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Sample records for glp-1 based therapy

  1. Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control

    Science.gov (United States)

    Lee, Young-Sun; Jun, Hee-Sook

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro, and their molecular mechanisms of anti-inflammatory action. PMID:27110066

  2. GLP-1-based therapies have no microvascular effects in type 2 diabetes mellitus

    NARCIS (Netherlands)

    Smits, Mark M.; Tonneijck, Lennart; Muskiet, Marcel H.A.; Hoekstra, Trynke; Kramer, Mark H.H.; Diamant, Michaela; Serné, Erik H.; Van Raalte, Daniël H.

    2016-01-01

    Objective - To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results - We studied 57 patients with type 2 diabetes mellitus

  3. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2003-01-01

    GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satie......, it is as yet uncertain wether DDP-IV inhibitors will affect gastrointestinal motility, appetite and food intake. Even the effects of GLP-1 effects on the pancreatic islets may be partly neurally mediated and therefore uninfluenced by DPP-IV inhibition....

  4. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2003-01-01

    GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety...... of the peptide is necessary because of an exceptionally rapid rate of degradation catalyzed the enzyme dipeptidyl peptidase IV. With inhibitors of this enzyme, it is possible to protect the endogenous hormone and thereby elevate both fasting and postprandial levels of the active hormone. This leads to enhanced...

  5. GLP-1-Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus: An Acute and 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    Smits, Mark M; Tonneijck, Lennart; Muskiet, Marcel H A; Hoekstra, Trynke; Kramer, Mark H H; Diamant, Michaela; Serné, Erik H; van Raalte, Daniël H

    2016-10-01

    To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m(2); HbA1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo (P>0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P2-week study, no effects on vasomotion were observed. Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1-based therapies on glucose are not mediated through microvascular responses. © 2016 American Heart Association, Inc.

  6. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    Introduction: Recently, glucagon-like peptide-1 receptor (GLP-1R) agonists have become available for the treatment of type 2 diabetes. These agents exploit the physiological effects of GLP-1, which is able to address several of the pathophysiological features of type 2 diabetes. GLP-1R agonists...... presently available are administered once or twice daily, but several once-weekly GLP-1R agonists are in late clinical development. Areas covered: The present review aims to give an overview of the clinical data on the currently available GLP-1R agonists used for treatment of type 2 diabetes, exenatide...... and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  7. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...

  8. South Asian Consensus Guideline: Use of GLP-1 analogue therapy in diabetes during Ramadan

    Directory of Open Access Journals (Sweden)

    Md Faruque Pathan

    2012-01-01

    Full Text Available Ramadan is a lunar based month, during which Muslims across the world observe the ritual fast. This provides a challenge not only to the diabetic patient who wishes to observe the fast but also to the health care professional managing his diabetes. The challenge is to use therapies which are effective in maintaining good glycemic control and at the same time have a low propensity to cause hypoglycemia during the several hours of no calorie intake. The GLP-1 analogues are unique agents which are effective in providing glycemic reduction with a very low risk of hypoglycemia and hence find an important place in the management of diabetes during Ramadan. This Consensus Statement describes the pre-Ramadan assessment, planning, prescription and management and monitoring of patients who are on GLP-1 analogues, with or without other antidiabetic therapies.

  9. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy.

    Science.gov (United States)

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Walker, Adrian B; Varughese, George I

    2014-03-01

    Rapid improvement in glycaemic control with GLP-1 receptor agonist (RA) therapy has been reported to be associated with significant progression of diabetic retinopathy. This deterioration is transient, and continuing GLP-1 RA treatment is associated with reversal of this phenomenon. Pre-existent maculopathy, higher grade of retinopathy and longer duration of diabetes may be risk factors for persistent deterioration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Prediction of response to GLP-1 receptor agonist therapy in Japanese patients with type 2 diabetes.

    Science.gov (United States)

    Imai, Kenjiro; Tsujimoto, Tetsuro; Goto, Atsushi; Goto, Maki; Kishimoto, Miyako; Yamamoto-Honda, Ritsuko; Noto, Hiroshi; Kajio, Hiroshi; Noda, Mitsuhiko

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists can maintain good glycemic control in some diabetic. Here we compared the clinical characteristics and parameters reflecting glucose metabolism at the time of the initiation of GLP-1 receptor agonist therapy between patients who responded well to therapy and those who did not. The records of 43 patients with type 2 diabetes who started receiving GLP-1 receptor agonist therapy during hospitalization were retrospectively reviewed. Glucagon stimulation tests were performed, and patients were started on liraglutide or exenatide therapy. Preprandial blood glucose levels were measured on days 2 and 3 of GLP-1 receptor agonist therapy. We used the Cox proportional hazard model to compare clinical parameters between responders (HbA1c level ratio [HR] for non-response was 5.3 (95% confidence interval [CI]: 1.16-24.6, P = 0.03) for insulin therapy and 5.0 (95% CI: 1.13-22.16, P = 0.03) for sulfonylurea therapy. Compared with the lowest tertile, the HRs for non-response in the highest tertile were 3.1 (95% CI: 1.04-8.97, P = 0.04) for the mean preprandial blood glucose level on days 2 and 3 and 3.4 (95% CI: 1.05-11.01, P = 0.04) for the body mass index. The response was not significantly associated with the duration of diabetes or the glucagon stimulation test results. A receiver operating curve analysis showed that the mean preprandial blood glucose level had the highest area under the curve value (=0.72) for the prediction of non-responders. In patients with poorly controlled diabetes, the response to GLP-1 receptor agonist therapy was significantly associated with the treatment used before the initiation of therapy, the body mass index, and the mean preprandial blood glucose level during the 2 days after the initiation of therapy.

  11. GLP-1

    DEFF Research Database (Denmark)

    Aaboe, Kasper; Krarup, Thure; Madsbad, Sten

    2008-01-01

    and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities......Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1...... stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function...

  12. Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists.

    Science.gov (United States)

    Evers, Andreas; Haack, Torsten; Lorenz, Martin; Bossart, Martin; Elvert, Ralf; Henkel, Bernd; Stengelin, Siegfried; Kurz, Michael; Glien, Maike; Dudda, Angela; Lorenz, Katrin; Kadereit, Dieter; Wagner, Michael

    2017-05-25

    Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.

  13. GLP-1 based therapeutics: simultaneously combating T2DM and obesity

    OpenAIRE

    Heppner, Kristy M.; Perez-Tilve, Diego

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are we...

  14. Increasing GLP-1 Circulating Levels by Bariatric Surgery or by GLP-1 Receptor Agonists Therapy: Why Are the Clinical Consequences so Different?

    Science.gov (United States)

    Amouyal, Chloé; Andreelli, Fabrizio

    2016-01-01

    The “incretin effect” is used to describe the observation that more insulin is secreted after the oral administration of glucose compared to that after the intravenous administration of the same amount of glucose. During the absorption of meals, the gut is thought to regulate insulin secretion by secreting a specific factor that targets pancreatic beta cells. Additional research confirmed this hypothesis with the discovery of two hormones called incretins: gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1). During meals, specific cells in the gut (L and K enteroendocrine cells) secrete incretins, causing an increase in the blood concentrations of, respectively, GLP-1 and GIP. Bariatric surgery is now proposed during the therapeutic management of type 2 diabetes in obese or overweight populations. It has been hypothesized that restoration of endogenous GLP-1 secretion after the surgery may contribute to the postsurgical resolution of diabetes. In 2005, the commercialization of GLP-1 receptor agonists gave the possibility to test this hypothesis. A few years later, it is now accepted that GLP-1 receptor agonists and bariatric surgery differently improve type 2 diabetes. These differences between endogenous and exogenous GLP-1 on glucose homeostasis emphasized the dual properties of GLP-1 as a peptide hormone and as a neurotransmitter. PMID:27382574

  15. Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes

    DEFF Research Database (Denmark)

    Østergaard, Lauge; Frandsen, Christian Seerup; Dejgaard, Thomas Fremming

    2017-01-01

    INTRODUCTION: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme...... Covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment......Lira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D....

  16. Combined MSC and GLP-1 Therapy Modulates Collagen Remodeling and Apoptosis following Myocardial Infarction

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    Elizabeth J. Wright

    2016-01-01

    Full Text Available Background. Mesenchymal stem cells (MSCs and glucagon-like peptide-1 (GLP-1 are being tested as treatment strategies for myocardial infarction (MI; however, their mechanisms in the heart are not fully understood. Methods. We examined the effects of MSCs, either native, or engineered to secrete a GLP-1 fusion protein (MSCs ± GLP-1, on human cardiomyocyte apoptosis in vitro. The effect on cardiac remodeling when encapsulated in alginate beads (CellBeads-MSC and CellBeads-MSC + GLP-1 was also evaluated in a pig MI model, whereby pigs were treated with Empty Beads, CellBeads-MSC, or CellBeads-MSC + GLP-1 and sacrificed at one or four weeks following MI. Results. MSC + GLP-1 conditioned media demonstrated antiapoptotic effects on ischaemic human cardiomyocytes in vitro. In vivo, qRT-PCR revealed large changes in the expression of several genes involved in extracellular matrix remodeling, which were altered following MSC ± GLP treatment. After four weeks, infarcted areas were imaged using atomic force microscopy, demonstrating significant alterations between groups in the structure of collagen fibrils and resulting scar. Conclusions. These data demonstrate that MSCs ± GLP-1 exhibit modulatory effects on healing post-MI, affecting both apoptosis and collagen scar formation. These data support the premise that both MSCs and GLP-1 could be beneficial in MI treatment.

  17. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity.

    Science.gov (United States)

    Lee, Shin J; Sanchez-Watts, Graciela; Krieger, Jean-Philippe; Pignalosa, Angelica; Norell, Puck N; Cortella, Alyssa; Pettersen, Klaus G; Vrdoljak, Dubravka; Hayes, Matthew R; Kanoski, Scott; Langhans, Wolfgang; Watts, Alan G

    2018-03-21

    Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

  18. Clinical and Patient-Related Variables Associated with Initiating GLP-1 Receptor Agonist Therapy in Type 2 Diabetes Patients in Primary Care in Germany.

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    Qing Qiao

    Full Text Available To investigate real-world clinical and patient-related variables associated with initiating GLP-1 receptor agonist (GLP-1RA treatment relative to initiation of other glucose-lowering therapies in type 2 diabetes (T2D patients of primary care in Germany.Data for 938 T2D patients who started therapy with a GLP-1RA within 823 practices of primary care throughout Germany were retrospectively analyzed (Disease Analyser: 01/2011-03/2014. 5,197 T2D patients who initiated other non-GLP-1RA antidiabetic therapies were selected as controls. Multivariate logistic regression analyses were applied to identify factors associated with GLP-1RA initiation in primary care.Mean age (SD of GLP-1RA users was 57.8 (11.8 years (males: 55.5% and the average BMI was 36.1 (6.7 kg/m2. 22.8% were in diabetologist care and 12.0% had private health insurance. In multivariate regression, choice of GLP-1RA therapy instead of a different glucose-lowering drug class was associated with obesity (odds ratio: 1.68; 95% CI: 1.34-2.10, private health insurance (2.42; 1.89-3.09, younger age (0.94; 0.93-0.95 per year, male sex (0.85; 0.73-0.99, diabetologist care (2.11; 1.73-2.57, and geographic practice location (East vs. West-Germany; 1.25; 1.05-1.49. Among co-medication, angiotensin II antagonists (increased and non-steroidal antirheumatic agents (decreased were related to GLP-1RA prescriptions (both p<0.001.Consistent with German guidelines, GLP-1RA is mainly prescribed preferentially in T2D patients who are obese. GLP-1RA drugs were more frequently used than other options in privately health insured patients and in patients seeing a diabetologist.

  19. Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes.

    Science.gov (United States)

    Østergaard, Lauge; Frandsen, Christian Seerup; Dejgaard, Thomas Fremming; Madsbad, Sten

    2017-06-01

    A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme 'Dual action of liraglutide and insulin degludec in type 2 diabetes' (DUAL™), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo. Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUAL™ development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies. Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D.

  20. Therapies for inter-relating diabetes and obesity - GLP-1 and obesity

    DEFF Research Database (Denmark)

    Iepsen, Eva Pers Winning; Torekov, Signe S; Holst, Jens Juul

    2014-01-01

    INTRODUCTION: The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) is associated with increased mortality, morbidity as well as public health care expenses worldwide. The need for effective and long-lasting pharmaceutical treatment is obvious. The record of anti......-obesity drugs has been poor so far and the only efficient treatment today is bariatric surgery. Research has indicated that appetite inhibiting hormones from the gut may have a therapeutic potential in obesity. The gut incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral...... and central pathways mediating satiety. Clinical trials have shown that two GLP-1 receptor agonists exenatide and liraglutide have a weight-lowering potential in non-diabetic obese individuals. Furthermore, they may also hold a potential in preventing diabetes as compared to other weight loss agents. AREAS...

  1. Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist.

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    Qinghua Wang

    2010-09-01

    Full Text Available GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2168 h. Intraperitoneal glucose tolerance test (IPGTT in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.

  2. Effects of GLP-1 in the kidney.

    Science.gov (United States)

    Skov, Jeppe

    2014-09-01

    The incretin hormone, glucagon-like peptide-1 (GLP-1), stimulates insulin secretion and forms the basis of a new drug class for diabetes treatment. GLP-1 has several extra-pancreatic properties which include effects on kidney function. Although renal GLP-1 receptors have been identified, their exact localization and physiological role are incompletely understood. GLP-1 increases natriuresis through inhibition of the sodium-hydrogen ion exchanger isoform 3 in the proximal tubule. This may in part explain why GLP-1 receptor agonists have antihypertensive effects. Glomerular filtration rate is regulated by GLP-1, but the mechanisms are complex and may depend on e.g. glycaemic conditions. Atrial natriuretic peptide or the renin-angiotensin system may be involved in the signalling of GLP-1-mediated renal actions. Several studies in rodents have shown that GLP-1 therapy is renoprotective beyond metabolic improvements in models of diabetic nephropathy and acute kidney injury. Inhibition of renal inflammation and oxidative stress probably mediate this protection. Clinical studies supporting GLP-1-mediated renal protection exist, but they are few and with limitations. However, acute and chronic kidney diseases are major global health concerns and measures improving renal outcome are highly needed. Therefore, the renoprotective potential of GLP-1 therapy need to be thoroughly investigated in humans.

  3. Regulation of Glucose Homeostasis by GLP-1

    Science.gov (United States)

    Nadkarni, Prashant; Chepurny, Oleg G.; Holz, George G.

    2014-01-01

    Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics. PMID:24373234

  4. Global gene expression profiling of pancreatic islets in mice during streptozotocin-induced β-cell damage and pancreatic Glp-1 gene therapy

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    Jason M. Tonne

    2013-09-01

    Streptozotocin (STZ, a glucosamine-nitrosourea compound, has potent genotoxic effects on pancreatic β-cells and is frequently used to induce diabetes in experimental animals. Glucagon-like peptide-1 (GLP-1 has β-cell protective effects and is known to preserve β-cells from STZ treatment. In this study, we analyzed the mechanisms of STZ-induced diabetes and GLP-1-mediated β-cell protection in STZ-treated mice. At 1 week after multiple low-dose STZ administrations, pancreatic β-cells showed impaired insulin expression, while maintaining expression of nuclear Nkx6.1. This was accompanied by significant upregulation of p53-responsive genes in islets, including a mediator of cell cycle arrest, p21 (also known as Waf1 and Cip1. STZ treatment also suppressed expression of a wide range of genes linked with key β-cell functions or diabetes development, such as G6pc2, Slc2a2 (Glut2, Slc30a8, Neurod1, Ucn3, Gad1, Isl1, Foxa2, Vdr, Pdx1, Fkbp1b and Abcc8, suggesting global β-cell defects in STZ-treated islets. The Tmem229B, Prss53 and Ttc28 genes were highly expressed in untreated islets and strongly suppressed by STZ, suggesting their potential roles in β-cell function. When a pancreas-targeted adeno-associated virus (AAV vector was employed for long-term Glp-1 gene delivery, pancreatic GLP-1 expression protected mice from STZ-induced diabetes through preservation of the β-cell mass. Despite its potent β-cell protective effects, however, pancreatic GLP-1 overexpression showed limited effects on the global gene expression profiles in the islets. Network analysis identified the programmed-cell-death-associated pathways as the most relevant network in Glp-1 gene therapy. Upon pancreatic GLP-1 expression, upregulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given the pro-β-cell-survival effects of Cxcl12 (Sdf-1 in inducing GLP-1 production in α-cells, pancreatic GLP-1-mediated Cxcl13 induction might also play a

  5. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches...... and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable...

  6. Oral l-Arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice

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    Clemmensen, Christoffer; Smajilovic, Sanela; Smith, Eric P.; Woods, Stephen C.; Bräuner-Osborne, Hans; Seeley, Randy J.; D'Alessio, David A.

    2013-01-01

    Pharmacological and surgical interventions that increase glucagon-like peptide 1 (GLP-1) action are effective to improve glucose homeostasis in type 2 diabetes mellitus. In light of this, nutritional strategies to enhance postprandial GLP-1 secretion, particularly in the context of diet-induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid l-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral l-arginine acts as a GLP-1 secretagogue in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered l-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral l-arginine increased plasma GLP-1 and insulin and substantially improved glucose clearance. To directly assess the contribution of GLP-1 receptor (GLP-1R)-signaling to these improvements, l-arginine was given to Glp1r knockout mice and their wild-type littermates. In this experiment oral l-arginine significantly augmented insulin secretion and improved glucose clearance in WT mice, but not in Glp1r knockout littermates. Taken together these findings identify l-arginine as a GLP-1 secretagogue in vivo and demonstrate that improvement of glucose tolerance by oral l-arginine depends on GLP-1R-signaling. These findings raise the intriguing possibility that l-arginine-based nutritional and/or pharmaceutical therapies may benefit glucose tolerance by improving the postprandial GLP-1 response in obese individuals. PMID:23959939

  7. Role and development of GLP-1 receptor agonists in the management of diabetes

    Directory of Open Access Journals (Sweden)

    Chee W Chia

    2009-05-01

    Full Text Available Chee W Chia, Josephine M EganNational Institutes of Health, National Institute on Aging, Intramural Research Program, Baltimore, Maryland, USAAbstract: Glucagon-like peptide-1 (GLP-1 is a hormone secreted from enteroendocrine L cells of the intestine in response to food. Exogenous GLP-1 administration at pharmacological doses results in many effects that are beneficial for treating type 2 diabetes, these include: (1 an increase in insulin secretion from β cells; (2 a suppression of glucagon secretion from α cells in the presence of hyperglycemia but not hypoglycemia; (3 a delay in gastric emptying and gut motility which in turns delays absorption of ingested nutrients and dampens post-prandial glucose excursion; and (4 an increase in the duration of postprandial satiety therefore suppressing appetite and decreasing food intake which eventually leads to weight loss. However, GLP-1 is subject to rapid enzymatic degradation, and therefore, not suitable for long-term treatment. A synthetic enzyme-resistant GLP-1 receptor agonist that reproduces the biological effects of GLP-1 is in use and more are under development. This review aims at providing a summary of the properties of GLP-1 and the development of GLP-1-based therapies for treatment of diabetes.Keywords: incretin, GLP-1, GLP-1R agonist, diabetes

  8. The peptide agonist-binding site of the glucagon-like peptide-1 (GLP-1) receptor based on site-directed mutagenesis and knowledge-based modelling.

