V.; Rocha, Nuno M.; Siddle, Kenneth; Semple, Robert K.

    2016-01-01

    Loss of function of the insulin receptor (INSR) in humans produces severe insulin resistance. Unlike “common” insulin resistance, this is associated with elevated plasma levels of the insulin-sensitising, adipose-derived protein adiponectin. The underlying mechanism for this paradox is unclear, and it is at odds with the acute stimulation of adiponectin secretion reported on insulin treatment of cultured adipocytes. Given recent evidence for ligand-independent actions of the INSR, we used a lentiviral system to knock down Insr or its substrates Irs1 and Irs2 conditionally in 3T3-L1 murine preadipocytes/adipocytes to assess whether acute loss of their expression has different consequences to withdrawal of insulin. Efficient knockdown of either Insr or Irs1/2 was achieved by conditional shRNA expression, severely attenuating insulin-stimulated AKT phosphorylation and glucose uptake. Dual knockdown of Irs1 and Irs2 but not Insr in preadipocytes impaired differentiation to adipocytes. Acute knockdown of Insr or both Irs1 and Irs2 in adipocytes increased Adipoq mRNA expression but reduced adiponectin secretion, assessed by immunoassay. Knockdown sustained for 14 days also reduced immunoassay-detected adiponectin secretion, and moreover induced delipidation of the cells. These findings argue against a distinct effect of Insr deficiency to promote adiponectin secretion as the explanation for paradoxical insulin receptoropathy-related hyperadiponectinaemia. PMID:26888756

  11. The Effects of Anti-insulin Antibodies and Cross-reactivity with Human Recombinant Insulin Analogues in the E170 Insulin Immunometric Assay

    OpenAIRE

    Kim, Serim; Yun, Yeo Min; Hur, Mina; Moon, Hee Won; Kim, Jin Q

    2011-01-01

    Background Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. Methods Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the e...

  12. THE EFFECT OF CONTINUOUS SUBCUTANEOUS INSULIN INFUSION TREATMENT, INSULIN ANALOG, AND HUMAN INSULIN OF CHILDREN WITH DIABETES

    Directory of Open Access Journals (Sweden)

    Elina Petkova

    2015-09-01

    Full Text Available The aim of this study is to evaluate the cost-effectiveness of  continuous subcutaneous insulin infusion (CSII to multiple daily insulin injection (MDI either with analogues or with human insulin, based on the achieved therapeutic results such as changes in glycated hemoglobin level (HbA1c in the various therapies. The study was performed with children with type-1 diabetes in Bulgaria. The objective of this study was to serve for the Bulgarian National Health Fund (NHIF.Methods: A combined retrospective and prospective study was performed at the Endocrinology diabetes and genetic diseases clinic.51 children with type-1 diabetes were observed for 7 months diveded into three group: Group 1- on continuous subcutaneous insulin infusion (CSII; Group 2- on multiple daily insulin analogues injections (MDI and Group 3 – on human insulin (HI.Patient demographic data, age, sex, weight, duration of disease, HbA1c – values before the start of the study and after the end of the observation and type of treatment (CSII; MDI or HI were observed. Cost-effectiveness, sensitivity and statistical analyses are applied to studied long-term therapeutic results.Results: The three groups of observed children do not differ statistically in age and gender. Most of the participants in Group 1 and Group 2 have suffered from diabetes from 5,6 years. The duration of diabetes was lower in the group of human insulin. All studied children are treated. By all of them the results of the treatment improved, but in the Group 1 the improvement of HbA1c is the highest. The average improvement of HbA1c in the Group 1 after the CSII introduction is 1.85, while after the application of analogue insulin is 0,59 and 0,28 respectively in the Group 3 after the treatment on human insulin.The cost of insulin pump, consumables- infusion set and insulin reservoir, blood glucose monitoring system, strips, needles and insulin cost was calculated.The total cost ot the treatment of diabetes

  13. [Insulin resistance - its causes and therapy possibilities].