    Science.gov (United States)

    Dods, Rachel L; Donnelly, Dan

    2015-11-23

    Glucagon-like peptide-1 (7-36)amide (GLP-1) plays a central role in regulating blood sugar levels and its receptor, GLP-1R, is a target for anti-diabetic agents such as the peptide agonist drugs exenatide and liraglutide. In order to understand the molecular nature of the peptide-receptor interaction, we used site-directed mutagenesis and pharmacological profiling to highlight nine sites as being important for peptide agonist binding and/or activation. Using a knowledge-based approach, we constructed a 3D model of agonist-bound GLP-1R, basing the conformation of the N-terminal region on that of the receptor-bound NMR structure of the related peptide pituitary adenylate cyclase-activating protein (PACAP21). The relative position of the extracellular to the transmembrane (TM) domain, as well as the molecular details of the agonist-binding site itself, were found to be different from the model that was published alongside the crystal structure of the TM domain of the glucagon receptor, but were nevertheless more compatible with published mutagenesis data. Furthermore, the NMR-determined structure of a high-potency cyclic conformationally-constrained 11-residue analogue of GLP-1 was also docked into the receptor-binding site. Despite having a different main chain conformation to that seen in the PACAP21 structure, four conserved residues (equivalent to His-7, Glu-9, Ser-14 and Asp-15 in GLP-1) could be structurally aligned and made similar interactions with the receptor as their equivalents in the GLP-1-docked model, suggesting the basis of a pharmacophore for GLP-1R peptide agonists. In this way, the model not only explains current mutagenesis and molecular pharmacological data but also provides a basis for further experimental design. © 2016 Authors.

  9. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Holst, Jens Juul; McGill, Maria A

    2012-01-01

    Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic ß-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1....... The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2...... diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches...

  10. GLP-1 and energy balance: an integrated model of short-term and long-term control

    Science.gov (United States)

    Barrera, Jason G.; Sandoval, Darleen A.; D’Alessio, David A.; Seeley, Randy J.

    2014-01-01

    Glucagon-like peptide 1 (GLP-1), a peptide secreted from the intestine in response to nutrient ingestion, is perhaps best known for its effect on glucose-stimulated insulin secretion. GLP-1 is also secreted from neurons in the caudal brainstem, and it is well-established that, in rodents, central administration of GLP-1 potently reduces food intake. Over the past decade, GLP-1 has emerged not only as an essential component of the system that regulates blood glucose levels but also as a viable therapeutic target for the treatment of type 2 diabetes mellitus. However, although GLP-1 receptor agonists are known to produce modest but statistically significant weight loss in patients with diabetes mellitus, our knowledge of how endogenous GLP-1 regulates food intake and body weight remains limited. The purpose of this Review is to discuss the evolution of our understanding of how endogenous GLP-1 modulates energy balance. Specifically, we consider contributions of both central and peripheral GLP-1 and propose an integrated model of short-term and long-term control of energy balance. Finally, we discuss this model with respect to current GLP-1-based therapies and suggest ongoing research in order to maximize the effectiveness of GLP-1-based treatment of obesity. PMID:21647189

  11. Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist.

    OpenAIRE

    Qinghua Wang; Kui Chen; Rui Liu; Fang Zhao; Sandeep Gupta; Nina Zhang; Gerald J Prud'homme

    2010-01-01

    GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2168 h. Intraperitoneal glucose tolerance test (IPGTT) in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose...

  12. Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Patrone, Cesare; Holst, Jens Juul

    2013-01-01

    Metformin is the most frequently prescribed drug for treatment of type 2 diabetes. It improves insulin resistance and glycemia by reducing hepatic gluconeogenesis. In addition, diabetic patients on metformin therapy have elevated levels of the insulinotropic hormone glucagon-like peptide-1 (GLP-1......) and metformin has been shown to regulate the expression of the GLP-1R in the pancreas....

  13. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...

  14. Incretin-based agents in type 2 diabetic patients at cardiovascular risk: compare the effect of GLP-1 agonists and DPP-4 inhibitors on cardiovascular and pancreatic outcomes.

    Science.gov (United States)

    Zhang, Zeqing; Chen, Xi; Lu, Puhan; Zhang, Jianhua; Xu, Yongping; He, Wentao; Li, Mengni; Zhang, Shujun; Jia, Jing; Shao, Shiying; Xie, Junhui; Yang, Yan; Yu, Xuefeng

    2017-03-01

    Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk. Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia. When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82-0.98) and CV mortality (RR = 0.84, 95% CI 0.73-0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14-2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia. GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia.

  15. Neuroprotective Mechanisms of Glucagon-like Peptide-1-based Therapies in Ischaemic Stroke

    DEFF Research Database (Denmark)

    Marlet, Ida R; Ölmestig, Joakim N E; Vilsbøll, Tina

    2018-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systemati......Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this Mini......Review was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non...

  16. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany

    Directory of Open Access Journals (Sweden)

    Qiao Q

    2016-06-01

    Full Text Available Qing Qiao,1 Mario JNM Ouwens,1 Susan Grandy,2 Kristina Johnsson,1 Karel Kostev3 1Global Medicines Development, AstraZeneca, Gothenburg, Sweden; 2Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA; 3Epidemiology and Evidence-Based Medicine, Real-World Evidence Solutions, IMS Health, Frankfurt am Main, Germany Aim: This study aimed to compare 6-month adherence to therapy with exenatide once weekly (Bydureon® vs liraglutide once daily (Victoza® in patients with type 2 diabetes under primary care in Germany.Methods: A nationwide longitudinal prescription database (LRx, (between January 2011 and September 2014 was used to analyze adherence to therapy. The proportion of days covered (PDC by prescription was used as a measure of adherence in the 6-month postindex period. Logistic regression analyses were performed to investigate the associations between glucagon-like peptide-1 receptor agonist therapy adjusting for age, sex, and cotherapy.Results: Therapy was initiated in 5,449 patients with exenatide once weekly (age: 59.7±11.8 years; 51.4% were male and in 24,648 patients with liraglutide once daily (age: 59.4±11.4 years; 49.7% were male. The median PDC was 0.88 for exenatide once weekly and 0.77 for liraglutide once daily (P<0.05. Once-weekly exenatide was associated with significantly higher adherence. Odds ratio (95% confidence interval for having a PDC of ≥0.80 was 1.78 (1.62–1.96 for exenatide once weekly compared with liraglutide once daily after adjusting for age, sex, and cotherapy.Conclusion: Adherence to treatment with exenatide once weekly was significantly increased compared to that with liraglutide once daily over 6 months in patients with type 2 diabetes. Keywords: type 2 diabetes, GLP-1 receptor agonists, adherence

  17. Albiglutide: a unique GLP-1 receptor agonist.

    Science.gov (United States)

    Rendell, Marc S

    2016-12-01

    Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

  18. A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism.

    Science.gov (United States)

    Grasset, Estelle; Puel, Anthony; Charpentier, Julie; Collet, Xavier; Christensen, Jeffrey E; Tercé, François; Burcelin, Rémy

    2017-05-02

    Glucagon-like peptide-1 (GLP-1)-based therapies control glycemia in type 2 diabetic (T2D) patients. However, in some patients the treatment must be discontinued, defining a state of GLP-1 resistance. In animal models we identified a specific set of ileum bacteria impairing the GLP-1-activated gut-brain axis for the control of insulin secretion and gastric emptying. Using prediction algorithms, we identified bacterial pathways related to amino acid metabolism and transport system modules associated to GLP-1 resistance. The conventionalization of germ-free mice demonstrated their role in enteric neuron biology and the gut-brain-periphery axis. Altogether, insulin secretion and gastric emptying require functional GLP-1 receptor and neuronal nitric oxide synthase in the enteric nervous system within a eubiotic gut microbiota environment. Our data open a novel route to improve GLP-1-based therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Pancreatic effects of GLP-1

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2014-01-01

    -dependent manner. But perhaps equally importantly, GLP-1’s glucose lowering effects are attributable to a strong inhibition of glucagon secretion, and, thereby, a reduction of hepatic glucose output. The effects of GLP-1 on insulin secretion are mediated by binding of the hormone to the receptor (GLP-1r......) on the pancreatic β-cell, which increases intracellular cAMP levels and sets in motion a plethora of events that lead to secretion. In contrast, the inhibitory effect of GLP-1 on the α-cell may be indirect, involving paracrine intra-islet regulation by somatostatin and possibly also insulin, although GLP-1 also...... inhibits glucagon secretion in patients with type 1 diabetes mellitus. Besides these acute effects on the endocrine pancreas, GLP-1 also appears to have a positive effect on β-cell mass. In the following we will review GLP-1’s pancreatic effects with particular focus on its effects on pancreatic islets...

  20. [Cardiovascular effects of GLP-1 receptor agonist treatment: focus on liraglutide].

    Science.gov (United States)

    Haluzík, Martin; Trachta, Pavel; Mráz, Miloš

    2015-01-01

    Cardiovascular risk reduction is the major aim of type 2 diabetes mellitus treatment. The effects of various antidiabetics on the cardiovascular complications are currently under careful scrutiny. Incretin-based therapy that utilizes the effects of glucagon-like peptide 1 (GLP-1) or stimulation of its receptor by GLP-1 receptor agonists represents one of the most promising approaches from the potential cardiovascular risk reduction point of view. Experimental studies have shown that the GLP-1 and GLP-1 agonists treatment improves endothelial function, decrease blood pressure and protects myocardium during experimentally-induced ischemia. Clinical studies with GLP-1 receptor agonists consistently show that, in addition to good antidiabetic efficacy, its long-term administration decreases blood pressure, body weight and improves circulating lipid levels while slightly increasing heart rate. In this paper, we focus on the cardiovascular effects of GLP-1 receptor agonist liraglutide. Preliminary analyses of cardiovascular complications in phase III trials with liraglutide indicate its good cardiovascular safety. A possibility of cardioprotective effects of liraglutide remains still open and is currently studied within a prospective cardiovascular trial LEADER.

  1. Bariatric surgery may reduce the risk of Alzheimer's diseases through GLP-1 mediated neuroprotective effects.

    Science.gov (United States)

    Keshava, Hari B; Mowla, Ashkan; Heinberg, Leslie J; Schauer, Philip R; Brethauer, Stacy A; Aminian, Ali

    2017-07-01

    Obesity and diabetes are associated with deficits in multiple neurocognitive domains and increased risk for dementia. Over the last two decades, there has been a significant increase in bariatric and metabolic surgery worldwide, driven by rising intertwined pandemics of obesity and diabetes, along with improvement in surgical techniques. Patients undergoing bariatric surgery achieve a significant decrease in their excess weight and a multitude of sequela associated with obesity, diabetes, and metabolic syndrome. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide that has been implicated as one of the weight loss-independent mechanisms in how bariatric surgery affects type 2 diabetes. GLP-1 improves insulin secretion, inhibits apoptosis and induce pancreatic islet neogenesis, promotes satiety, and can regulate heart rate and blood pressure. Moreover, numerous studies have demonstrated potential neuroprotective and neurotrophic effects of GLP-1. Increased GLP-1 activity has been shown to increase cortical activity, promote neuronal growth, and inhibit neuronal degeneration. Specifically, in experimental studies on Alzheimer's disease, GLP-1 decreases amyloid deposition and neurofibrillary tangles. Furthermore, recent studies have also suggested that GLP-1 based therapies, new class of antidiabetic drugs, have favorable effects on neurodegenerative disorders such as Alzheimer's disease. We present a hypothesis that bariatric surgery can help delay or even prevent the onset of Alzheimer's disease in long-term by increasing the levels of GLP-1. This hypothesis has a potential for many studies from basic science projects to large population studies to fully understand the neurological and cognitive consequences of bariatric surgery and associated rise in GLP-1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Andersen, Ove; Haugaard, Steen B; Holst, J J

    2005-01-01

    with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; Pgroups (7689+/-1097 vs. 8041+/-998 pmol/L/180 min, respectively; not significant). In pooled study groups, the GIP incrAUC correlated positively with the ISR incr......OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV......-infected patients on highly active antiretroviral therapy (HAART). METHODS: Eighteen HIV-infected male patients (six lipodystrophic and 12 nonlipodystrophic) with normal glucose tolerance (NGT) were compared with 10 HIV-infected male patients (eight lipodystrophic and two nonlipodystrophic) with IGT. Plasma...

  3. GLP-1 defects in diabetes

    DEFF Research Database (Denmark)

    Janus, Charlotte; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2015-01-01

    with type 2 diabetes (T2D) but the underlying mechanisms are still incompletely understood. In subjects with impaired glucose tolerance (IGT) and T2D, reduced levels of circulating GLP-1 have been observed in cross-sectional studies. Regardless of other changes, a reduced GLP-1 secretion must result...... glucose disturbances to frank diabetes. Therefore, further studies are required. Ideally, longitudinal studies of predisposed subjects (i.e. obesity, first-degree relatives, post gestational diabetes) followed until diagnosis of T2D would be necessary for elucidating if, indeed, impaired GLP-1 secretion...

  4. GLP-1 defects in diabetes

    DEFF Research Database (Denmark)

    Janus, Charlotte; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2015-01-01

    glucose disturbances to frank diabetes. Therefore, further studies are required. Ideally, longitudinal studies of predisposed subjects (i.e. obesity, first-degree relatives, post gestational diabetes) followed until diagnosis of T2D would be necessary for elucidating if, indeed, impaired GLP-1 secretion...... with type 2 diabetes (T2D) but the underlying mechanisms are still incompletely understood. In subjects with impaired glucose tolerance (IGT) and T2D, reduced levels of circulating GLP-1 have been observed in cross-sectional studies. Regardless of other changes, a reduced GLP-1 secretion must result...

  5. Harnessing the incretin system beyond glucose control: potential cardiovascular benefits of GLP-1 receptor agonists in type 2 diabetes.

    Science.gov (United States)

    Cariou, B

    2012-10-01

    The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors--such as hypertension, dyslipidaemia and obesity--must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  6. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...... for using GLP-1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined....

  7. SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

    Directory of Open Access Journals (Sweden)

    Gurgle HE

    2016-06-01

    Full Text Available Holly E Gurgle, Karen White, Carrie McAdam-Marx Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, UT, USA Abstract: Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium–glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient. Keywords: type 2 diabetes mellitus, GLP-1 receptor agonist, SGLT2 inhibitor, A1c, weight loss, adverse effect

  8. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2004-01-01

    analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies...... with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation......Glucagon-like peptide-1 (GLP-1) is a peptide hormone from the gut that stimulates insulin secretion and protects beta-cells, inhibits glucagon secretion and gastric emptying, and reduces appetite and food intake. In agreement with these actions, it has been shown to be highly effective...

  9. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology.

    Science.gov (United States)

    Drucker, D J; Rosen, C F

    2011-11-01

    Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

  10. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence...... for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes......, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential...

  11. Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test

    DEFF Research Database (Denmark)

    Møller, Jonas B.; Jusko, William J.; Gao, Wei

    2011-01-01

    GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study....... The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two...... to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate...

  12. Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Andersen, O; Haugaard, S B; Holst, Jens Juul

    2005-01-01

    concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared...... with NGT patients (1455+/-422 vs. 409+/-254 pmol/L/180 min, respectively; PISR incr......, which may represent a compensatory mechanism rather than explain the IGT; (2) that the GIP response may be associated with ISR independently of plasma glucose in nondiabetic HIV-infected males on HAART....

  13. Neuroprotective properties of GLP-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Burcelin, Remy; Nathanson, Esther

    2011-01-01

    emptying. Furthermore, data are beginning to emerge that indicate a potential role for GLP-1 in neuroprotection. The increased risk of Alzheimer's disease, Parkinson's disease and stroke in people with type 2 diabetes suggests that shared mechanisms/pathways of cell death, possibly related to insulin...

  14. Glucagon-like peptide-1 (GLP-1)

    DEFF Research Database (Denmark)

    Skov, Jeppe; Dejgaard, Anders; Frøkiær, Jørgen

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone with multiple actions in addition to control of glucose homeostasis. GLP-1 is known to cause natriuresis in humans, but the effects on basic renal physiology are still partly unknown.......Glucagon-like peptide-1 (GLP-1) is an incretin hormone with multiple actions in addition to control of glucose homeostasis. GLP-1 is known to cause natriuresis in humans, but the effects on basic renal physiology are still partly unknown....

  15. Brain GLP-1 and insulin sensitivity.

    Science.gov (United States)

    Sandoval, Darleen; Sisley, Stephanie R

    2015-12-15

    Type 2 diabetes is often treated with a class of drugs referred to as glucagon-like peptide-1 (GLP-1) analogs. GLP-1 is a peptide secreted by the gut that acts through only one known receptor, the GLP-1 receptor. The primary function of GLP-1 is thought to be lowering of postprandial glucose levels. Indeed, medications utilizing this system, including the long-acting GLP-1 analogs liraglutide and exenatide, are beneficial in reducing both blood sugars and body weight. GLP-1 analogs were long presumed to affect glucose control through their ability to increase insulin levels through peripheral action on beta cells. However, multiple lines of data point to the ability of GLP-1 to act within the brain to alter glucose regulation. In this review we will discuss the evidence for a central GLP-1 system and the effects of GLP-1 in the brain on regulating multiple facets of glucose homeostasis including glucose tolerance, insulin production, insulin sensitivity, hepatic glucose production, muscle glucose uptake, and connections of the central GLP-1 system to the gut. Although the evidence indicates that GLP-1 receptors in the brain are not necessary for physiologic control of glucose regulation, we discuss the research showing a strong effect of acute manipulation of the central GLP-1 system on glucose control and how it is relevant to type 2 diabetic patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Inflammation meets metabolic disease: Gut feeling mediated by GLP-1

    Directory of Open Access Journals (Sweden)

    Tamara eZietek

    2016-04-01

    Full Text Available Chronic diseases such as obesity and diabetes, cardiovascular and inflammatory bowel diseases (IBD share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways like the unfolded protein response (UPR, alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular the L cell-derived incretin hormone glucagon-like peptide 1 (GLP-1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D. Yet, accumulating data indicates a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment including the microbiota via receptors and transporters. Subsequently mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling.This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity and disease.

  17. A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion.

    Science.gov (United States)

    Shigeto, Makoto; Cha, Chae Young; Rorsman, Patrik; Kaku, Kohei

    2017-04-01

    Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and K ATP channels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca 2+ ] in isolated β cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca 2+ and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs.

  18. Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit

    DEFF Research Database (Denmark)

    Vilsbøll, T; Garber, A J

    2012-01-01

    The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-...... for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.......The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non...

  19. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    Science.gov (United States)

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine"). Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  20. Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiovascular risk factors

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Vilsbøll, Tina; Knop, Filip K

    2018-01-01

    trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical...

  1. GLP-1 nanomedicine alleviates gut inflammation.

    Science.gov (United States)

    Anbazhagan, Arivarasu N; Thaqi, Mentor; Priyamvada, Shubha; Jayawardena, Dulari; Kumar, Anoop; Gujral, Tarunmeet; Chatterjee, Ishita; Mugarza, Edurne; Saksena, Seema; Onyuksel, Hayat; Dudeja, Pradeep K

    2017-02-01

    The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1β, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD). Published by Elsevier Inc.

  2. GLP-1R and amylin agonism in metabolic disease: complementary mechanisms and future opportunities

    Science.gov (United States)

    Roth, Jonathan D; Erickson, Mary R; Chen, Steve; Parkes, David G

    2012-01-01

    The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the β-cell hormone amylin have translated into hormone-based therapies for diabetes. Both classes of molecules also exhibit weight-lowering effects and have been investigated for their anti-obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP-1 and amylin agonism. Despite their similarities (e.g. both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycaemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds important implications for the development of novel, combination-based therapies, which are increasingly the norm for diabetes/metabolic disease. Finally, the future of GLP-1- and amylin agonist-based therapeutics is discussed. LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-1 PMID:21671898

  3. Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor.

    Science.gov (United States)

    Shaaban, Ghina; Oriowo, Mabayoje; Al-Sabah, Suleiman

    2016-12-26

    The glucagon-like peptide-1 receptor (GLP-1R) is an important target in the treatment of type 2 diabetes mellitus. The aim of this study was to compare the rate of agonist stimulated desensitization and internalization of GLP-1R. To this end, an N-terminally myc-tagged GLP-1R was stably expressed in HEK-293 cells. Homologous desensitization was assessed by measuring the cAMP response to agonist stimulation following pre-incubation with agonist for up to 120 min. Receptor internalization was monitored using an indirect ELISA-based method and confocal microscopy. Pre-incubation with GLP-1 resulted in a time-dependent loss of response to a second stimulation. Washing cells following pre-incubation failed to bring cAMP levels back to basal. Taking this into account, two desensitization rates were calculated: "apparent" (t 1/2 = 19.27 min) and "net" (t 1/2 = 2.99 min). Incubation of cells with GLP-1 also resulted in a time-dependent loss of receptor cell surface expression (t 1/2 = 2.05 min). Rapid agonist-stimulated internalization of GLP-1R was confirmed using confocal microscopy. Stimulation of GLP-1R with GLP-1 results in rapid desensitization and internalization of the receptor. Interestingly, the rate of "net" desensitization closely matches the rate of internalization. Our results suggest that agonist-bound GLP-1R continues to generate cAMP after it has been internalized.

  4. Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor

    OpenAIRE

    Li, Naichang; Lu, Jing; Willars, Gary B.

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compo...

  5. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  6. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations.

    Science.gov (United States)

    Carris, Nicholas W; Taylor, James R; Gums, John G

    2014-12-01

    Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin-GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

  7. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1 metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Directory of Open Access Journals (Sweden)

    Naichang Li

    Full Text Available Glucagon-like peptide-1 (GLP-1 released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R. GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+ signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  8. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Science.gov (United States)

    Li, Naichang; Lu, Jing; Willars, Gary B

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+) signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  9. Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor

    Science.gov (United States)

    Li, Naichang; Lu, Jing; Willars, Gary B.

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7–36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9–36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently ‘compound 2’ has been described as both an agonist and positive allosteric modulator of GLP-1 7–36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9–39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9–36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9–36 amide for key cellular responses including AMP generation, Ca2+ signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy. PMID:23094100

  10. Once-weekly GLP-1 agonists: How do they differ from exenatide and liraglutide?

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip Krag

    2010-01-01

    Incretin mimetics offer a new modality in diabetes treatment. This modality is based on the effects of the naturally occurring glucoregulatory gut hormone glucagon-like peptide-1 (GLP-1), which counteracts several pathophysiologic traits in type 2 diabetes. GLP-1 receptor agonists with extended...... the presently published data (with emphasis on clinical pharmacokinetics, efficacy, and safety) on GLP-1 agonists, which currently are in development and intended for once-weekly dosing: albiglutide/albugon, CJC-1131, CJC-1134-PC, exenatide once weekly, and taspoglutide....... half-lives entailing fewer injections and presumably an improved throughout-the-day glycemic control are in clinical development. This article summarizes the physiologic effects of GLP-1; the effects of the already marketed GLP-1 analogues for daily dosing, exenatide and liraglutide; and reviews...

  11. Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption

    NARCIS (Netherlands)

    ten Kulve, Jennifer S.; Veltman, Dick J.; van Bloemendaal, Liselotte; Groot, Paul F. C.; Ruhe, Henricus G.; Barkhof, Frederik; Diamant, Michaela; Ijzerman, Richard G.

    Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using

  12. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

    Science.gov (United States)

    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Involvement of gut microbiota in association between GLP-1/GLP-1 receptor expression and gastrointestinal motility.

    Science.gov (United States)

    Yang, Mo; Fukui, Hirokazu; Eda, Hirotsugu; Xu, Xin; Kitayama, Yoshitaka; Hara, Ken; Kodani, Mio; Tomita, Toshihiko; Oshima, Tadayuki; Watari, Jiro; Miwa, Hiroto

    2017-04-01

    The microbiota in the gut is known to play a pivotal role in host physiology by interacting with the immune and neuroendocrine systems in gastrointestinal (GI) tissues. Glucagon-like peptide 1 (GLP-1), a gut hormone, is involved in metabolism as well as GI motility. We examined how gut microbiota affects the link between GLP-1/GLP-1 receptor (GLP-1R) expression and motility of the GI tract. Germ-free (GF) mice (6 wk old) were orally administered a fecal bacterial suspension prepared from specific pathogen-free (SPF) mice, and then after fecal transplantation (FT) GI tissues were obtained from the GF mice at various time points. The expression of GLP-1 and its receptor was examined by immunohistochemistry, and gastrointestinal transit time (GITT) was measured by administration of carmine red solution. GLP-1 was expressed in endocrine cells in the colonic mucosa, and GLP-1R was expressed in myenteric neural cells throughout the GI wall. GLP-1R-positive cells throughout the GI wall were significantly fewer in GF mice with FT than in GF mice without gut microbiota reconstitution. GITT was significantly shorter in GF mice with FT than in control GF mice without FT and correlated with the number of GLP-1R-positive cells throughout the GI wall. GITT was significantly longer in GF control mice than in SPF mice. When those mice were treated with GLP-1 agonist extendin4, GITT was significantly longer in the GF mice. The gut microbiota may accelerate or at least modify GI motility while suppressing GLP-1R expression in myenteric neural cells throughout the GI tract. NEW & NOTEWORTHY The gut microbiota has been intensively studied, because it plays a pivotal role in various aspects of host physiology. On the other hand, glucagon-like peptide 1 (GLP-1) plays important roles in metabolism as well as gastrointestinal motility. In the present study, we have suggested that the gut microbiota accelerates gastrointestinal motility while suppressing the expression of GLP-1 receptor in

  14. Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor

    Directory of Open Access Journals (Sweden)

    Ghina Shaaban

    2016-12-01

    Full Text Available The glucagon-like peptide-1 receptor (GLP-1R is an important target in the treatment of type 2 diabetes mellitus. The aim of this study was to compare the rate of agonist stimulated desensitization and internalization of GLP-1R. To this end, an N-terminally myc-tagged GLP-1R was stably expressed in HEK-293 cells. Homologous desensitization was assessed by measuring the cAMP response to agonist stimulation following pre-incubation with agonist for up to 120 min. Receptor internalization was monitored using an indirect ELISA-based method and confocal microscopy. Pre-incubation with GLP-1 resulted in a time-dependent loss of response to a second stimulation. Washing cells following pre-incubation failed to bring cAMP levels back to basal. Taking this into account, two desensitization rates were calculated: “apparent” (t1/2 = 19.27 min and “net” (t1/2 = 2.99 min. Incubation of cells with GLP-1 also resulted in a time-dependent loss of receptor cell surface expression (t1/2 = 2.05 min. Rapid agonist-stimulated internalization of GLP-1R was confirmed using confocal microscopy. Stimulation of GLP-1R with GLP-1 results in rapid desensitization and internalization of the receptor. Interestingly, the rate of “net” desensitization closely matches the rate of internalization. Our results suggest that agonist-bound GLP-1R continues to generate cAMP after it has been internalized.

  15. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shuyuan [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Chen, Jiaxi [The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX (United States); Huang, Pintong [Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province (China); Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Grayburn, Paul A., E-mail: paulgr@baylorhealth.edu [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX (United States)

    2015-03-20

    Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation.

  16. A novel humanized GLP-1 receptor model enables both affinity purification and Cre-LoxP deletion of the receptor.

    Directory of Open Access Journals (Sweden)

    Lucy S Jun

    Full Text Available Class B G protein-coupled receptors (GPCRs are important regulators of endocrine physiology, and peptide-based therapeutics targeting some of these receptors have proven effective at treating disorders such as hypercalcemia, osteoporosis, and type 2 diabetes mellitus (T2DM. As next generation efforts attempt to develop novel non-peptide, orally available molecules for these GPCRs, new animal models expressing human receptor orthologs may be required because small molecule ligands make fewer receptor contacts, and thus, the impact of amino acid differences across species may be substantially greater. The objective of this report was to generate and characterize a new mouse model of the human glucagon-like peptide-1 receptor (hGLP-1R, a class B GPCR for which established peptide therapeutics exist for the treatment of T2DM. hGLP-1R knock-in mice express the receptor from the murine Glp-1r locus. Glucose tolerance tests and gastric emptying studies show hGLP-1R mice and their wild-type littermates display similar physiological responses for glucose metabolism, insulin secretion, and gastric transit, and treatment with the GLP-1R agonist, exendin-4, elicits similar responses in both groups. Further, ex vivo assays show insulin secretion from humanized islets is glucose-dependent and enhanced by GLP-1R agonists. To enable additional utility, the targeting construct of the knock-in line was engineered to contain both flanking LoxP sites and a C-terminal FLAG epitope. Anti-FLAG affinity purification shows strong expression of hGLP-1R in islets, lung, and stomach. We crossed the hGLP-1R line with Rosa26Cre mice and generated global Glp-1r-/- animals. Immunohistochemistry of pancreas from humanized and knock-out mice identified a human GLP-1R-specific antibody that detects the GLP-1R in human pancreas as well as in the pancreas of hGLP-1r knock-in mice. This new hGLP-1R model will allow tissue-specific deletion of the GLP-1R, purification of potential

  17. Removal of Duodenum Elicits GLP-1 Secretion

    DEFF Research Database (Denmark)

    Muscogiuri, Giovanna; Mezza, Teresa; Prioletta, Annamaria

    2013-01-01

    OBJECTIVETo evaluate the effect of removal of the duodenum on the complex interplay between incretins, insulin, and glucagon in nondiabetic subjects.RESEARCH DESIGN AND METHODSFor evaluation of hormonal secretion and insulin sensitivity, 10 overweight patients without type 2 diabetes (age 61 ± 19......) secretion (P = 0.0004), while both fasting and postprandial glucose levels increased (P = 0.0001); GLP-1 and glucagon responses to the mixed meal increased significantly after surgery (P = 0.02 and 0.031). While changes in GIP levels did not correlate with insulin, glucagon, and glucose levels, the increase...... in GLP-1 secretion was inversely related to the postsurgery decrease in insulin secretion (R(2) = 0.56; P = 0.012) but not to the increased glucagon secretion, which correlated inversely with the reduction of insulin (R(2) = 0.46; P = 0.03) and C-peptide (R(2) = 0.37; P = 0.04). Given that the remaining...

  18. Adverse Effects of GLP-1 Receptor Agonists

    OpenAIRE

    Filippatos, Theodosios D.; Panagiotopoulou, Thalia V.; Elisaf, Moses S.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of ...

  19. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter

    DEFF Research Database (Denmark)

    Larsen, Philip J; Holst, Jens Juul

    2005-01-01

    normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter...

  20. New screening strategy and analysis for identification of allosteric modulators for glucagon-like peptide-1 receptor using GLP-1 (9-36) amide.

    Science.gov (United States)

    Nakane, Atsushi; Gotoh, Yusuke; Ichihara, Junji; Nagata, Hidetaka

    2015-12-15

    The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be obviously different among HIT-465, HIT-736, and Novo Nordisk compound 2. This work may enable the design of new classes of drug candidates by targeting modulation of GLP-1 (7-36) amide and GLP-1 (9-36) amide. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas.

    Science.gov (United States)

    Smits, M M; Tonneijck, L; Muskiet, M H A; Kramer, M H H; Cahen, D L; van Raalte, D H

    2016-03-01

    The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β-cell function. © 2015 John Wiley & Sons Ltd.

  2. Cardiovascular safety and benefits of GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Brønden, Andreas; Lauritsen, Tina Vilsbøll

    2017-01-01

    INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss...... and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients...

  3. GLP-1 Receptor Agonists and Type 1 Diabetes - Where Do We Stand?

    Science.gov (United States)

    Popovic, Djordje S; Stokic, Edita; Popovic, Stevan L

    2015-01-01

    Type 1 diabetes (T1DM) is a disease characterized by autoimmune mediated destruction of the insulin producing beta cells of endocrine pancreas. Beside insulin deficiency, T1DM is also characterized by abnormal suppression of glucagon secretion in response to hyperglycemia. All these abnormalities are likely to leave patients dependent upon exogenous insulin administration for survival. GLP-1 is a hormone secreted by L-cells of distal small intestine and colon. GLP-1 exerts its effects through the interaction with GLP-1 receptor expressed in the pancreatic islets, lung, hypothalamus, stomach, heart and kidney. It belongs to the group of incretin peptides and it stimulates insulin and inhibits glucagon secretion. Actions of GLP-1 also include delaying of gastric emptying, reduction of appetite and induction of satiety. On the other hand, evidences mainly collected from animal models, have indicated the role of GLP-1 in increasing beta cell proliferation and differentiation and in decreasing the rate of beta cell apoptosis. GLP-1 receptor agonists are approved for the treatment of type 2 diabetes where they have established very important position. However, they are still not approved for use in T1DM, although they could have beneficial effects in both new onset and longstanding T1DM patients, mainly as an adjunctive therapy to insulin in order to improve glycemic control and body weight management in longstanding disease or to reduce insulin requirements or even to delay the absolute dependence upon insulin administration in new onset T1DM. Randomized, long-term, placebo controlled clinical trials are warranted before the official implementation of GLP-1 receptor agonists in the treatment of T1DM.

  4. Comparison of GLP-1 analogues versus sitagliptin in the management of type 2 diabetes: systematic review and meta-analysis of head-to-head studies.

    Directory of Open Access Journals (Sweden)

    Tiansheng Wang

    Full Text Available BACKGROUND: Incretin-based therapies which include glucagon-like peptide-1 (GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4 inhibitors are recommended by several practice guidelines as second-line agents for add-on therapy to metformin in patients with type 2 diabetes (T2DM who do not achieve glycemic control with metformin plus lifestyle interventions alone. The purpose of this study is to perform a systematic review with meta-analysis of existing head to head studies to compare the efficacy and safety of GLP-1 analogues with DPP-4 inhibitors. METHODS: We performed a systematic review and meta-analysis of head-to-head studies to compare GLP-1 analogues with DPP-4 inhibitors in the management of type 2 diabetes. A random effects model was selected to perform the meta-analyses, results were expressed as weighted mean differences for continuous outcomes and relative risks for dichotomous outcomes, both with 95% confidence intervals, and with I2 values and P values as markers of heterogeneity. RESULTS: Four head-to-head randomized controlled studies with 1755 patients were included. Compared to sitagliptin, GLP-1 analogues are more effective in reducing HbA1C (weight mean difference -0.41%, 95% CI -0.51 to -0.31 and body weight (weight mean difference -1.55 kg, 95% CI -1.98 to -1.12. Conversely, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events compared to sitagliptin: nausea (relative risk 3.14, 95% CI 2.15 to 4.59, vomiting (relative risk 2.60, 95% CI 1.48 to 4.56, diarrhea (relative risk 1.82, 95% CI 1.24 to 2.69, and constipation (relative risk 2.50, 95% CI 1.33 to 4.70. CONCLUSIONS: The result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parameters, however, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse

  5. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond

    Directory of Open Access Journals (Sweden)

    Lalita Prasad-Reddy

    2015-07-01

    Full Text Available The prevalence of type 2 diabetes is increasing at an astounding rate. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1 receptor agonists represent a unique approach to the treatment of diabetes, with benefits extending outside glucose control, including positive effects on weight, blood pressure, cholesterol levels, and beta-cell function. They mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. Their effects include increasing insulin secretion, decreasing glucagon release, increasing satiety, and slowing gastric emptying. There are currently four approved GLP-1 receptor agonists in the United States: exenatide, liraglutide, albiglutide, and dulaglutide. A fifth agent, lixisenatide, is available in Europe. There are important pharmacodynamic, pharmacokinetic, and clinical differences of each agent. The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Other warnings and precautions include pancreatitis and thyroid cell carcinomas. GLP-1 receptor agonists are an innovative and effective option to improve blood glucose control, with other potential benefits of preserving beta-cell function, weight loss, and increasing insulin sensitivity. Once-weekly formulations may also improve patient adherence. Overall, these are effective agents for patients with type 2 diabetes, who are either uncontrolled on metformin or intolerant to metformin.

  6. Choosing between GLP-1 Receptor Agonists and DPP-4 Inhibitors: A Pharmacological Perspective

    Directory of Open Access Journals (Sweden)

    Dominique Xavier Brown

    2012-01-01

    Full Text Available In recent years the incretin therapies have provided a new treatment option for patients with type 2 diabetes mellitus (T2DM. The incretin therapies focus on the increasing levels of the two incretin hormones, glucagon-like peptide 1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP. This results in increased glucose dependent insulin synthesis and release. GLP-1 receptor agonists such as liraglutide and exenatide exert an intrinsic biological effect on GLP-1 receptors directly stimulating the release of insulin from pancreatic beta cells. DPP-4 inhibitors such as sitagliptin and linagliptin prevent the inactivation of endogenous GLP-1 and GIP through competitive inhibition of the DPP-4 enzyme. Both incretin therapies have good safety and tolerability profiles and interact minimally with a number of medications commonly prescribed in T2DM. This paper focuses on the pharmacological basis by which the incretin therapies function and how this knowledge can inform and benefit clinical decisions. Each individual incretin agent has benefits and pitfalls relating to aspects such as glycaemic and nonglycaemic efficacy, safety and tolerability, ease of administration, and cost. Overall, a personalized medicine approach has been found to be favourable, tailoring the incretin agent to benefit and suit patient's needs such as renal impairment (RI or hepatic impairment (HI.

  7. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2004-01-01

    in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant...... with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation...