    Science.gov (United States)

    Pelikánová, Terezie

    2014-09-01

    Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re-assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone.Key words: cytokines - insulin resistance - insulin signalling cascade. PMID:25294764

  14. CHEMICAL DERIVATION OF HUMAN INSULIN SUPERAGONISM

    Institute of Scientific and Technical Information of China (English)

    MA Baoquan; KANG Wei; YAN Junkai

    2007-01-01

    The role of three highly conserved insulin residues TyrB26 was studied to better understand the relationship between insulin and receptor from rat adipose tissue plasma membranes. Insulin analogues with a single amino acid substitution or single N-methylation of the peptide bond in the position B26 were all shortened in the C-terminus of the B-chain by four amino acids. The effect of modifications was followed by the binding to the insulin receptor. From our results, we can deduce several conclusions: (1) the replacement of tyrosine in the position B26 by histidine,[N-MeHisB26]-des-tetrapeptide-(B27~B30)-insulin-B26-amide and [N-MeGluB26]-des-tetrapeptide(B27~B30)-insulin-B26-amide, have no significant effect on the binding affinity and they show binding affinity 105%, 190% and 208%, respectively, of that of human insulin; (2) [AadB26]-des-tetrapeptide-(B27~B30)-insulin-B26-amide and [Phe(4-carboxyB26)]-des-tetrapeptide(B27~B30)-insulin-B26-amide affect the potency highly positively in vitro studies; they show binding affinity 529 and 289 %, respectively, of that of human insulin.

  15. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    International Nuclear Information System (INIS)

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-125I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis

  16. [Insulin therapy for type 1 diabetes mellitus: past and present].

    Science.gov (United States)

    Pires, Antonio Carlos; Chacra, Antonio Roberto

    2008-03-01

    The discovery of insulin can be considered the milestone of diabetes mellitus history and a great achievement for its treatment. The first insulin available was the regular. Afterwards, Hagedorn added the protamine to the insulin, thus, creating the NPH insulin. In the 1950s an insulin free of protamine was synthesized: the lente insulin. With the advent of molecular biology, synthetic human insulin was synthesized using recombinant DNA technology. Most recently several types of insulin analogues were available, providing the patients with better metabolic control. Type 1 diabetes mellitus treatment includes plain substitution and individualization for short-acting plus long-acting insulin according to the physician's assistance, besides regular practice of physical activities and diet orientations. In type 1 diabetes mellitus the insulin of low variability is the best choice since basal/bolus insulin therapy or continuous subcutaneous insulin infusion pump can mimetize the physiological release of insulin by beta cells. PMID:18438537

  17. Producing Insulin from Neural Cells

    OpenAIRE

    Yuichi Hori; Xueying Gu; Xiaodong Xie; Kim, Seung K.

    2005-01-01

    BACKGROUND: Success in islet-transplantation-based therapies for type 1 diabetes, coupled with a worldwide shortage of transplant-ready islets, has motivated efforts to develop renewable sources of islet-replacement tissue. Islets and neurons share features, including common developmental programs, and in some species brain neurons are the principal source of systemic insulin. METHODS AND FINDINGS: Here we show that brain-derived human neural progenitor cells, exposed to a series of signals t...

  18. Diabetes, insulin and cancer risk

    OpenAIRE

    2012-01-01

    There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown. On the other hand, there are ongoing debates about the risk association of insulin use with cancer. We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer, as well as the current understanding of metabolic pathways impl...

  19. Insulin dysfunction and Tau pathology

    Directory of Open Access Journals (Sweden)

    Emmanuel Planel

    2014-02-01

    Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

  20. Subcutaneous insulin substitution in insulin-dependent diabetes mellitus. Pharmacokinetic and pharmacodynamic studies.

    Science.gov (United States)

    Olsson, P O

    1987-01-01

    Determination of free and total insulin with radioimmunoassay, after precipitation of endogenous insulin antibodies with polyethylene glycol, was evaluated. Insulin substitution in insulin-dependent diabetic patients was investigated, embracing the 24 h free insulin and glucose profiles with different regimens, the miscibility of insulin preparations, the overnight metabolic control, and bolus doses of different size with infusion pumps. In the free and total insulin assay precipitation of immunoglobulins with polyethylene glycol was almost complete and the recovery was high. Compared to immediately precipitated and assayed plasma samples at 37 degrees C, free insulin slightly decreased in immediately processed serum (20 degrees C), and also in plasma after 3 h at 20 degrees C. In stored (-20 degrees C) unprecipitated plasma samples free insulin increased after 4 weeks and also in serum samples after 26 weeks, whereas stored PEG-supernates were stable. In healthy controls a low basal insulin was found, increasing about tenfold postprandially. No morning rise in free insulin or glucose was found. The 24 h free insulin profile was strikingly unphysiological with 1 or 2 dose regimens; there was preprandial and nocturnal hyperinsulinaemia but absence of meal-related free insulin peaks. A considerable glucose rise was found after breakfast. Intensive regimens with conventional injections or infusion pumps, gave 24 h free insulin profiles that were similar to the physiological. However, the prandial peaks were retarded; and hyperinsulinaemia was shown with infusion pumps during daytime. An immediate loss of regular insulin was demonstrated after mixture with semisynthetic human lente insulin in vitro and in vivo, but not after mixture with biosynthetic human NPH insulin. The morning glucose control was similar with a bedtime injection of intermediate-acting insulin or continuous subcutaneous insulin infusion, but less hyperinsulinaemia overnight was found with the

  1. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB; Dela, Flemming; Fenger, Mogens; Richelsen, Bjørn; Madsbad, Sten; Iversen, Johan; Pedersen, Erik Steen

    2006-01-01

    lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp...... clamp values combined) correlated strongly and positively in both LIPO (R2 = 0.43, P < .001) and controls (R2 = 0.60, P < .0001). Fasting FFA and LIPOX did not differ between study groups; however, the insulin-mediated suppression of FFA and LIPOX was attenuated in LIPO (P's < .05). Our data indicate...... that higher TNF-alpha, independently of insulin sensitivity, is associated with attenuated insulin-mediated suppression of FFA and LIPOX in HIV-LIPO, suggesting in turn that TNF-alpha stimulates lipolysis in this syndrome. Furthermore, FFA may be a major determinant of LIPOX in HIV-infected patients on...

  2. ApoE4 expression accelerates hippocampus-dependent cognitive deficits by enhancing Aβ impairment of insulin signaling in an Alzheimer’s disease mouse model

    Science.gov (United States)

    Chan, Elizabeth S.; Shetty, Mahesh Shivarama; Sajikumar, Sreedharan; Chen, Christopher; Soong, Tuck Wah; Wong, Boon-Seng

    2016-01-01

    The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice. PMID:27189808

  3. Fish oil and argan oil intake differently modulate insulin resistance and glucose intolerance in a rat model of dietary-induced obesity.

    Science.gov (United States)

    Samane, Samira; Christon, Raymond; Dombrowski, Luce; Turcotte, Stéphane; Charrouf, Zoubida; Lavigne, Charles; Levy, Emile; Bachelard, Hélène; Amarouch, Hamid; Marette, André; Haddad, Pierre Selim

    2009-07-01

    We investigated the potential metabolic benefits of fish oil (FO) or vegetable argan oil (AO) intake in a dietary model of obesity-linked insulin resistance. Rats were fed a standard chow diet (controls), a high-fat/high-sucrose (HFHS) diet, or an HFHS diet in which 6% of the fat was replaced by either FO or AO feeding, respectively. The HFHS diet increased adipose tissue weight and insulin resistance as revealed by increased fasting glucose and exaggerated glycemic and insulin responses to a glucose tolerance test (intraperitoneal glucose tolerance test). Fish oil feeding prevented fat accretion, reduced fasting glycemia, and normalized glycemic or insulin responses to intraperitoneal glucose tolerance test as compared with HFHS diet. Unlike FO consumption, AO intake failed to prevent obesity, yet restored fasting glycemia back to chow-fed control values. Insulin-induced phosphorylation of Akt and Erk in adipose tissues, skeletal muscles, and liver was greatly attenuated in HFHS rats as compared with chow-fed controls. High-fat/high-sucrose diet-induced insulin resistance was also confirmed in isolated hepatocytes. Fish oil intake prevented insulin resistance by improving or fully restoring insulin signaling responses in all tissues and isolated hepatocytes. Argan oil intake also improved insulin-dependent phosphorylations of Akt and Erk; and in adipose tissue, these responses were increased even beyond values observed in chow-fed controls. Taken together, these results strongly support the beneficial action of FO on diet-induced insulin resistance and glucose intolerance, an effect likely explained by the ability of FO to prevent HFHS-induced adiposity. Our data also show for the first time that AO can improve some of the metabolic and insulin signaling abnormalities associated with HFHS feeding. PMID:19394055