  8. GLP-1 and Amylin in the Treatment of Obesity

    DEFF Research Database (Denmark)

    Jorsal, T; Rungby, J; Knop, F K

    2016-01-01

    for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially...... producing a more effective treatment strategy to combat the rapidly increasing global obesity....

  9. The central GLP-1: implications for food and drug reward

    Directory of Open Access Journals (Sweden)

    Karolina Patrycja Skibicka

    2013-10-01

    Full Text Available Glucagon-like-peptide-1 (GLP-1 and its long acting analogues comprise a novel class of type 2 diabetes (T2D treatment. What makes them unique among other T2D drugs is their concurrent ability to reduce food intake, a great benefit considering the frequent comorbidity of T2D and obesity. The precise neural site of action underlying this beneficial effect is vigorously researched. In accordance with the classical model of food intake control GLP-1 action on feeding has been primarily ascribed to receptor populations in the hypothalamus and the hindbrain. In contrast to this common view, relevant GLP-1 receptor populations are distributed more widely, with a prominent mesolimbic complement emerging. The physiological relevance of the mesolimbic GLP-1 is suggested by the demonstration that similar anorexic effects can be obtained by independent stimulation of the mesolimbic and hypothalamic GLP-1 receptors. Results reviewed here support the idea that mesolimbic GLP-1 receptors are sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation. In parallel, emerging evidence suggests that the range of action of GLP-1 on reward behavior is not limited to food-derived reward but extends to cocaine, amphetamine and alcohol reward. The new discoveries concerning GLP-1 action on the mesolimbic reward system significantly extend the potential therapeutic range of this drug target.

  10. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter

    2015-01-01

    AIMS: In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim...

  11. Inhibition of glucagon secretion by GLP-1 agonists and DPP4 inhibitors

    DEFF Research Database (Denmark)

    Hansen, Morten; Juul Hare, Kristine; Holst, Jens Juul

    2011-01-01

    with emphasis on their glucagon-lowering effects. Finally, we review available glucagon data from current clinical studies on incretin-based treatment modalities (dipeptidyl peptidase 4 [DPP4] inhibitors and GLP-1 receptor agonists). Most of these studies suggest that both DPP4 inhibitors and GLP-1 receptor......*both known to contribute significantly to the hyperglycemic state of patients with T2DM. This article outlines the role of hyperglucagonemia in type 2 diabetic pathophysiology, summarizes the physiologic effects of glucagon-like peptide-1 (GLP-1), and gives an introduction to incretin-based treatments...... agonists lower fasting and postprandial plasma glucagon, and recent data suggest that these effects contribute importantly to the glucose-lowering effect of these treatments....

  12. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip K; Holst, Jens J

    2009-01-01

    Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys...... residues, is able to withstand physiological degradation by dipeptidyl peptidase IV. In vitro, lixisenatide bound to human GLP-1R with a greater affinity than native human GLP-1 (7-36 amide). In various in vitro and in vivo models of T2DM, lixisenatide improved glycemic measures and demonstrated promising...... pancreatic beta-cell-preserving actions. In patients with T2DM, subcutaneously administered lixisenatide displayed linear pharmacokinetics. In two phase II clinical trials, lixisenatide improved glucose tolerance, resulted in weight loss and lowered HbA1C, thereby causing significantly more patients...

  13. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence...

  14. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip K; Holst, Jens J

    2009-01-01

    Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys...... of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM....

  15. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    International Nuclear Information System (INIS)

    Rouse, Rodney; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-01-01

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment

  16. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Rouse, Rodney, E-mail: rodney.rouse@fda.hhs.gov; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-04-15

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

  17. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

    Directory of Open Access Journals (Sweden)

    Valborg Gudmundsdottir

    Full Text Available Glucagon-like peptide 1 (GLP-1 stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126. This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100. Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05 with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated

  18. GLP-1 improves neuropathology after murine cold lesion brain trauma

    DEFF Research Database (Denmark)

    DellaValle, Brian; Hempel, Casper; Johansen, Flemming Fryd

    2014-01-01

    OBJECTIVES: In this study, we address a gap in knowledge regarding the therapeutic potential of acute treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist after severe brain trauma. Moreover, it remains still unknown whether GLP-1 treatment activates the protective, anti-neurodegener......OBJECTIVES: In this study, we address a gap in knowledge regarding the therapeutic potential of acute treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist after severe brain trauma. Moreover, it remains still unknown whether GLP-1 treatment activates the protective, anti...... brain trauma. METHODS: Severe trauma was induced with a stereotactic cryo-lesion in mice and thereafter treated with vehicle, liraglutide, or liraglutide + GLP-1 receptor antagonist. A therapeutic window was established and lesion size post-trauma was determined. Reactive oxygen species were visualized...... the GLP-1 receptor. Reactive species generation was reduced by ∼40-60%. Necrotic and apoptotic tone maintained similar to sham in diseased animals with Lira treatment. Phosphorylation of CREB was markedly increased by Lira in a GLP-1 receptor-dependent manner. CREB-regulated cytoprotective and anti...

  19. Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection a b

    OpenAIRE

    Ussher, John R.; Baggio, Laurie L.; Campbell, Jonathan E.; Mulvihill, Erin E.; Kim, Minsuk; Kabir, M. Golam; Cao, Xiemin; Baranek, Benjamin M.; Stoffers, Doris A.; Seeley, Randy J.; Drucker, Daniel J.

    2014-01-01

    GLP-1R agonists improve outcomes in ischemic heart disease. Here we studied GLP-1R-dependent adaptive and cardioprotective responses to ventricular injury. Glp1r −/− hearts exhibited chamber-specific differences in gene expression, but normal mortality and left ventricular (LV) remodeling after myocardial infarction (MI) or experimental doxorubicin-induced cardiomyopathy. Selective disruption of the cardiomyocyte GLP-1R in Glp1r CM−/− mice produced no differences in survival or LV remodeling ...

  20. Comparative effectiveness of glycemic control in patients with type 2 diabetes treated with GLP-1 receptor agonists: a network meta-analysis of placebo-controlled and active-comparator trials

    Directory of Open Access Journals (Sweden)

    Orme ME

    2017-03-01

    Full Text Available Michelle E Orme,1 Hiep Nguyen,2 Jackie Y Lu,3 Susan A Thomas3 1ICERA Consulting Ltd, Swindon, UK; 2AstraZeneca, Wilmington, DE, 3AstraZeneca, Fort Washington, PA, USABackground: Clinical studies of patients with type 2 diabetes show that GLP-1 receptor agonists (GLP-1 RAs improve glycemic control and promote weight loss. We conducted a Bayesian network meta-analysis (NMA of placebo- and active-controlled randomized trials to assess the comparative effectiveness of liraglutide, albiglutide, dulaglutide, and exenatide twice daily and once weekly, with a focus on glycemic control. Materials and methods: We searched Medline, Embase, and the Cochrane Library (up to December 2014 for core registration programs for US-approved GLP-1 RAs. Patients reaching an A1C target of <7% were analyzed with a binomial model and change in A1C from baseline with a normal model. A covariate analysis assessed the impact of baseline A1C and treatment background on outcomes. Results: The base-case NMA used 23 trials reporting A1C outcomes at ~6 month follow-up. The results, unadjusted and adjusted for baseline A1C, indicated that all GLP-1 RAs resulted in statistically significantly lower A1C at follow-up compared with placebo. The odds of reaching the <7% target were also significantly better compared with placebo. With dulaglutide, exenatide once weekly, and liraglutide, the absolute reduction in A1C at 6 months was 0.9%–1.4%, and was significantly better than exenatide twice daily. Albiglutide was not significantly different from exenatide twice daily. We estimate that ~50% of patients will meet the <7% A1C target within 6 months of commencing GLP-1 RAs. Conclusion: This was a comprehensive assessment of the comparative effectiveness of GLP-1 RAs and A1C outcome. GLP-1 RAs are a viable addition to oral antidiabetes therapy, and dulaglutide, exenatide once weekly, and liraglutide are the most effective. Keywords: type 2 diabetes, glucagon-like peptide-1-receptor

  1. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Emerging technologies to achieve oral delivery of GLP-1 and GLP-1 analogs for treatment of type 2 diabetes mellitus (T2DM

    Directory of Open Access Journals (Sweden)

    Shengwu Ma

    2017-04-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a gastrointestinal (GI peptide hormone that stimulates insulin secretion, gene expression and β-cell proliferation, representing a potentially novel and promising therapeutic agent for the treatment of T2DM. DPP-IV-resistant, long-acting GLP-1 analogs have already been approved by FDA as injectable drugs for treating patients with T2DM. Oral delivery of therapeutic peptides and proteins would be preferred owing to advantages of lower cost, ease of administration and greater patient adherence. However, oral delivery of proteins can be affected by rapid enzymatic degradation in the GI tract and poor penetration across the intestinal membrane, which may require amounts that exceed practical consideration. Various production strategies have been explored to overcome challenges associated with the oral delivery of therapeutic peptides and proteins. The goal of this review is to provide an overview of the current state of progress made towards the oral delivery of GLP-1 and its analogs in the treatment of T2DM, with special emphasis on the development of plant and food-grade bacterial delivery systems. Recently, genetically engineered plants and food-grade bacteria have been increasingly explored as novel carrier systems for the oral delivery of peptide and protein drugs. These have a largely unexplored potential to serve both as an expression system and as a delivery vehicle for clinically relevant, cost effective therapeutics. As such, they hold great promise for human biopharmaceuticals and novel therapies against various diseases.

  3. Switch to Combined GLP1 Receptor Agonist Lixisenatide with Basal Insulin Glargine in Poorly Controlled T2DM Patients with Premixed Insulin Therapy: A Clinical Observation and Pilot Study in Nine Patients.

    Science.gov (United States)

    Harreiter, Jürgen; Kosi-Trebotic, Lana; Lukas, Albert; Wolf, Peter; Winhofer, Yvonne; Luger, Anton; Kautzky-Willer, Alexandra; Krebs, Michael R

    2017-06-01

    To prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting. Nine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher. Five of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% ± 0.5% (6 mmol/mol) and mean weight loss of -1.4 ± 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 ± 26 IU with iPremix formulations to 47 ± 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients. The conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix. EU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491. Sponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis.

  4. Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms.

    Directory of Open Access Journals (Sweden)

    Belén Picatoste

    Full Text Available BACKGROUND: Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1 enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart. METHODS: Goto-Kakizaki (GK rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin or vehicle (n=10, each. After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays. RESULTS: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36, alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells. CONCLUSIONS: Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36 promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

  5. The GLP-1 analogue liraglutide improves first-phase insulin secretion and maximal beta-cell secretory capacity over 14 weeks of therapy in subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Madsbad, Sten; Vilsbøll, Tina; Brock, Birgitte

    Aims: We investigated the clinical effect of liraglutide, a long- acting GLP-1 analogue, on insulin secretion in Type 2 diabetes. Methods: Thirty-nine subjects (28 completed) from a randomised trial received a hyperglycaemic clamp (20 mM) with intravenous arginine stimulation, and an insulin...... with placebo, the 1.25 and 1.9 mg/day doses of liraglutide increased maximal beta-cell secretory capacity with 6.3 pM (95% CI: 2.9–9.6) B114%, and 7.2 pM (95% CI: 3.3–11.0) B97%, respectively. These doses also increased first-phase insulin secretion relative to placebo by 11.0 pMh (95% CI: 6.6–15.4) B124...... group. Conclusion: In subjects with Type 2 diabetes, 14 weeks’ once-daily liraglutide (1.25 and 1.9 mg/day) markedly improves beta-cell function, significantly increases first-phase insulin secretion and maximal beta-cell secretory capacity....

  6. Enhancing the GLP-1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells

    OpenAIRE

    Li, Yazhou; Tweedie, David; Mattson, Mark P.; Holloway, Harold W.; Greig, Nigel H.

    2010-01-01

    Increasing evidence suggests that glucagon-like peptide-1 (GLP-1), an incretin hormone of current interest in type 2 diabetes, is neuroprotective in both cell culture and animal models. To characterize the neuroprotective properties of GLP-1 and associated underlying mechanisms, we over-expressed the GLP-1 receptor (R) on human neuroblastoma SH-SY5Y cells to generate a neuronal culture system featuring enhanced GLP-1R signaling. In GLP-1R over-expressing SH-SY5Y (SH-hGLP-1R#9) cells, GLP-1 an...

  7. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart

    DEFF Research Database (Denmark)

    Sonne, David P; Engstrøm, Thomas; Treiman, Marek

    2007-01-01

    to exert cardiovascular effects in a number of experimental models. Here we tested exendin-4 (Exe-4), a peptide agonist at GLP-1 receptors, and GLP-1(9-36) amide, the primary endogenous metabolite of GLP-1 (both in the concentration range 0.03-3.0 nM), for their protective effects against ischemia......Glucagon-Like Peptide-1 (GLP-1) is an incretin peptide secreted from intestinal L-cells, whose potent plasma glucose-lowering action has prompted intense efforts to develop GLP-1 receptor-targeting drugs for treatment of diabetic hyperglycemia. More recently, GLP-1 and its analogues have been shown.......2% of the ischemic area, pGLP-1 receptor antagonist. In contrast, both Exe-4 and GLP-1(9-36) amide were able to augment left ventricular performance (left ventricular developed pressure and rate-pressure product) during...

  8. The antagonistic metabolite of GLP-1, GLP-1 (9-36)amide, does not influence gastric emptying and hunger sensations in man

    DEFF Research Database (Denmark)

    Nagell, Carl Frederic; Pedersen, Jan F; Holst, Jens Juul

    2007-01-01

    OBJECTIVE: Glucagon-like peptide-1 (GLP-1 (7-36)amide) is an intestinal hormone that is released in response to meal ingestion. GLP-1 reduces postprandial gastric and exocrine pancreatic secretion and is believed to inhibit gastric emptying. Furthermore, GLP-1 may play a role in hunger and thirst...... regulation. In vivo, GLP-1 is rapidly (within minutes) converted into a metabolite, GLP-1 (9-36)amide, which has been shown to act as a GLP-1 receptor antagonist in vitro and in anaesthetized pigs. The purpose of this study was to assess the effect of infusion of GLP-1 (9-36)amide on hunger ratings...... and antral emptying of a meal. MATERIAL AND METHODS: Six healthy volunteers were tested in a double-blind, placebo-controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scale scoring during infusions of saline or GLP-1 (9...

  9. GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, M.; Brock, B.; Egefjord, L.

    2017-01-01

    Objectives: Glucose enters the brain tissue from plasma by facilitated diffusion across the two membranes of the endothelium of the blood-brain barrier (BBB), mediated by the glucose transporter 1 (GLUT1). There is evidence in Alzheimer's disease (AD) of reduction of glucose transport across...... the blood-brain barrier, due to diminished GLUT1 translocation and expression at the BBB. Reduced BBB GLUT1 expression is known to aggravate AD pathology and further impair cognitive function, implying that GLUT1 may be a potential target of therapy directed towards AD neurovascular dysfunction...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

  10. GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

    DEFF Research Database (Denmark)

    Hegedüs, Laszlo; Moses, Alan C; Zdravkovic, Milan

    2011-01-01

    to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. Methods: Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy....... There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. Aim: The aim of the study was to determine serum CT response over time...

  11. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice

    Directory of Open Access Journals (Sweden)

    Laurie L. Baggio

    2017-11-01

    Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

  12. Genetic determinants of circulating GIP and GLP-1 concentrations

    DEFF Research Database (Denmark)

    Almgren, Peter; Lindqvist, Andreas; Krus, Ulrika

    2017-01-01

    The secretion of insulin and glucagon from the pancreas and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract is essential for glucose homeostasis. Several novel treatment strategies for type 2 diabetes (T2D......) mimic GLP-1 actions or inhibit incretin degradation (DPP4 inhibitors), but none is thus far aimed at increasing the secretion of endogenous incretins. In order to identify new potential therapeutic targets for treatment of T2D, we performed a meta-analysis of a GWAS and an exome-wide association study...... of circulating insulin, glucagon, GIP, and GLP-1 concentrations measured during an oral glucose tolerance test in up to 7,828 individuals. We identified 6 genome-wide significant functional loci associated with plasma incretin concentrations in or near the SLC5A1 (encoding SGLT1), GIPR, ABO, GLP2R, F13A1...

  13. Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans

    Directory of Open Access Journals (Sweden)

    Martin Heni

    2015-12-01

    Conclusions: The postprandial release of GLP-1 might alter reward processes in the orbitofrontal cortex and might thereby support the termination of food intake and reduce hunger. While obese persons showed brain insulin resistance, no GLP-1 resistance was observed. Our study provides novel insight into the central regulation of food intake by the incretin hormone GLP-1.

  14. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

    Science.gov (United States)

    Fortin, Samantha M; Roitman, Mitchell F

    2017-07-01

    Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Effect of Oxyntomodulin, Glucagon, GLP-1 and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite and Resting Energy Expenditure

    DEFF Research Database (Denmark)

    Bagger, Jonatan I; Holst, Jens J; Hartmann, Bolette

    2015-01-01

    young healthy male volunteers (aged 22 [range 18–32] y; body mass index 23 [21–26] kg/m2; fasting plasma glucose 5.1 [4.4–5.4] mmol/L; and glycated hemoglobin A1c 40 (37–42) mmol/mol). Interventions: Five 4-hour liquid meal tests during the infusion of saline, GLP-1 (1 pmol × kg−1 × min−1), glucagon (0.......86 pmol × kg−1 × min−1), oxyntomodulin (3 pmol × kg−1 × min−1), or glucagon+GLP-1 (same doses). Main Outcome Measures: We evaluated resting energy expenditure (measured as oxygen uptake, gastric emptying (GE), composite appetite scores (CAS), and food intake. Results: Oxyntomodulin, GLP-1, and GLP-1......+glucagon slowed GE and reduced CAS, whereas glucagon did not affect GE and CAS. All infusions caused a similar decrease in food intake compared with saline (total intake (g [95% confidence interval]), saline 811 [729, 892], GLP-1 669 [586, 750], glucagon 686 [604, 768], oxyntomodulin 689 [608, 771...

  16. Differentiating among incretin-based therapies in the management of patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Cobble Michael

    2012-03-01

    Full Text Available Abstract The glucagon-like peptide-1 receptor (GLP-1R agonists and dipeptidyl peptidase-4 (DPP-4 inhibitors have become important options for the management of patients with type 2 diabetes mellitus. While the GLP-1R agonists and DPP-4 inhibitors act on the incretin system to regulate glucose homeostasis, there are important clinical differences among the five agents currently available in the U.S. For example, the GLP-1R agonists require subcutaneous administration, produce pharmacological levels of GLP-1 activity, promote weight loss, have a more robust glucose-lowering effect, and have a higher incidence of adverse gastrointestinal effects. In contrast, the DPP-4 inhibitors are taken orally, increase the half-life of endogenous GLP-1, are weight neutral, and are more commonly associated with nasopharyngitis. Differences in efficacy, safety, tolerability, and cost among the incretin-based therapies are important to consider in the primary care management of patients with type 2 diabetes mellitus.

  17. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  18. PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.

    Science.gov (United States)

    Nakamura, Taichi; Ito, Tetsuhide; Uchida, Masahiko; Hijioka, Masayuki; Igarashi, Hisato; Oono, Takamasa; Kato, Masaki; Nakamura, Kazuhiko; Suzuki, Koichi; Jensen, Robert T; Takayanagi, Ryoichi

    2014-01-01

    There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation

  19. A review of the new GLP-1 receptor agonist/basal insulin fixed-ratio combination products.

    Science.gov (United States)

    Nuffer, Wesley; Guesnier, Ashley; Trujillo, Jennifer M

    2018-03-01

    There have been several new treatment approaches established for the management of hyperglycemia in type 2 diabetes (T2D), with treatment guidelines listing both glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and basal insulin therapies as considerations for patients who have failed to control their blood glucose with oral antidiabetic agents. New studies have highlighted the importance of initiating combination therapy earlier in the T2D disease process to avoid clinical inertia and prevent the long-term complications arising from uncontrolled diabetes. Until recently, both GLP-1 RAs and basal insulin therapies were only available as single agents, but there are now two combination pen devices that deliver both a GLP-1 RA and basal insulin simultaneously. This article reviews the current clinical evidence evaluating the use of these combination GLP-1 RA/basal insulin preparations to treat T2D, presents both potential benefits as well as possible downsides with the use of these agents, and discusses the current place in therapy these products represent in the management of T2D.

  20. Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Trujillo, Jennifer M; Nuffer, Wesley

    2014-11-01

    To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from +0.28 to -1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs. © The Author(s) 2014.

  1. REVIEWMolecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation

    Science.gov (United States)

    Pabreja, K; Mohd, M A; Koole, C; Wootten, D; Furness, S G B

    2014-01-01

    The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide. Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5 PMID:23889512

  2. GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.

    Science.gov (United States)

    Pastel, Emilie; McCulloch, Laura J; Ward, Rebecca; Joshi, Shivam; Gooding, Kim M; Shore, Angela C; Kos, Katarina

    2017-03-01

    Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide ( n =22) or calorie restriction based on dietetic counselling ( n =8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg, P =0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α ( TNFA ) AT-expression ( P =0.0005), macrophage chemoattractant protein-1 ( MCP-1 ) expression ( P =0.027) and its serum levels ( P =0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 ( CD14 ) expression ( P =0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β ( TGFB ) and collagen type 1 alpha 1 chain ( COL1A1 ) ( TGFB1 : before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU, P =0.006; COL1A1 : 0.84±0.09 AU compared with 1.49±0.26 AU, P =0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re

  3. {sup 18}F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kiesewetter, Dale O.; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Gao, Haokao [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Fourth Military Medical University, Department of Cardiology, Xijing Hospital, Xi' an (China)

    2012-03-15

    Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic {beta}-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic {beta}-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. We prepared {sup 18}F radioligands for GLP-1R by the reaction of [{sup 18}F]FBEM, a maleimide prosthetic group, with [Cys{sup 0}] and [Cys{sup 40}] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. The [{sup 18}F]FBEM-[Cys{sup x}]-exendin-4 analogs were obtained in good yield (34.3 {+-} 3.4%, n = 11), based on the starting compound [{sup 18}F]FBEM, and had a specific activity of 45.51 {+-} 16.28 GBq/{mu}mol (1.23 {+-} 0.44 Ci/{mu}mol, n = 7) at the end of synthesis. The C-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4, had higher affinity for INS-1 tumor cells (IC{sub 50} 1.11 {+-} 0.057 nM) and higher tumor uptake (25.25 {+-} 3.39 %ID/g at 1 h) than the N-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 (IC{sub 50} 2.99 {+-} 0.06 nM, uptake 7.20 {+-} 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys{sup x}]-exendin-4 (p < 0.05). [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4 and [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors

  4. On the physiology of GIP and GLP-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2005-01-01

    and secretion, and perhaps its actions on appetite and food intake, all of which may be even more physiologically important than its effects on the beta cells. Cardiovascular and neuroprotective actions of GLP-1 have also recently been reported. Regarding GIP, several lines of evidence suggest that GIP...

  5. Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas.

    NARCIS (Netherlands)

    Brom, M.; Joosten, L.; Oyen, W.J.G.; Gotthardt, M.; Boerman, O.C.

    2012-01-01

    Internalizing agonists are usually selected for peptide receptor targeting. There is increasing evidence that non-internalizing receptor antagonists can be used for this purpose. We investigated whether the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin(9-39) can be used for in vivo

  6. GLP-1 receptor localization in monkey and human tissue

    DEFF Research Database (Denmark)

    Pyke, Charles; Heller, R Scott; Kirk, Rikke K

    2014-01-01

    Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure ...

  7. Immunoassays for the incretin hormones GIP and GLP-1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Holst, Jens J

    2009-01-01

    metabolites which have lost their insulinotropic activities. These metabolites are the major circulating forms of the incretins, accounting for 60-80% of total immunoreactive GLP-1 and GIP in the peripheral plasma, while concentrations of the intact forms can be very low and, in some cases, barely detectable...

  8. [Preparation and the biological effect of fusion protein GLP-1-exendin-4/ IgG4(Fc) fusion protein as long acting GLP-1 receptor agonist].

    Science.gov (United States)

    Zheng, Yun-cheng

    2015-12-01

    GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for treatment of diabetes due to its short half-life (t½, 2-5 min). Exendin-4 is a polypeptide isolated from lizard saliva, which can bind to GLP-1 receptor, produce physiological effects similar to GLP-1, t½ up to 2.5 h, therefore, we developed a long-lasting GLP-1 receptor agonists and GLP-1-exendin-4 fusion IgG4 Fc [GLP-1-exendin-4/ IgG4(Fc)]. We constructed the eukaryotic expression vector of human GLP-1-exendin-4/IgG4(Fc)-pOptiVEC- TOPO by gene recombination technique and expressed the fusion protein human GLP-1-IgG4 (Fc) in CHO/DG44 cells. The fusion protein stimulated the INS-1 cells secretion of insulin, GLP-1, exendin-4 and fusion protein in CD1 mice pharmacokinetic experiments, as well as GLP-1, exendin-4 and fusion protein did anti-diabetic effect on streptozotocin induced mice. Results demonstrated that the GLP-1-exendin-4/IgG4(Fc) positive CHO/DG44 clones were chosen and the media from these positive clones. Western blotting showed that one protein band was found to match well with the predicted relative molecular mass of human GLP-1-exendin-4/IgG4(Fc). Insulin RIA showed that GLP-1-exendin-4/IgG4(Fc) dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (ip), the fusion protein peaked at 30 min in circulation and maintained a plateau for 200 h. Natural biological half-life of exendin-4 was (1.39 ± 0.28) h, GLP-1 in vivo t½ 4 min, indicating that fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1-exendin-4/IgG4(Fc) was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced diabetes in mice, longer duration of the biological activity of the fusion protein. The biological activity was significantly higher than that of GLP-1 and exendin-4. GLP-1-exendin-4/IgG4(Fc) has good anti-diabetic activity

  9. GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice

    DEFF Research Database (Denmark)

    Jolivalt, CG; Fineman, M; Deacon, Carolyn F.

    2011-01-01

    Aim: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces glucose-dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP-1 receptors (GLP-1Rs) in peripheral nerve and to assess the impact of GLP-1R agonists on diab...... that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control....

  10. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice

    OpenAIRE

    Lamont, Benjamin J.; Li, Yazhou; Kwan, Edwin; Brown, Theodore J.; Gaisano, Herbert; Drucker, Daniel J.

    2011-01-01

    Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor–dependent (GLP-1R–dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R ...

  11. Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

    DEFF Research Database (Denmark)

    Alssema, Marjan; Rijkelijkhuizen, Josina M; Holst, Jens Juul

    2013-01-01

    -based study. METHODS: A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose......AUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. CONCLUSION: This study confirms that in type 2 diabetes......, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study....

  12. Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

    Science.gov (United States)

    Horner, Katy; Lee, SoJung

    2015-11-01

    During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents.

  13. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

    DEFF Research Database (Denmark)

    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  14. GLP-1 Induces Barrier Protective Expression in Brunner's Glands and Regulates Colonic Inflammation

    DEFF Research Database (Denmark)

    Bang-Berthelsen, Claus Heiner; Holm, Thomas L.; Pyke, Charles

    2016-01-01

    , and that prophylactic treatment with 0.6 mg/kg liraglutide improves disease in AdTr colitis. In addition, GLP-1 receptor agonists upregulate IL-33, mucin 5b, and CCL20 in murine Brunner's glands. Taken together, our data indicate that GLP-1 receptor agonists affect gut homeostasis in both proximal and distal parts......Background: Beneficial roles for glucagon-like peptide 1 (GLP-1)/GLP-1R signaling have recently been described in diseases, where low-grade inflammation is a common phenomenon. We investigated the effects of GLP-1 in Brunner's glands and duodenum with abundant expression of GLP-1 receptors, as well...... as GLP-1 effect on colonic inflammation.Methods: RNA from Brunner's glands of GLP-1R knockout and wild-type mice were subjected to full transcriptome profiling. Array results were validated by quantitative reverse transcription polymerase chain reaction in wild-type mice and compared with samples from...

  15. Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture

    Directory of Open Access Journals (Sweden)

    Andrea V. Rozo

    2017-07-01

    Conclusion: These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.

  16. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice.

    Science.gov (United States)

    Baggio, Laurie L; Ussher, John R; McLean, Brent A; Cao, Xiemin; Kabir, M Golam; Mulvihill, Erin E; Mighiu, Alexandra S; Zhang, Hangjun; Ludwig, Andreas; Seeley, Randy J; Heximer, Scott P; Drucker, Daniel J

    2017-11-01

    Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1r CM-/- ). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1r CM-/- mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1r CM-/- mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the

  17. Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward.

    Directory of Open Access Journals (Sweden)

    Rozita H Shirazi

    Full Text Available Glucagon-like-peptide-1 (GLP-1 is a gut- and neuro-peptide with an important role in the regulation of food intake and glucose metabolism. Interestingly, GLP-1 receptors (GLP-1R are expressed in key mesolimbic reward areas (including the ventral tegmental area, VTA, innervated by hindbrain GLP-1 neurons. Recently GLP-1 has emerged as a potential regulator of food reward behavior, an effect driven by the mesolimbic GLP-1Rs. Its role in other reward behaviors remains largely unexplored. Since a considerable overlap has been suggested for circuitry controlling reward behavior derived from food and alcohol we hypothesized that GLP-1 and GLP-1Rs could regulate alcohol intake and alcohol reward. We sought to determine whether GLP-1 or its clinically safe stable analogue, Exendin-4, reduce alcohol intake and reward. To determine the potential role of the endogenous GLP-1 in alcohol intake we evaluated whether GLP-1R antagonist, Exendin 9-39, can increase alcohol intake. Furthermore, we set out to evaluate whether VTA GLP-1R activation is sufficient to reduce alcohol intake. Male Wistar rats injected peripherally with GLP-1 or Exendin-4 reduced their alcohol intake in an intermittent access two bottle free choice drinking model. Importantly, a contribution of endogenously released GLP-1 is highlighted by our observation that blockade of GLP-1 receptors alone resulted in an increased alcohol intake. Furthermore, GLP-1 injection reduced alcohol reward in the alcohol conditioned place preference test in mice. To evaluate the neuroanatomical substrate linking GLP-1 with alcohol intake/reward, we selectively microinjected GLP-1 or Exendin 4 into the VTA. This direct stimulation of the VTA GLP-1 receptors potently reduced alcohol intake. Our findings implicate GLP-1R signaling as a novel modulator of alcohol intake and reward. We show for the first time that VTA GLP-1R stimulation leads to reduced alcohol intake. Considering that GLP-1 analogues are already

  18. Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients

    DEFF Research Database (Denmark)

    Nielsen, Bent Roni Ranghøj; Wiggers, H; Halbirk, M

    2012-01-01

    calorimetry, forearm, and tracer methods.7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body...

  19. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Gribble, Fiona M; Hartmann, Bolette

    2014-01-01

    was metabolized and stimulated GLP-1 secretion dose-dependently (EC50 = 0.155 mM) by ATP-sensitive potassium channel closure and cell depolarization. Because fructose elicits GLP-1 secretion without simultaneous release of glucagonotropic GIP, the pathways underlying fructose-stimulated GLP-1 release might...... be useful targets for type 2 diabetes mellitus and obesity drug development....

  20. [Extrapancreatic effects of GLP-1 receptor agonists: an open window towards new treatment goals in type 2 diabetes].

    Science.gov (United States)

    Salvador, Javier; Andrada, Patricia

    2014-09-01

    The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  1. GLP-1 receptor agonist-induced polyarthritis: a case report.

    Science.gov (United States)

    Ambrosio, Maria Luisa; Monami, Matteo; Sati, Lavinia; Marchionni, Niccolò; Di Bari, Mauro; Mannucci, Edoardo

    2014-08-01

    Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.

  2. Incretin-based therapy and type 2 diabetes

    DEFF Research Database (Denmark)

    Hare, Kristine J; Knop, Filip Krag

    2010-01-01

    This chapter focuses on the incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), and their therapeutic potential in treating patients with type 2 diabetes. Type 2 diabetes is characterized by insulin resistance, impaired glucose-induced insulin...... secretion, and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for type 2 diabetes are often unsatisfactory....... Two new drug classes based on the actions of the incretin hormones have been approved for therapy of type 2 diabetes: injectable long-acting stable analogs of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation...

  3. GLP-1 regulation of glucagon, somatostatin and insulin in naidm patients: evidence of direct inhibition of A - cells by GLP - 1

    International Nuclear Information System (INIS)

    Naveed, A.K.; Khan, F.A.

    2006-01-01

    Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut into the circulation after meals and is the most potent physiological insulinotropic hormone in man. In contrast to presently available therapeutic agents for non-insulin dependent diabetes mellitus (NIDDM), GLP-1 has the advantages of both suppressing glucagon secretion and delaying gastric emptying. We report first study of subcutaneous GLP-1 treatment to determine the optimum dose required to control the NIDDM. Seven patients, with poorly controlled NIDDM were entered in the study who visited at four visits with intervals of 2-4 days and received saline, 40, 100 and 200 nmol subcutaneous GLP-1, immediately after meals. A standerdized test meal was given. A significant hypoglycaemic response (p<0.05) was achieved in patients given 40, 100 and 200 nmol GLP-1. An increase in insulin levels (p<0.05) was observed as compared to control, when 100 and 200 nmol GLP-1 was given. There was no significant difference between insulin and glucose responses when 100 and 200 nmol of GLP-1 were compared with each. The glucagon levels were significant less (p< 0.05) in patients, given 100 and 200 nmol doses as compared to control. Glucagon inhibitory response to GLP-1, when given in doses of 200 nmol was more (p< 0.05) than 100 nmol GLP-1. Somatostatin levels decreased dose dependently by GLP-1 infusions. It is concluded that suppression of glucagon secretion and inhibition of somatostatin corresponded to dose of GLP-1 used. There was no significant difference in glucose and insulin levels between 100 and 200 nmol GLP-1 doses. Therefore, present study has helped in ascertaining the optimum dose for GLP-1 i.e. 100 nmol. Down regulation of GLP-1 receptors on cells occurred at higher dose while, A and D cells inhibition occurred dose dependently. These results revealed that GLP-1 affects A and D cells directly and also through stimulation of cells. These findings will significantly contribute in the possible role

  4. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin

    DEFF Research Database (Denmark)

    Egerod, Kristoffer Lihme; Engelstoft, Maja Storm; Grunddal, Kaare Villum

    2012-01-01

    peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1...

  5. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    OpenAIRE

    Jingru Meng; Xue Ma; Ning Wang; Min Jia; Long Bi; Yunying Wang; Mingkai Li; Huinan Zhang; Xiaoyan Xue; Zheng Hou; Ying Zhou; Zhibin Yu; Gonghao He; Xiaoxing Luo

    2016-01-01

    Summary Glucagon-like peptide 1 (GLP-1) plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4) promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These function...

  6. Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage

    DEFF Research Database (Denmark)

    Hou, Jack; Manaenko, Anatol; Hakon, Jakob

    2012-01-01

    receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation......, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic...

  7. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Østergaard, L; Frandsen, Christian S.; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases...... gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA....

  8. Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide

    Directory of Open Access Journals (Sweden)

    Jonathan Pinkney

    2010-08-01

    Full Text Available Jonathan Pinkney1, Thomas Fox1, Lakshminarayan Ranganath21Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom; 2Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, United KingdomAbstract: Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1 plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A1c of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2–7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose-lowering effect was observed in the only head-to-head comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications.Keywords: diabetes, weight loss, glycemic control

  9. Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2σ-Fc.

    Science.gov (United States)

    Yang, Yi; Chen, Fang; Wan, Deyou; Liu, Yunhui; Yang, Li; Feng, Hongru; Cui, Xinling; Gao, Xin; Song, Haifeng

    2016-01-01

    Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes.

  10. Expression and Characterization of a Potent Long-Acting GLP-1 Receptor Agonist, GLP-1-IgG2σ-Fc.

    Directory of Open Access Journals (Sweden)

    Yi Yang

    Full Text Available Human GLP-1 (glucagon-like peptide-1 can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes.

  11. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

    Science.gov (United States)

    Østergaard, L; Frandsen, Christian S; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

  12. Therapy for obesity based on gastrointestinal hormones

    DEFF Research Database (Denmark)

    Bagger, Jonatan I; Christensen, Mikkel; Knop, Filip K

    2011-01-01

    for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesity-related diseases. Recently, incretin-based therapy was proposed...... for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings...... have led to a greater interest in the physiology of intestinal peptides with potential weight-reducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity....

  13. Incretin-based therapy and type 2 diabetes

    DEFF Research Database (Denmark)

    Hare, Kristine J; Knop, Filip Krag

    2010-01-01

    secretion, and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for type 2 diabetes are often unsatisfactory....... Two new drug classes based on the actions of the incretin hormones have been approved for therapy of type 2 diabetes: injectable long-acting stable analogs of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation...... of incretin mimetics and incretin enhancers, review clinical experience gathered so far, and discuss future expectations for incretin-based therapy....

  14. Microbial regulation of GLP-1 and L-cell biology

    DEFF Research Database (Denmark)

    Greiner, Thomas U; Bäckhed, Gert Fredrik

    2016-01-01

    BACKGROUND: The gut microbiota is associated with several of metabolic diseases, including obesity and type 2 diabetes and affects host physiology through distinct mechanisms. The microbiota produces a vast array of metabolites that signal to host cells in the intestine as well as in more distal...... interacts with L-cells in the small and large intestine and the resulting effects on the host. MAJOR CONCLUSIONS: Microbial metabolites can be sensed differently by specific subpopulations of enteroendocrine cells. Furthermore, hormones such as GLP-1 can have different functions when originating from...... the small intestine or colon. This article is part of a special issue on microbiota....

  15. Solution behaviour of Human Serum Albumin and GLP-1variants

    DEFF Research Database (Denmark)

    Sønderby, Pernille

    interaction is critical for the long term stability of a pharmaceutical. Protein complex formation is important for extended half-life in vivo and is essential to cellular communication such as the induction of the insulin response. This thesis focuses on human serum albumin (HSA) as a central player...... by a repulsive network of HSA molecules screening the interaction of other proteins, hereby decreasing the aggregation propensity. Glucagon-like peptide 1 (GLP-1) is an incretin hormone used in the treatment of diabetes mellitus type 2. Due to its very limited half-life of approximately 3 minutes, Novo Nordisk A...

  16. The anorectic effect of GLP-1 in rats is nutrient dependent.

    Directory of Open Access Journals (Sweden)

    Darleen Sandoval

    Full Text Available GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd cerebroventricularly (i3vt-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1's anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

  17. The Anorectic Effect of GLP-1 in Rats Is Nutrient Dependent

    Science.gov (United States)

    Sandoval, Darleen; Barrera, Jason G.; Stefater, Margaret A.; Sisley, Stephanie; Woods, Stephen C.; D’Alessio, David D.; Seeley, Randy J.

    2012-01-01

    GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3rd cerebroventricularly (i3vt)-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1′s anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake. PMID:23284795

  18. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2011-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist 125 I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic β-cells and mouse insulinomas, but it does not label human pancreatic β-cells and insulinomas. High affinity displacement (IC 50 approximately 2 nM) is observed in mouse β-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist 125 I-GLP-1(7-36)amide intensively labels mouse pancreatic β-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  19. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Bern (Switzerland)

    2011-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist {sup 125}I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic {beta}-cells and mouse insulinomas, but it does not label human pancreatic {beta}-cells and insulinomas. High affinity displacement (IC{sub 50} approximately 2 nM) is observed in mouse {beta}-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist {sup 125}I-GLP-1(7-36)amide intensively labels mouse pancreatic {beta}-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  20. GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects.

    Science.gov (United States)

    Lin, J; Hodge, R J; O'Connor-Semmes, R L; Nunez, D J

    2015-10-01

    We investigated the effects of a long-duration glucagon-like peptide-1 (GLP-1) receptor agonist, GSK2374697, on postprandial endogenous total GLP-1 and peptide YY (PYY). Two cohorts of healthy subjects, one normal/overweight and one obese, were randomized to receive GSK2374697 2 mg (n = 8 each) or placebo (n = 4 and n = 2) subcutaneously on days 1, 4 and 7. Samples for plasma endogenous GLP-1 and PYY were collected after breakfast on days -1 and 12. Weighted mean area under the curve (0-4 h) of total GLP-1 and PYY in treated subjects was reduced compared with placebo. The least squares mean difference for change from baseline was -1.24 pmol/l [95% confidence interval (CI) -2.33, -0.16] and -4.47 pmol/l (95% CI -8.74, -0.20) for total GLP-1 and PYY, respectively, in normal/overweight subjects (p GLP-1). In healthy subjects, GSK2374697 reduced postprandial total GLP-1 and PYY levels, suggesting feedback suppression of enteroendocrine L-cell secretion of these peptides. © 2015 John Wiley & Sons Ltd.

  1. Oral L-Arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Smajilovic, Sanela; Smith, Eric P

    2013-01-01

    -induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid l-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral l-arginine acts as a GLP-1 secretagogue...... in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered l-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral l-arginine increased plasma GLP-1...... and insulin and substantially improved glucose clearance. To directly assess the contribution of GLP-1 receptor (GLP-1R)-signaling to these improvements, l-arginine was given to Glp1r knockout mice and their wild-type littermates. In this experiment oral l-arginine significantly augmented insulin secretion...

  2. Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation.

    Science.gov (United States)

    Koole, Cassandra; Wootten, Denise; Simms, John; Miller, Laurence J; Christopoulos, Arthur; Sexton, Patrick M

    2012-02-03

    The glucagon-like peptide-1 receptor (GLP-1R) is a therapeutically important family B G protein-coupled receptor (GPCR) that is pleiotropically coupled to multiple signaling effectors and, with actions including regulation of insulin biosynthesis and secretion, is one of the key targets in the management of type II diabetes mellitus. However, there is limited understanding of the role of the receptor core in orthosteric ligand binding and biological activity. To assess involvement of the extracellular loop (ECL) 2 in ligand-receptor interactions and receptor activation, we performed alanine scanning mutagenesis of loop residues and assessed the impact on receptor expression and GLP-1(1-36)-NH(2) or GLP-1(7-36)-NH(2) binding and activation of three physiologically relevant signaling pathways as follows: cAMP formation, intracellular Ca(2+) (Ca(2+)(i)) mobilization, and phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2). Although antagonist peptide binding was unaltered, almost all mutations affected GLP-1 peptide agonist binding and/or coupling efficacy, indicating an important role in receptor activation. However, mutation of several residues displayed distinct pathway responses with respect to wild type receptor, including Arg-299 and Tyr-305, where mutation significantly enhanced both GLP-1(1-36)-NH(2)- and GLP-1(7-36)-NH(2)-mediated signaling bias for pERK1/2. In addition, mutation of Cys-296, Trp-297, Asn-300, Asn-302, and Leu-307 significantly increased GLP-1(7-36)-NH(2)-mediated signaling bias toward pERK1/2. Of all mutants studied, only mutation of Trp-306 to alanine abolished all biological activity. These data suggest a critical role of ECL2 of the GLP-1R in the activation transition(s) of the receptor and the importance of this region in the determination of both GLP-1 peptide- and pathway-specific effects.

  3. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    Science.gov (United States)

    Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

    2016-01-01

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

  4. Functional importance of GLP-1 receptor species and expression levels in cell lines.

    Science.gov (United States)

    Knudsen, Lotte Bjerre; Hastrup, Sven; Underwood, Christina Rye; Wulff, Birgitte Schjellerup; Fleckner, Jan

    2012-04-10

    Of the mammalian species, only the GLP-1 receptors of rat and human origin have been described and characterized. Here, we report the cloning of the homologous GLP-1 receptors from mouse, rabbit, pig, cynomolgus monkey and chimp. The GLP-1 receptor is highly conserved across species, thus underlining the physiological importance of the peptide hormone and its receptor across a wide range of mammals. We expressed the receptors by stable transfection of BHK cells, both in cell lines with high expression levels of the cloned receptors, as well as in cell lines with lower expression levels, more comparable to endogenous expression of these receptors. High expression levels of cloned GLP-1 receptors markedly increased the potency of GLP-1 and other high affinity ligands, whereas the K(d) values were not affected. For a low affinity ligand like the ago-allosteric modulator Compound 2, expression levels of the human GLP-1 receptor were important for maximal efficacy as well as potency. The two natural metabolites of GLP-1, GLP-1(9-37) and GLP-1(9-36)amide were agonists when tested on a cell line with high expression of the recombinant human GLP-1 receptor, whereas they behaved as (low potent) antagonists on a cell line that expressed the receptor endogenously, as well as cells expressing a moderate level of the recombinant human GLP-1 receptor. The amide form was a more potent agonist than the free acid from. In conclusion, receptor expression level is an important parametre for selecting cell lines with cloned GLP-1 receptors for functional characterization of physiological and pharmaceutical ligands. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. GLP-1 Amidation Efficiency Along the Length of the Intestine in Mice, Rats and Pigs and in GLP-1 Secreting Cell Lines

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Windeløv, Johanne Agerlin

    2014-01-01

    , it is essential to know whether or not the molecule one wants to measure is amidated. We performed a detailed analysis of extractable GLP-1 from duodenum, proximal jejunum, distal ileum, caecum, proximal colon and distal colon of mice (n=9), rats (n=9) and pigs (n=8) and determined the degree of amidation...... and whether this varied with the six different locations. We also analyzed the amidation in 3 GLP-1 secreting cell lines (GLUTag, NCI-H716 and STC-1). To our surprise there were marked differences between the 3 species with respect to the concentration of GLP-1 in gut. In the mouse, concentrations increased...

  6. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker; Holst, Jens Juul; Rattigan, Stephen

    2014-01-01

    The insulinotropic gut hormone, glucagon-like-peptide-1 (GLP-1) has been proposed to have effects on vascular function and glucose disposal. However, whether GLP-1 is able to increase microvascular recruitment (MVR) in humans has not been investigated. GLP-1 was infused in the femoral artery...... in overnight fasted healthy young men. Microvascular recruitment was measured with real time contrast-enhanced ultrasound and leg glucose uptake by the leg balance technique with and without inhibition of the insulinotropic response of GLP-1 by co-infusion of octreotide. As a positive control, MVR and leg...

  7. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    Directory of Open Access Journals (Sweden)

    Jingru Meng

    2016-04-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4 promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs, but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis.

  8. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

    Science.gov (United States)

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-12-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.

  9. Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia

    Directory of Open Access Journals (Sweden)

    Adham Mottalib

    2016-07-01

    Full Text Available Diabetes-specific nutritional formulas (DSNFs are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP effects of 2 DSNFs; Glucerna (GL and Ultra Glucose Control (UGC versus oatmeal (OM on glucose, insulin, glucagon-like peptide-1 (GLP-1, free fatty acids (FFA and triglycerides (TG. After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0–240 after GL and UGC was lower than OM (p < 0.001 for both. Insulin positive AUC0–120 after UGC was higher than after OM (p = 0.02. GLP-1 AUC0–120 and AUC0–240 after GL and UGC was higher than after OM (p < 0.001 for both. FFA and TG levels were not different between meals. Intake of DSNFs improves PP glucose for 4 h in comparison to oatmeal of similar caloric level. This is achieved by either direct stimulation of insulin secretion or indirectly by stimulating GLP-1 secretion. The difference between their effects is probably related to their unique blends of amino acids, carbohydrates and fat.

  10. [Treatment strategy for elderly diabetic patient with insulin or GLP-1 receptor agonist].

    Science.gov (United States)

    Ando, Yasuyo

    2013-11-01

    It has been established that diabetes is an independent risk factor for microvascular and macrovascular complications, and many studies indicate that diabetic subjects are at greater risk of dementia, depression and fracture. Risk reductions for microvascular, macrovascular and death were observed by intensive therapy using insulin or oral diabetic agents. But a history of hypoglycemia was increased myocardial infarction, mortality, dementia and fracture. So it is important that optimum glycemic control has to be achieved without hypoglycemia. Treatment with a long-acting basal insulin analogue or glucagon-like peptide-1(GLP-1) receptor agonist, provide effective glycemic control without serious hypoglycemia in elderly patients. Self-monitoring of blood glucose might be effective in improving glycemic control in elderly patients, and it is useful for the diagnosis of hypoglycemia.

  11. The endocrine disrupting potential of monosodium glutamate (MSG) on secretion of the glucagon-like peptide-1 (GLP-1) gut hormone and GLP-1 receptor interaction.

    Science.gov (United States)

    Shannon, Maeve; Green, Brian; Willars, Gary; Wilson, Jodie; Matthews, Natalie; Lamb, Joanna; Gillespie, Anna; Connolly, Lisa

    2017-01-04

    Monosodium glutamate (MSG) is a suspected obesogen with epidemiological evidence positively correlating consumption to increased body mass index and higher prevalence of metabolic syndrome. ELISA and high content analysis (HCA) were employed to examine the disruptive effects of MSG on the secretion of enteroendocrine hormone glucagon-like peptide-1 (GLP-1) and GLP-1 receptor (GLP-1R), respectively. Following 3h MSG exposure of the enteroendocrine pGIP/neo: STC-1 cell line model (500μg/ml) significantly increased GLP-1 secretion (1.8 fold; P≤0.001), however, 72h exposure (500μg/ml) caused a 1.8 fold decline (P≤0.05). Also, 3h MSG exposure (0.5-500μg/ml) did not induce any cytotoxicity (including multiple pre-lethal markers) but 72h exposure at 250-500μg/ml, decreased cell number (11.8-26.7%; P≤0.05), increased nuclear area (23.9-29.8%; P≤0.001) and decreased mitochondrial membrane potential (13-21.6%; P≤0.05). At 500μg/ml, MSG increased mitochondrial mass by 16.3% (P≤0.01). MSG did not agonise or antagonise internalisation of the GLP-1R expressed recombinantly in U2OS cells, following GLP-1 stimulation. In conclusion, 72h exposure of an enteroendocrine cell line at dietary levels of MSG, results in pre-lethal cytotoxicity and decline in GLP-1 secretion. These adverse events may play a role in the pathogenesis of obesity as outlined in the obesogen hypothesis by impairing GLP-1 secretion, related satiety responses and glucose-stimulated insulin release. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Distinguishing among incretin-based therapies. Introduction.

    Science.gov (United States)

    Campbell, R Keith; Cobble, Michael E; Reid, Timothy S; Shomali, Mansur E

    2010-09-01

    The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

  13. Comparative Effects of the Endogenous Agonist Glucagon-Like Peptide-1 (GLP-1)-(7-36) Amide and the Small-Molecule Ago-Allosteric Agent “Compound 2” at the GLP-1 Receptor

    OpenAIRE

    Coopman, Karen; Huang, Yan; Johnston, Neil; Bradley, Sophie J.; Wilkinson, Graeme F.; Willars, Gary B.

    2010-01-01

    Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to cons...

  14. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

    Science.gov (United States)

    Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of ...

  15. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss.

    Science.gov (United States)

    Secher, Anna; Jelsing, Jacob; Baquero, Arian F; Hecksher-Sørensen, Jacob; Cowley, Michael A; Dalbøge, Louise S; Hansen, Gitte; Grove, Kevin L; Pyke, Charles; Raun, Kirsten; Schäffer, Lauge; Tang-Christensen, Mads; Verma, Saurabh; Witgen, Brent M; Vrang, Niels; Bjerre Knudsen, Lotte

    2014-10-01

    Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.

  16. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion : A DIRECT study

    NARCIS (Netherlands)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani; Brorsson, Caroline; van Leeuwen, Nienke; Banasik, Karina; Mahajan, Anubha; Groves, Christopher J; van de Bunt, Martijn; Dawed, Adem Y; Fritsche, Andreas; Staiger, Harald; Simonis-Bik, Annemarie M C; Deelen, Joris; Kramer, Mark H H; Dietrich, Axel; Hübschle, Thomas; Willemsen, Gonneke; Häring, Hans-Ulrich; de Geus, Eco J C; Boomsma, Dorret I; Eekhoff, Elisabeth M W; Ferrer, Jorge; McCarthy, Mark I; Pearson, Ewan R; Gupta, Ramneek; Brunak, Søren; 't Hart, Leen M

    2018-01-01

    Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin

  17. GLP-1 acts on habenular avoidance circuits to control nicotine intake.

    Science.gov (United States)

    Tuesta, Luis M; Chen, Zuxin; Duncan, Alexander; Fowler, Christie D; Ishikawa, Masago; Lee, Brian R; Liu, Xin-An; Lu, Qun; Cameron, Michael; Hayes, Matthew R; Kamenecka, Theodore M; Pletcher, Matthew; Kenny, Paul J

    2017-05-01

    Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors, respectively, decreased nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreased nicotine intake. Conversely, Glp1r knockout mice consumed greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to the interpeduncular nucleus (IPN). Activation of GLP-1 receptors in the MHb-IPN circuit abolished nicotine reward and decreased nicotine intake, whereas their knockdown or pharmacological blockade increased intake. GLP-1 neurons may therefore serve as 'satiety sensors' for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.

  18. GLP-1 does not not acutely affect insulin sensitivity in healthy man

    DEFF Research Database (Denmark)

    Orskov, L; Holst, J J; Møller, J

    1996-01-01

    Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7-36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyper insulinaemic (0.8 mU.kg-1.min-1), euglycaemic (5 mmol...

  19. Evidence for paracrine/autocrine regulation of GLP-1-producing cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Zhang, Qimin; Holst, Jens Juul

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent stud...

  20. GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; IJzerman, R.G.; ten Kulve, J.S.; Barkhof, F.; Konrad, R.J.; Drent, M.L.; Veltman, D.J.; Diamant, M.

    2014-01-01

    Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We

  1. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

    DEFF Research Database (Denmark)

    Ørgaard, Anne; Holst, Jens J

    2017-01-01

    AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion...... effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists........ The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1...

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

    DEFF Research Database (Denmark)

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

    2003-01-01

    The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucose-mediated insulin secretion, insulin gene expression, and beta-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes....... 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...... that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the beta-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless...

  3. The regulation of function, growth and survival of GLP-1-producing L-cells

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Holst, Jens Juul; Kappe, Camilla

    2016-01-01

    that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells......Glucagon-like peptide-1 (GLP-1) is a peptide hormone, released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. In addition to potentiation of meal-stimulated insulin secretion, GLP-1 signalling exerts numerous pleiotropic effects on various tissues, regulating energy....... The mechanisms inducing this lipototoxicity involved increased production of reactive oxygen species (ROS). In this review, regulation of GLP-1-secreting cells is discussed, with a focus on the mechanisms underlying GLP-1 secretion, long-term regulation of growth, differentiation and survival under normal...

  4. Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects.

    Science.gov (United States)

    Kappe, Camilla; Fransson, Liselotte; Wolbert, Petra; Ortsäter, Henrik

    2015-09-01

    Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum- and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion. © 2015 Authors; published by Portland Press Limited.

  5. GLP-1 response to sequential mixed meals: influence of insulin resistance.

    Science.gov (United States)

    Rebelos, Eleni; Astiarraga, Brenno; Bizzotto, Roberto; Mari, Andrea; Manca, Maria Laura; Gonzalez, Alex; Mendez, Armando; Martinez, Claudia A; Hurwitz, Barry E; Ferrannini, Ele

    2017-12-15

    Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n =41) or insulin resistant (IR, n =41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P =0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  6. Effects of endogenous GLP-1 and GIP on glucose tolerance after Roux-en-Y gastric bypass surgery

    DEFF Research Database (Denmark)

    Svane, Maria S; Bojsen-Moller, Kirstine N; Nielsen, Signe

    2016-01-01

    Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously...... secreted GLP-1 and GIP on glucose tolerance and beta-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin 9-39 (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose tolerant patients were studied after RYGB...... postprandial hyperglucagonaemia compared with placebo, whereas sitagliptin had no effect despite 2-3-fold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or beta-cell function during GLP-1R blockage. This study confirms the importance of GLP-1...

  7. Transmembrane α-Helix 2 and 7 Are Important for Small Molecule-Mediated Activation of the GLP-1 Receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye; Møller Knudsen, Sanne; Schjellerup Wulff, Birgitte

    2011-01-01

    Glucagon-like peptide-1 (GLP-1) activates the GLP-1 receptor (GLP-1R), which belongs to family B of the G-protein-coupled receptors. We previously identified a selective small molecule ligand, compound 2, that acted as a full agonist and allosteric modulator of GLP-1R. In this study......, the structurally related small molecule, compound 3, stimulated cAMP production from GLP-1R, but not from the homologous glucagon receptor (GluR). The receptor selectivity encouraged a chimeric receptor approach to identify domains important for compound 3-mediated activation of GLP-1R. A subsegment of the GLP-1R...... transmembrane domain containing TM2 to TM5 was sufficient to transfer compound 3 responsiveness to GluR. Therefore, divergent residues in this subsegment of GLP-1R and GluR are responsible for the receptor selectivity of compound 3. Functional analyses of other chimeric receptors suggested that the existence...