  4. Cardiac Insulin Resistance and MicroRNA Modulators

    Directory of Open Access Journals (Sweden)

    Lakshmi Pulakat

    2012-01-01

    Full Text Available Cardiac insulin resistance is a metabolic and functional disorder that is often associated with obesity and/or the cardiorenal metabolic syndrome (CRS, and this disorder may be accentuated by chronic alcohol consumption. In conditions of over-nutrition, increased insulin (INS and angiotensin II (Ang II activate mammalian target for rapamycin (mTOR/p70 S6 kinase (S6K1 signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2, it also renders cardioprotection via increased Ang II receptor 2 (AT2R upregulation and adaptive hypertrophy. In the INS-resistant and hyperinsulinemic Zucker obese (ZO rat, a rodent model for CRS, activation of mTOR/S6K1signaling in cardiac tissue is regulated by protective feed-back mechanisms involving mTOR↔AT2R signaling loop and profile changes of microRNA that target S6K1. Such regulation may play a role in attenuating progressive heart failure. Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy.

  5. Vascular Function, Insulin Action and Exercise: An Intricate Interplay

    OpenAIRE

    Zheng, Chao; Liu, Zhenqi

    2015-01-01

    Insulin enhances the compliance of conduit arteries, relaxes resistance arterioles to increase tissue blood flow and dilates precapillary arterioles to expand muscle microvascular blood volume. These actions are impaired in the insulin resistant states. Exercise ameliorates endothelial dysfunction and improves insulin responses in insulin resistant patients, but the precise underlying mechanisms remain unclear. The microvasculature critically regulates insulin action in muscle by modulating i...

  6. A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Qilu [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Zhao, Leping [Department of Pharmacy, the Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang (China); Wang, Yi; Zhang, Yali [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Li, Zhaoyu [Department of International High School, Shanghai Jiaotong University Nanyang Affiliated (Kunshan) School, Minhang District, Shanghai (China); Pan, Yong; Kanchana, Karvannan; Wang, Jingying; Tong, Chao [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China); Li, Dan, E-mail: yqyyld@163.com [Department of Nephrology, the Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang (China); Liang, Guang, E-mail: wzmcliangguang@163.com [Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang (China)

    2015-01-15

    Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future. - Highlights: • Inflammation plays a central role in the development of diabetic nephropathy. • Compound L6H21 reduced the high glucose-mediated inflammation in NRK-52E cells. • Compound L6H21 attenuated the inflammation-mediated renal injury. • L6H21 exhibited anti-inflammatory effects via inactivation of NF-κB/MAPKs. • MAPKs/NF-κB may be a novel therapeutic target in diabetic nephropathy treatment.

  7. Associations of insulin and insulin-like growth factors with physical performance in old age in the Boyd Orr and Caerphilly studies.

    Directory of Open Access Journals (Sweden)

    Kate Birnie

    Full Text Available OBJECTIVE: Insulin and the insulin-like growth factor (IGF system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age. METHODS: Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63-86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men; and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women. RESULTS: In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: -0.2%, 3.2%; p = 0.08, but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08, although associations were attenuated after controlling for body mass index (BMI and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02, but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance. CONCLUSIONS: There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings.

  8. Insulin Expression in Rats Exposed to Cadmium

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objectives To investigate the effects of cadmium exposure on insulin expression in rats. Methods Eighteen adult SD assessed. The levels of cadmium and zinc in pancreas, blood and urine glucose, serum insulin and urine NAG (N-acyetyl-β-glucosaminidase) were determined. The gene expressions of metallothionein (MT) and insulin were also measured,and the oral glucose tolerance tests (OGTT) were carried out. Results The contents of cadmium in pancreas in cadmium-treated rats were higher than that in the control group, which was associated with slight increase of zinc in pancreas.not change significantly after cadmium administration, and the UNAG had no change in Cd-treated group. The gene expression the change of the expression of insulin, MT-Ⅰ and MT-Ⅱ genes. Cadmium can influence the biosynthesis of insulin, but does not induce the release of insulin. The dysfunction of pancreas occurs earlier than that of kidney after administration of cadmium.

  9. Radioimmunoassay in the detection of insulin secretion

    International Nuclear Information System (INIS)

    Some antihypertensive drugs have been shown to cause clinically significant alteration in the endocrine function. This study was conducted to investigate the effect of a new antihypertensive drug, rilmenidine on insulin secretion, which is an important determinant for glucose metabolism. In-vitro method was used to study the direct effect of rilmenidine on glucose induced insulin secretion using isolated rat pancreas. Insulin was assayed using radioimmunoassay. Concentrations of rilmenidine used were based on the peak plasma concentration achieved with an oral standard dose of 1 mg. This study showed that rilmenidine at low concentration was able to stimulate insulin secretion whereas at higher concentration inhibited the insulin secretion. This probably was due to its effect on the imidazoline receptor and the alpha2 adrenoceptor known to induce and inhibit insulin secretion respectively. (Author)

  10. Josephson tunnel junction microwave attenuator

    DEFF Research Database (Denmark)

    Koshelets, V. P.; Shitov, S. V.; Shchukin, A. V.;

    1993-01-01

    A new element for superconducting electronic circuitry-a variable attenuator-has been proposed, designed, and successfully tested. The principle of operation is based on the change in the microwave impedance of a superconductor-insulator-superconductor (SIS) Josephson tunnel junction when dc biased...

  11. Compact plasmonic variable optical attenuator

    DEFF Research Database (Denmark)

    Leosson, Kristjan; Rosenzveig, Tiberiu; Hermannsson, Pétur Gordon;

    2008-01-01

    We demonstrate plasmonic nanowire-based thermo-optic variable optical attenuators operating in the 1525-1625 nm wavelength range. The devices have a footprint as low as 1 mm, extinction ratio exceeding 40 dB, driving voltage below 3 V, and full modulation bandwidth of 1 kHz. The polarization...

  12. Attenuation of Vrancea events revisited

    International Nuclear Information System (INIS)

    New aspects of the frequency-dependent attenuation of the seismic waves traveling from Vrancea subcrustal sources toward NW (Transylvanian Basin) and SE (Romanian Plain) are evidenced by the recent experimental data made available by the CALIXTO'99 tomography experiment. The observations validate the previous theoretical computations performed for the assessment, by means of a deterministic approach, of the seismic hazard in Romania. They reveal an essential aspect of the seismic ground motion attenuation, that has important implications on the probabilistic assessment of seismic hazard from Vrancea intermediate-depth earthquakes. The attenuation toward NW is shown to be a much stronger frequency-dependent effect than the attenuation toward SE and the seismic hazard computed by the deterministic approach fits satisfactorily well the observed ground motion distribution in the low-frequency band (< 1 Hz). The apparent contradiction with the historically-based intensity maps arises mainly from a systematic difference in the vulnerability (buildings eigenperiod) of the buildings in the intra- and extra-Carpathians regions. (author)

  13. Historical data enhances safety supervision system performance in T1DM insulin therapy risk management.

    Science.gov (United States)

    Hughes-Karvetski, Colleen; Patek, Stephen D; Breton, Marc D; Kovatchev, Boris P

    2013-02-01

    Safety measures to prevent or mitigate hypoglycemia are an important component of open loop, closed loop, and advisory mode insulin therapy control settings in type 1 diabetes. In recent work, we introduce a method for the automatic, gradual attenuation of the insulin pump delivery rate when a risk of hypoglycemia is detected, a method that we refer to as brakes. In the methods presented here, we demonstrate the use of historical glucose measurement data to inform and enhance the ability of the brakes to prevent hypoglycemia in real-time. The updated brakes are based on a patient-specific, time-varying model that reflects the typical trajectory of glycemic fluctuations throughout the day. Historical heightened risk of hypoglycemia throughout the day prompts an increase in the aggressiveness of insulin attenuation as compared to the original brakes that are based on real-time data alone. Through the use of available real-time data supplemented with historical glucose information to assess hypoglycemic risk, we are able to better anticipate and prevent hypoglycemia. PMID:22342221

  14. Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity

    DEFF Research Database (Denmark)

    Gjessing, H J; Matzen, L E; Pedersen, P C;

    1988-01-01

    Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a...... fasting plasma C-peptide concentration above 0.20 nmol/l a few days before insulin withdrawal. Insulin sensitivity was measured as the glucose disappearance rate (k) during an intravenous insulin tolerance test. Two patients were considered insulin-requiring due to high fasting blood glucose levels...... stimulated C-peptide levels and insulin sensitivity (r = 0.41, p less than 0.05). Fasting and stimulated C-peptide concentrations of 0.40 and 0.70 nmol/l, respectively, separated non-insulin-requiring patients from a group consisting of both insulin- and non-insulin-requiring patients. At these C...