  8. Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Has a Critical Role in GLP-1 Peptide Binding and Receptor Activation*

    Science.gov (United States)

    Koole, Cassandra; Wootten, Denise; Simms, John; Miller, Laurence J.; Christopoulos, Arthur; Sexton, Patrick M.

    2012-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is a therapeutically important family B G protein-coupled receptor (GPCR) that is pleiotropically coupled to multiple signaling effectors and, with actions including regulation of insulin biosynthesis and secretion, is one of the key targets in the management of type II diabetes mellitus. However, there is limited understanding of the role of the receptor core in orthosteric ligand binding and biological activity. To assess involvement of the extracellular loop (ECL) 2 in ligand-receptor interactions and receptor activation, we performed alanine scanning mutagenesis of loop residues and assessed the impact on receptor expression and GLP-1(1–36)-NH2 or GLP-1(7–36)-NH2 binding and activation of three physiologically relevant signaling pathways as follows: cAMP formation, intracellular Ca2+ (Ca2+i) mobilization, and phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2). Although antagonist peptide binding was unaltered, almost all mutations affected GLP-1 peptide agonist binding and/or coupling efficacy, indicating an important role in receptor activation. However, mutation of several residues displayed distinct pathway responses with respect to wild type receptor, including Arg-299 and Tyr-305, where mutation significantly enhanced both GLP-1(1–36)-NH2- and GLP-1(7–36)-NH2-mediated signaling bias for pERK1/2. In addition, mutation of Cys-296, Trp-297, Asn-300, Asn-302, and Leu-307 significantly increased GLP-1(7–36)-NH2-mediated signaling bias toward pERK1/2. Of all mutants studied, only mutation of Trp-306 to alanine abolished all biological activity. These data suggest a critical role of ECL2 of the GLP-1R in the activation transition(s) of the receptor and the importance of this region in the determination of both GLP-1 peptide- and pathway-specific effects. PMID:22147710

  9. GLP-1 Receptor Agonists: Nonglycemic Clinical Effects in Weight Loss and Beyond

    Science.gov (United States)

    Ryan, Donna; Acosta, Andres

    2015-01-01

    Obective Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for treatment of type 2 diabetes since they mimic the actions of native GLP-1 on pancreatic islet cells, stimulating insulin release, while inhibiting glucagon release, in a glucose-dependent manner. The observation of weight loss has led to exploration of their potential as antiobesity agents, with liraglutide 3.0 mg day−1 approved for weight management in the US on December 23, 2014, and in the EU on March 23, 2015. This review examines the potential nonglycemic effects of GLP-1 receptor agonists. Methods A literature search was conducted to identify preclinical and clinical evidence on nonglycemic effects of GLP-1 receptor agonists. Results GLP-1 receptors are distributed widely in a number of tissues in humans, and their effects are not limited to the well-recognized effects on glycemia. Nonglycemic effects include weight loss, which is perhaps the most widely recognized nonglycemic effect. In addition, effects on the cardiovascular, neurologic, and renal systems and on taste perception may occur independently of weight loss. Conclusions GLP-1 receptor agonists may provide other nonglycemic clinical effects besides weight loss. Understanding these effects is important for prescribers in using GLP-1 receptor agonists for diabetic patients, but also if approved for chronic weight management. PMID:25959380

  10. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

    Science.gov (United States)

    De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

    2016-01-01

    While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness

    DEFF Research Database (Denmark)

    Svendsen, Berit; Pais, Ramona; Engelstoft, Maja S

    2016-01-01

    the secretion of both GLP1 and GIP, whereas bombesin/neuromedin C only stimulated GLP1 secretion. Expression analysis showed high expression of the bombesin 2 receptor in GLP1 positive cells, but no expression in GIP-positive cells. These data indicate both expressional and functional differences between...

  12. 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

    /v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration...... 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...

  13. GLP-1 Receptor Agonist and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jinmi Lee

    2012-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, one of the most common liver diseases, is caused by the disruption of hepatic lipid homeostasis. It is associated with insulin resistance as seen in type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1 is an incretin that increases insulin sensitivity and aids glucose metabolism. In recent in vivo and in vitro studies, GLP-1 presents a novel therapeutic approach against NAFLD by increasing fatty acid oxidation, decreasing lipogenesis, and improving hepatic glucose metabolism. In this report, we provide an overview of the role and mechanism of GLP-1 in relieving NAFLD.

  14. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans

    DEFF Research Database (Denmark)

    Schjoldager, B T; Mortensen, P E; Christiansen, J

    1989-01-01

    Glucagon-like peptide 1 amide (GLP-1 amide), a predicted product of the glucagon gene (proglucagon 72-107-amide), and truncated GLP-1 (proglucagon 78-107-amide), recently isolated from porcine small intestine, were infused in doses of 100 and 400 ng/kg/hr and 12.5 and 50 ng/kg/hr, respectively...... of truncated GLP increased from approximately 7 pmol/liter to 28 +/- 3 pmol/liter during the high rate of infusion. A similar increase was seen in response to a mixed meal in eight normal volunteers. The metabolic clearance rate (MCR) of GLP-1 was 2.2 +/- 0.3 and 2.6 +/- 0.3 ml/kg/min, respectively...

  15. Type 2 diabetes mellitus and the cardiometabolic syndrome: impact of incretin-based therapies

    Directory of Open Access Journals (Sweden)

    Schwartz S

    2010-07-01

    Full Text Available Stanley Schwartz1, Benjamin A Kohl21Department of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania, USA; 2Department of Anesthesiology and Critical Care, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USAAbstract: The rates of type 2 diabetes mellitus, obesity, and cardiovascular disease (CVD continue to increase at epidemic proportions. It has become clear that these disease states are not independent but are frequently interrelated. By addressing conditions such as obesity,­ ­insulin resistance, stress hyperglycemia, impaired glucose tolerance, and diabetes ­mellitus, with its micro- and macrovascular complications, a specific treatment strategy can be ­developed. These conditions can be addressed by early identification of patients at high risk for type 2 diabetes, prompt and aggressive treatment of their hyperglycemia, recognition of the pleiotropic and synergistic benefits of certain antidiabetes agents on CVD, and thus, avoiding potential complications including hypoglycemia and weight gain. Incretin-based therapies, which include glucagon-like peptide-1 (GLP-1 receptor agonists and dipeptidyl peptidase-IV (DPP-IV inhibitors, have the potential to alter the course of type 2 diabetes and associated CVD complications. Advantages of these therapies include glucose-dependent enhancement of insulin secretion, infrequent instances of hypoglycemia, weight loss with GLP-1 receptor agonists, weight maintenance with DPP-IV inhibitors, decreased blood pressure, improvements in dyslipidemia, and potential beneficial effects on CV function.Keywords: cardiovascular disease, glucose control, GLP-1 receptor agonists, DPP-IV inhibitors

  16. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes

    DEFF Research Database (Denmark)

    Nauck, M A; Vardarli, I; Deacon, C F

    2011-01-01

    The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP......-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency...... with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some...

  17. Preserved GLP-1 effects in a diabetic patient with Cushing's disease

    DEFF Research Database (Denmark)

    Ritzel, R A; Kleine, N; Holst, Jens Juul

    2007-01-01

    CONTEXT: A patient with diabetes mellitus, who participated in a study with intravenous administration of GLP-1, was later found to have Cushing's disease (markedly elevated 24 h urinary cortisol excretion and inadequate suppression of fasting cortisol with 2 mg dexamethasone). His diabetic state...... mellitus due to Cushing's disease with GLP-1 actions in typical type 2 diabetes. DESIGN AND METHODS: GLP-1 (1.2 pmol/kg/min) and placebo had been infused into ten patients with diabetes mellitus over 4 h in the fasting state. The results from the patient with Cushing's disease (C) were compared to the data...... with Cushing's disease compared to those with type 2 diabetes. CONCLUSIONS: The insulinotropic, glucagonostatic and glucose-lowering actions of GLP-1 in a patient with diabetes mellitus due to cortisol excess were similar to actions in typical type 2 diabetes. Therefore incretin mimetics might be a novel...

  18. Crystal structure of the GLP-1 receptor bound to a peptide agonist.

    Science.gov (United States)

    Jazayeri, Ali; Rappas, Mathieu; Brown, Alastair J H; Kean, James; Errey, James C; Robertson, Nathan J; Fiez-Vandal, Cédric; Andrews, Stephen P; Congreve, Miles; Bortolato, Andrea; Mason, Jonathan S; Baig, Asma H; Teobald, Iryna; Doré, Andrew S; Weir, Malcolm; Cooke, Robert M; Marshall, Fiona H

    2017-06-08

    Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

  19. The insulinotropic effect of exogenous GLP-1 is not affected by acute vagotomy in anaesthetized pigs

    DEFF Research Database (Denmark)

    Veedfald, Simon; Hansen, Marie; Christensen, Louise Wulff

    2016-01-01

    -arterially(mesenteric) for 1 h at 3 pmol kg(-1) min(-1) or 30 pmol kg(-1) min(-1) . During steady state (21 min into the GLP-1 infusion), glucose (0.2 g/kg, iv) was administered over 9 min to stimulate beta cell secretion. 30 min after the glucose infusion GLP-1 infusions were discontinued. Following a washout period...... the vagal trunks were severed in 4/6 groups (vagal trunks were left intact in 2/6 groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1...

  20. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Sikirica MV

    2017-09-01

    expectations of GLP1 RAs and physicians’ patient-management practices may help increase GLP1 RA adherence and thereby potentially enhance diabetes care. Keywords: antidiabetic drug, cross-sectional survey, discontinuation, incretins, incretin therapy, glycemic control

  1. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans.

    Science.gov (United States)

    van Bloemendaal, Liselotte; IJzerman, Richard G; Ten Kulve, Jennifer S; Barkhof, Frederik; Konrad, Robert J; Drent, Madeleine L; Veltman, Dick J; Diamant, Michaela

    2014-12-01

    Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning.

    Science.gov (United States)

    Basalay, Marina V; Mastitskaya, Svetlana; Mrochek, Aleksander; Ackland, Gareth L; Del Arroyo, Ana Gutierrez; Sanchez, Jenifer; Sjoquist, Per-Ove; Pernow, John; Gourine, Alexander V; Gourine, Andrey

    2016-12-01

    Although the nature of the humoral factor which mediates cardioprotection established by remote ischaemic conditioning (RIc) remains unknown, parasympathetic (vagal) mechanisms appear to play a critical role. As the production and release of many gut hormones is modulated by the vagus nerve, here we tested the hypothesis that RIc cardioprotection is mediated by the actions of glucagon-like peptide-1 (GLP-1). A rat model of myocardial infarction (coronary artery occlusion followed by reperfusion) was used. Remote ischaemic pre- (RIPre) or perconditioning (RIPer) was induced by 15 min occlusion of femoral arteries applied prior to or during the myocardial ischaemia. The degree of RIPre and RIPer cardioprotection was determined in conditions of cervical or subdiaphragmatic vagotomy, or following blockade of GLP-1 receptors (GLP-1R) using specific antagonist Exendin(9-39). Phosphorylation of PI3K/AKT and STAT3 was assessed. RIPre and RIPer reduced infarct size by ∼50%. In conditions of bilateral cervical or subdiaphragmatic vagotomy RIPer failed to establish cardioprotection. GLP-1R blockade abolished cardioprotection induced by either RIPre or RIPer. Exendin(9-39) also prevented RIPre-induced AKT phosphorylation. Cardioprotection induced by GLP-1R agonist Exendin-4 was preserved following cervical vagotomy, but was abolished in conditions of M3 muscarinic receptor blockade. These data strongly suggest that GLP-1 functions as a humoral factor of remote ischaemic conditioning cardioprotection. This phenomenon requires intact vagal innervation of the visceral organs and recruitment of GLP-1R-mediated signalling. Cardioprotection induced by GLP-1R activation is mediated by a mechanism involving M3 muscarinic receptors. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

  3. Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs

    DEFF Research Database (Denmark)

    Nagell, Carl Frederik; Wettergren, André; Ørskov, Cathrine

    2006-01-01

    receptors have been identified in several organs including the stomach, brain and pancreas. The GLP-1 mechanism of action on insulin secretion is at least partly mediated via receptors on the pancreatic islet, but the mechanism by which GLP-1 retards gastric emptying is not known and may involve neural...... the antral contractile force, with the amplitude falling from 29.9+/-5.7 mm to 14.6+/-3.5 mm (p

  4. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential.

    Science.gov (United States)

    Fujita, Hiroki; Morii, Tsukasa; Fujishima, Hiromi; Sato, Takehiro; Shimizu, Tatsunori; Hosoba, Mihoko; Tsukiyama, Katsushi; Narita, Takuma; Takahashi, Takamune; Drucker, Daniel J; Seino, Yutaka; Yamada, Yuichiro

    2014-03-01

    Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.

  5. Comparative effects of the endogenous agonist glucagon-like peptide-1 (GLP-1)-(7-36) amide and the small-molecule ago-allosteric agent "compound 2" at the GLP-1 receptor.

    Science.gov (United States)

    Coopman, Karen; Huang, Yan; Johnston, Neil; Bradley, Sophie J; Wilkinson, Graeme F; Willars, Gary B

    2010-09-01

    Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to consider the impact of compound 2 on G protein activation, Ca(2+) signaling and receptor internalization and particularly to compare compound 2 and GLP-1 across a range of functional assays in intact cells. GLP-1 and compound 2 activated Galpha(s) in cell membranes and increased cellular cAMP in intact cells, with compound 2 being a partial and almost full agonist, respectively. GLP-1 increased intracellular [Ca(2+)] by release from intracellular stores, which was mimicked by compound 2, with slower kinetics. In either intact cells or membranes, the orthosteric antagonist exendin-(9-39), inhibited GLP-1 cAMP generation but increased the efficacy of compound 2. GLP-1 internalized enhanced green fluorescent protein-tagged GLP-1Rs, but the speed and magnitude evoked by compound 2 were less. Exendin-(9-39) inhibited internalization by GLP-1 and also surprisingly that by compound 2. Compound 2 displays GLP-1R agonism consistent with action at an allosteric site, although an orthosteric antagonist increased its efficacy on cAMP and blocked compound 2-mediated receptor internalization. Full assessment of the properties of compound 2 was potentially hampered by damaging effects that were particularly manifest in either longer term assays with intact cells or in acute assays with membranes.

  6. Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1)

    DEFF Research Database (Denmark)

    Bak, Monika Judyta; Albrechtsen, Nicolai Jacob Wewer; Pedersen, Jens

    2014-01-01

    AIMS: To evaluate performances of commercially available glucagon-like peptide-1 (GLP-1) assays and implications for clinical studies. MATERIALS AND METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2 , 7-36NH2 , 9-36NH2 , 1-37, 7-37 and 9-37) were added...... recovery of non-active forms was incomplete, especially in plasma. Millipore Total GLP-1 ELISA kit detected all isoforms in buffer, but mainly amidated forms in plasma. The Alpco, Phoenix and Bio-Rad kits detected only amidated GLP-1,but the Alpco kit had a limited measurement range (30 pmol....../l), the Phoenix kit had incomplete recovery in plasma and the Bio-Rad kit was insensitive (detection limit in plasma 40 pmol/l). The pattern of postprandial GLP-1 responses in clinical samples was similar between the kits tested, but the absolute concentrations measured varied. CONCLUSIONS: The specificity...

  7. Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

    Directory of Open Access Journals (Sweden)

    Lorène J. Lebrun

    2017-10-01

    Full Text Available Summary: Glucagon-like peptide 1 (GLP-1 is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS administration in mice via a Toll-like receptor 4 (TLR4-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation. : Lebrun et al. demonstrate that enteroendocrine L cells sense lipopolysaccharides (pro-inflammatory bacterial compounds after gut injury and respond by secreting glucagon-like peptide 1. These findings expand concepts of L cell function to include roles as both a nutrient and pathogen sensor, linking glucagon-like peptide secretion to gut inflammation. Keywords: glucagon-like peptide 1, lipopolysaccharides, enteroendocrine cells, TLR4, gut injury, intestinal ischemia, inflammation

  8. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

    DEFF Research Database (Denmark)

    Christensen, Louise Wulff; Kuhre, Rune Ehrenreich; Janus, Charlotte

    2015-01-01

    -protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam....../L LA, all significantly increased GLP-1 secretion compared to basal levels (Pagonists was ineffective. Thus, both natural and small-mole- cule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion......Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G...

  9. Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice

    International Nuclear Information System (INIS)

    Kubo, Fumiyo; Miyatsuka, Takeshi; Sasaki, Shugo; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Shimo, Naoki; Watada, Hirotaka; Kaneto, Hideaki; Gannon, Maureen; Matsuoka, Taka-aki; Shimomura, Iichiro

    2016-01-01

    Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1 PB -CreER TM ; CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions. - Highlights: • Expression levels of incretin receptors were significantly decreased in diabetic db/db islets after the age of eight weeks. • A transgenic mouse model expressing Glp1r specifically in β cells was generated. • Exogenous expression of Glp1r in β cells did not affect metabolic profiles in nondiabetic mice. • Sustained expression of Glp1r in diabetic db/db β cells deteriorated glucose

  10. Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice

    Energy Technology Data Exchange (ETDEWEB)

    Kubo, Fumiyo [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Miyatsuka, Takeshi, E-mail: miyatsuka-takeshi@umin.net [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Sasaki, Shugo; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Shimo, Naoki [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Watada, Hirotaka [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Kaneto, Hideaki [Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan Okayama 701-0192 (Japan); Gannon, Maureen [Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2220 Pierce Ave. 746 PRB, Nashville, TN 37232-6303 (United States); Matsuoka, Taka-aki; Shimomura, Iichiro [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2016-02-26

    Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1{sup PB}-CreER{sup TM}; CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions. - Highlights: • Expression levels of incretin receptors were significantly decreased in diabetic db/db islets after the age of eight weeks. • A transgenic mouse model expressing Glp1r specifically in β cells was generated. • Exogenous expression of Glp1r in β cells did not affect metabolic profiles in nondiabetic mice. • Sustained expression of Glp1r in diabetic db/db β cells deteriorated

  11. The Dietary Furocoumarin Imperatorin Increases Plasma GLP-1 Levels in Type 1-Like Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Lin-Yu Wang

    2017-10-01

    Full Text Available Imperatorin, a dietary furocoumarin, is found not only in medicinal plants, but also in popular culinary herbs, such as parsley and fennel. Recently, imperatorin has been shown to activate GPR119 in cells. Another GPR, GPR131, also called TGR5 or G-protein-coupled bile acid receptor 1 (GPBAR1, is known to regulate glucose metabolism. Additionally, TGR5 activation increases glucagon-like peptide (GLP-1 secretion to lower blood sugar levels in animals. Therefore, the present study aims to determine whether the effects of imperatorin on GLP-1 secretion are mediated by TGR5. First, we transfected cultured Chinese hamster ovary cells (CHO-K1 cells with the TGR5 gene. Glucose uptake was confirmed in the transfected cells using a fluorescent indicator. Moreover, NCI-H716 cells, which secrete GLP-1, were used to investigate the changes in calcium concentrations and GLP-1 levels. In addition, streptozotocin (STZ-induced type 1-like diabetic rats were used to identify the effects of imperatorin in vivo. Imperatorin dose-dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In STZ diabetic rats, similar to the results in NCI-H716 cells, imperatorin induced a marked increase of GLP-1 secretion that was reduced, but not totally abolished, by a dose of triamterene that inhibited TGR5. Moreover, increases in GLP-1 secretion induced by imperatorin and GPR119 activation were shown in NCI-H716 cells. We demonstrated that imperatorin induced GLP-1 secretion via activating TGR5 and GPR119. Therefore, imperatorin shall be considered as a TGR5 and GPR119 agonist.

  12. A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving 1-2 Oral Anti-Diabetic Drugs.

    Science.gov (United States)

    Witkowski, Michal; Wilkinson, Lars; Webb, Neil; Weids, Alan; Glah, Divina; Vrazic, Hrvoje

    2018-04-19

    Once-weekly semaglutide is a new glucagon-like peptide-1 (GLP-1) analogue administered at a 1.0 or 0.5 mg dose. As head-to-head trials assessing once-weekly semaglutide as an add-on to 1-2 oral anti-diabetic drugs (OADs) vs other GLP-1 receptor agonists (GLP-1 RAs) are limited, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of once-weekly semaglutide vs GLP-1 RAs in patients with type 2 diabetes (T2D) inadequately controlled on 1-2 OADs. A systematic literature review (SLR) was conducted in order to identify trials of GLP-1 RAs in patients inadequately controlled on 1-2 OADs. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in a NMA), which included the key outcomes of change from baseline in glycated hemoglobin (HbA 1c ), systolic blood pressure (SBP), and weight, as well as discontinuation due to adverse events (AEs). Data were synthesized using a NMA and a Bayesian framework. In total, 26 studies were included across the base case analyses. Once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA 1c and weight vs all GLP-1 RA comparators. Once-weekly semaglutide 0.5 mg also achieved significantly greater reductions in HbA 1c and weight compared with the majority of other GLP-1 RAs. Both doses of once-weekly semaglutide were associated with similar odds of discontinuation due to AEs compared with other GLP-1 RAs. Overall, once-weekly semaglutide 1.0 mg as an add-on to 1-2 OADs is the most efficacious GLP-1 RA in terms of the reduction of HbA 1c and weight from baseline after 6 months of treatment. In addition, the analysis suggests that once-weekly semaglutide is well tolerated and not associated with an increase in discontinuations due to AEs compared with other GLP-1 RAs. Novo Nordisk.

  13. Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men.

    Directory of Open Access Journals (Sweden)

    Niina Matikainen

    Full Text Available Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP but the effect of these on human postprandial lipid metabolism is not fully clarified.To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL response to a fat-rich meal.Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2 male subjects. Triglycerides (TG, apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2 were measured after the fat-rich meal.Postprandial responses (area under the curve, AUC for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins.The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively. Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest.In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor.

  14. The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

    DEFF Research Database (Denmark)

    Lehrskov-Schmidt, Louise; Lehrskov-Schmidt, Lars; Nielsen, Signe T

    2015-01-01

    Context: GLP-1 analogues have recently been promoted as anti-hyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: To determine whether infusion of TNF-α at high physiological...... levels impairs GLP-1's effects on glucose metabolism. Design: Randomized, controlled, cross-over trial. Setting: Hospital clinical research laboratory. Participants: Twelve healthy males (age 24±3 y; BMI 22.9±1.3 kg/m(2)). Interventions: Following an overnight fast, either saline (0.9%) or recombinant...... human TNF-α (1000 ng/m(2)/h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg/min) began. From t = 4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg/min. Plasma glucose was clamped at 5 mmol/L throughout via a variable-rate 20% dextrose infusion. Trials were 7...

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

    DEFF Research Database (Denmark)

    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......, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 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...

  16. Gastric bypass in the pig increases GIP levels and decreases active GLP-1 levels.

    Science.gov (United States)

    Lindqvist, Andreas; Ekelund, Mikael; Pierzynowski, Stefan; Groop, Leif; Hedenbro, Jan; Wierup, Nils

    2017-04-01

    Gastric bypass surgery results in remission of type 2 diabetes in the majority of patients. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been implicated in the observed remission. Most knowledge so far has been generated in obese subjects. To isolate the surgical effects of gastric bypass on metabolism and hormone responses from the confounding influence of obesity, T2D, or food intake, we performed gastric bypass in lean pigs, using sham-operated and pair-fed pigs as controls. Thus, pigs were subjected to Roux-en-Y gastric bypass (RYGB) or sham surgery and oral glucose tolerance tests (OGTT). RYGB pigs and sham pigs exhibited similar basal and 120-min glucose levels in response to the OGTT. However, RYGB pigs had approximately 1.6-fold higher 30-min glucose (pRYGB pigs (pRYGB pigs. Although total GLP-1 release increased approximately 2.1-fold after RYGB (pRYGB pigs (pRYGB in lean pigs increases the response of GIP, total GLP-1, and insulin, but reduces levels of active GLP-1 in response to an oral glucose load. These data challenge the role of active GLP-1 as a contributor to remission from diabetes after RYGB. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance.

    Directory of Open Access Journals (Sweden)

    Sophie R Sayers

    Full Text Available Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1 in response to food transit. Deletion of the tumour suppressor kinase LKB1 from proglucagon-expressing cells leads to the generation of intestinal polyps but no change in circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMP-activated protein kinase (AMPK in these cells.Loss of AMPK from proglucagon-expressing cells was achieved using a preproglucagon promoter-driven Cre (iGluCre to catalyse recombination of floxed alleles of AMPKα1 and α2. Oral and intraperitoneal glucose tolerance were measured using standard protocols. L-cell mass was measured by immunocytochemistry. Hormone and peptide levels were measured by electrochemical-based luminescence detection or radioimmunoassay.Recombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreatic alpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, mice deleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01 in L-cell mass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01 and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01 GLP-1 levels. Oral, but not intraperitoneal, glucose tolerance was significantly improved by AMPK deletion, whilst insulin and glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT: 0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01.AMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targeted inhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms of type 2 diabetes.

  18. Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome.

    Science.gov (United States)

    Tesauro, Manfredi; Schinzari, Francesca; Adamo, Angelo; Rovella, Valentina; Martini, Francesca; Mores, Nadia; Barini, Angela; Pitocco, Dario; Ghirlanda, Giovanni; Lauro, Davide; Campia, Umberto; Cardillo, Carmine

    2013-03-01

    Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS. Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5). In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both). In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.

  19. The spectrum of antidiabetic actions of GLP-1 in patients with diabetes

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Holst, Jens J; Knop, Filip K

    2009-01-01

    This article focusses on the antidiabetic therapeutic potential of the incretin hormone glucagon-like peptide-1 (GLP-1) in the treatment of patients with type 2 diabetes mellitus (T2DM). T2DM is characterised by insulin resistance, impaired glucose-induced insulin secretion and inappropriately...... regulated glucagon secretion, which in combination eventually result in hyperglycaemia and, in the longer term, microvascular and macrovascular diabetic complications. Traditional treatment modalities - even multidrug approaches - for T2DM are often unsatisfactory in making patients reach glycaemic goals...... effects. Therefore, the actions of GLP-1, which include the potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion and suppresses food intake and appetite....

  20. The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty

    DEFF Research Database (Denmark)

    Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F.

    2013-01-01

    received GLP-1 (7-36 amide) or saline infusions during and after a standardized liquid mixed meal and a subsequent ad libitum meal. Despite no effect on appetite sensations, GLP-1 significantly reduced ad libitum food intake in the control group but had no effect in the vagotomized group. Gastric emptying...... was unaffected by exogenous GLP-1 in vagotomized subjects but was suppressed in controls. GLP-1 significantly reduced glucagon secretion in both groups, but levels were approximately twofold higher and were nonsuppressible in the early phase of the meal in vagotomized subjects. Our results demonstrate...

  1. Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation.

    Science.gov (United States)

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-09-15

    The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), an important drug target in the treatment of type 2 diabetes, is a G-protein coupled receptor (GPCR) that mediates insulin secretion by GLP-1. The N-terminus controls GLP-1R biosynthetic trafficking to the cell surface but the C-terminus involvement in that trafficking is unknown. The aim of this study was to identify distinct regions within the C-terminal domain required for human GLP-1R (hGLP-1R) cell surface expression, activity and internalisation using a number of C-terminal deletions and site-directed mutations. The results of this study revealed that the residues 411-418 within the C-terminal domain of the hGLP-1R are critical in targeting the newly synthesised receptor to the plasma membrane. The residues 419-430 are important for cAMP producing activity of the receptor, most likely by coupling to Gαs. However, the residues 431-450 within the C-terminus are essential for agonist-induced hGLP-1R internalisation. In conclusion, these findings demonstrate the hGLP-1R has distinct regions within the C-terminal domain required for its cell surface expression, activity and agonist-induced internalisation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Torekov, Signe Sørensen; Kipnes, M S; Harley, R E

    2011-01-01

    To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles.......To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles....

  3. Development of a cysteine-deprived and C-terminally truncated GLP-1 receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye; Knudsen, Lotte Bjerre; Garibay, Patrick W.

    2013-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) belongs to family B of the G-protein coupled receptors (GPCRs), and has become a promising target for the treatment of type 2 diabetes. Here we describe the development and characterization of a fully functional cysteine-deprived and C-terminally trun......The glucagon-like peptide-1 receptor (GLP-1R) belongs to family B of the G-protein coupled receptors (GPCRs), and has become a promising target for the treatment of type 2 diabetes. Here we describe the development and characterization of a fully functional cysteine-deprived and C...

  4. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian

    2014-01-01

    We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD......) exposure. Here we assess whether a single peptide possessing balanced coagonism at the glucagon-like peptide 1 (GLP-1) and glucagon receptors can restore leptin responsiveness in DIO mice maintained on a HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce an ∼15% body...

  5. Influence of GLP-1 on myocardial glucose metabolism in healthy men during normo- or hypoglycemia

    DEFF Research Database (Denmark)

    Gejl, Michael; Lerche, Susanne; Mengel, Annette

    2014-01-01

    ) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia....... GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia)....

  6. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

    DEFF Research Database (Denmark)

    Toft-Nielsen, M; Madsbad, Sten; Holst, Jens Juul

    1998-01-01

    The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impo......The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects...

  7. A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice*

    Science.gov (United States)

    Gault, Victor A.; Bhat, Vikas K.; Irwin, Nigel; Flatt, Peter R.

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA2]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA2]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA2]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes. PMID:24165127

  8. A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice.

    Science.gov (United States)

    Gault, Victor A; Bhat, Vikas K; Irwin, Nigel; Flatt, Peter R

    2013-12-06

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.

  9. A tripeptide Diapin effectively lowers blood glucose levels in male type 2 diabetes mice by increasing blood levels of insulin and GLP-1.

    Directory of Open Access Journals (Sweden)

    Jifeng Zhang

    Full Text Available The prevalence of type 2 diabetes (T2D is rapidly increasing worldwide. Effective therapies, such as insulin and Glucagon-like peptide-1 (GLP-1, require injections, which are costly and result in less patient compliance. Here, we report the identification of a tripeptide with significant potential to treat T2D. The peptide, referred to as Diapin, is comprised of three natural L-amino acids, GlyGlyLeu. Glucose tolerance tests showed that oral administration of Diapin effectively lowered blood glucose after oral glucose loading in both normal C57BL/6J mice and T2D mouse models, including KKay, db/db, ob/ob mice, and high fat diet-induced obesity/T2D mice. In addition, Diapin treatment significantly reduced casual blood glucose in KKay diabetic mice in a time-dependent manner without causing hypoglycemia. Furthermore, we found that plasma GLP-1 and insulin levels in diabetic models were significantly increased with Diapin treatment compared to that in the controls. In summary, our findings establish that a peptide with minimum of three amino acids can improve glucose homeostasis and Diapin shows promise as a novel pharmaceutical agent to treat patients with T2D through its dual effects on GLP-1 and insulin secretion.

  10. Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia.

    Science.gov (United States)

    Mottalib, Adham; Mohd-Yusof, Barakatun-Nisak; Shehabeldin, Mohamed; Pober, David M; Mitri, Joanna; Hamdy, Osama

    2016-07-22

    Diabetes-specific nutritional formulas (DSNFs) are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP) effects of 2 DSNFs; Glucerna (GL) and Ultra Glucose Control (UGC) versus oatmeal (OM) on glucose, insulin, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and triglycerides (TG). After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0-240) after GL and UGC was lower than OM (p related to their unique blends of amino acids, carbohydrates and fat.

  11. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

    DEFF Research Database (Denmark)

    Jensen, Elisa Pouline; Poulsen, Steen Seier; Kissow, Hannelouise

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) has a range of extra-pancreatic effects, including renal. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of this study...... investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of 125I-GLP-1, 125I-exendin-4 and 125I-exendin 9-39 was observed in the renal vasculature including afferent arterioles. Infusion of GLP-1 increased BP, RBF and urinary flow...... was to localize renal GLP-1 receptors and describe GLP-1 mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using 125I-GLP-1...

  12. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors

    DEFF Research Database (Denmark)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J

    2017-01-01

    in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e...... to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect...... of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague...

  13. Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Bonde, L; Vilsbøll, T; Nielsen, T

    2013-01-01

    AIM: We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS: Eleven women with GDM [plasma glucose (PG) concentration...

  14. Physiological Gut Oxygenation Alters GLP-1 Secretion from the Enteroendocrine Cell Line STC-1.

    Science.gov (United States)

    Kondrashina, Alina; Papkovsky, Dmitri; Giblin, Linda

    2018-02-01

    Enteroendocrine cell lines are routinely assayed in simple buffers at ≈20% oxygen to screen foods for bioactives that boost satiety hormone levels. However, in vivo, enteroendocrine cells are exposed to different phases of food digestion and function at low oxygen concentration, ranging from 7.5% in the stomach to 0.5% in the colon-rectal junction. The objective of this study is to investigate the effect of physiologically relevant O 2 concentrations of the gut on the production and secretion of the satiety hormone, glucagon-like peptide 1 (GLP-1), from the murine enteroendocrine cell line, secretin tumor cell line (STC-1), in response to dairy macronutrients as they transit the gut. GLP-1 exocytosis from STC-1 cells is influenced by both oxygen concentration and by individual macronutrients. At low oxygen, STC-1 cell viability is significantly improved for all macronutrient stimulations and cyclic adenosine monophosphate levels are dampened. GLP-1 secretion from STC-1 cells is influenced by both the phase of yogurt digestion and corresponding O 2 concentration. Atmospheric oxygen at 4.5% combined with upper gastric digesta, which simulates ileum conditions, yields the highest GLP-1 response. This demonstrates the importance of considering physiological oxygen levels and food digestion along gastrointestinal tract for reliable in vitro analysis of gut hormone secretion. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Gq and Gs signaling acting in synergy to control GLP-1 secretion

    DEFF Research Database (Denmark)

    Pedersen, Maria Hauge; Ekberg, Jeppe Hvidtfeldt; Engelstoft, Maja Storm

    2017-01-01

    GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed i...

  16. The Role of GLP-1 in the Metabolic Success of Bariatric Surgery.

    Science.gov (United States)

    Hutch, Chelsea R; Sandoval, Darleen

    2017-12-01

    Two of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered metabolic surgeries because they are thought to affect metabolism in a weight loss-independent manner. In support of this classification, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation of type 2 diabetes mellitus (T2DM) medication can occur before substantial postoperative weight loss. The mechanisms that underlie this effect are unknown. However, one of the common findings after VSG and RYGB in both animal models and humans is the sharp postprandial rise in several gut peptides, including the incretin and satiety peptide glucagonlike peptide-1 (GLP-1). The increase in endogenous GLP-1 signaling has been considered a primary pathway leading to postsurgical weight loss and improvements in glucose metabolism. However, the degree to which GLP-1 and other gut peptides are responsible for the metabolic successes after bariatric surgery is continually debated. In this review we discuss the mechanisms underlying the increase in GLP-1 and its potential role in the metabolic improvements after bariatric surgery, including remission of T2DM. Understanding the role of changes in gut peptides, or lack thereof, will be crucial in understanding the critical factors necessary for the metabolic success of bariatric surgery. Copyright © 2017 Endocrine Society.

  17. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    Science.gov (United States)

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the Brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose Homeostasis. The objective of this study was to determine whethe...

  18. Presence and dynamics of leptin, GLP-1, and PYY in human breast milk at early postpartum.

    Science.gov (United States)

    Schueler, Jessica; Alexander, Brenda; Hart, Ann Marie; Austin, Kathleen; Larson-Meyer, D Enette

    2013-07-01

    The presence of appetite hormones, namely glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and leptin in breast milk may be important in infant feeding regulation and infant growth. This study evaluated whether concentrations of GLP-1, PYY, and leptin change across a single feeding (from fore- to hindmilk), and are associated with maternal and infant anthropometrics. Thirteen postpartum women (mean ± SD: 25.6 ± 4.5 years, 72.0 ± 11.9 kg) provided fore- and hindmilk samples 4-5 weeks after delivery and underwent measurements of body weight and composition by Dual X-ray Absorptiometry. GLP-1, PYY, and leptin concentrations were measured using radioimmunoassay, and milk fat content was determined by creamatocrit. Concentration of GLP-1 and content of milk fat was higher in hindmilk than foremilk (P ≤ 0.05). PYY and leptin concentrations did not change between fore- and hindmilk. Both leptin concentration and milk fat content were correlated with indices of maternal adiposity, including body mass index (r = 0.65-0.85, P hormones in breast milk may be important in infant appetite and growth regulation. Copyright © 2013 The Obesity Society.

  19. The combination of insulin and GLP-1 analogues in the treatment of type 2 diabetes

    NARCIS (Netherlands)

    van der Klauw, M. M.; Wolffenbuttel, B. H. R.

    2012-01-01

    GLP-1 analogues have been proven to be effective in the treatment of type 2 diabetes mellitus. They stimulate insulin production and secretion, and suppress glucagon secretion, depending on the blood glucose level. They also have an effect on the brain, enhancing satiety, and on the gut, where they

  20. Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2)

    DEFF Research Database (Denmark)

    Orskov, C; Holst, J J

    1987-01-01

    Gene-sequencing studies have shown that the glucagon precursor contains two additional glucagon-like sequences, the so-called glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). We developed radio-immunoassays against synthetic peptides corresponding to these sequences. Antisera were raised in rabb...

  1. Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats

    NARCIS (Netherlands)

    Donahey, Jamie C.K.; Dijk, Gertjan van; Woods