  15. Increased skeletal muscle capillarization enhances insulin sensitivity.

    Science.gov (United States)

    Akerstrom, Thorbjorn; Laub, Lasse; Vedel, Kenneth; Brand, Christian Lehn; Pedersen, Bente Klarlund; Lindqvist, Anna Kaufmann; Wojtaszewski, Jørgen F P; Hellsten, Ylva

    2014-12-15

    Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. Therefore, we investigated whether increased skeletal muscle capillarization increases insulin sensitivity. Skeletal muscle-specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist prazosin to the drinking water of Sprague-Dawley rats (n = 33), whereas 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-wk prazosin treatment, which ensured that prazosin was cleared from the blood stream. Whole body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin sensitivity was assessed by administration of 2-deoxy-[(3)H]glucose during the plateau phase of the clamp. Whole body insulin sensitivity increased by ∼24%, and insulin-stimulated skeletal muscle 2-deoxy-[(3)H]glucose disposal increased by ∼30% concomitant with an ∼20% increase in skeletal muscle capillarization. Adipose tissue insulin sensitivity was not affected by the treatment. Insulin-stimulated muscle glucose uptake was enhanced independent of improvements in skeletal muscle insulin signaling to glucose uptake and glycogen synthesis, suggesting that the improvement in insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose in the muscle. The prazosin treatment did not affect the rats on any other parameters measured. We conclude that an increase in skeletal muscle capillarization is associated with increased insulin sensitivity. These data point toward the importance of increasing skeletal muscle capillarization for prevention or treatment of type 2 diabetes. PMID:25352432

  16. Insulin signaling pathways in lepidopteran steroidogenesis

    Directory of Open Access Journals (Sweden)

    WendySmith

    2014-02-01

    Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

  17. Insulin and metabolic substrates during human sepsis

    OpenAIRE

    Finney, Simon J

    2004-01-01

    Rusavy and colleagues recently endeavoured to dissect out the metabolic effects of insulin in patients with severe sepsis, in the setting of normoglycaemia. Twenty stable patients were studied 3–7 days after admission using a euglycaemic clamp at two supraphysiological insulin levels. Increased doses of exogenous insulin caused preferential use of glucose as a metabolic substrate, while total energy expenditure remained constant. Consequently, hyperinsulinaemia reduced tissue oxygen demand an...

  18. Leptin therapy, insulin sensitivity, and glucose homeostasis

    OpenAIRE

    Gilberto Paz-Filho; Claudio Mastronardi; Ma-Li Wong; Julio Licinio

    2012-01-01

    Glucose homeostasis is closely regulated not only by insulin, but also by leptin. Both hormones act centrally, regulating food intake and adiposity in humans. Leptin has several effects on the glucose-insulin homeostasis, some of which are independent of body weight and adiposity. Those effects of leptin are determined centrally in the hypothalamus and peripherally in the pancreas, muscles and liver. Leptin has beneficial effects on the glucose-insulin metabolism, by decreasing glycemia, insu...

  19. Adipose Inflammation, Insulin Resistance, and Cardiovascular Disease

    OpenAIRE

    Shah, Arti; Mehta, Nehal; Reilly, Muredach P.

    2008-01-01

    Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand ac...

  20. Insulin Sensitivity and Insulin Clearance are Heritable and Have Strong Genetic Correlation in Mexican Americans

    OpenAIRE

    Goodarzi, Mark O; Langefeld, Carl D.; Xiang, Anny H.; Chen, Yii-Der I.; Guo, Xiuqing; Hanley, Anthony J. G.; Raffel, Leslie J.; Kandeel, Fouad; Thomas A Buchanan; Norris, Jill M.; Fingerlin, Tasha E.; Lorenzo, Carlos; Rewers, Marian J; Haffner, Steven M.; Donald W Bowden

    2014-01-01

    Objective We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). Design and Methods GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (SI), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance ...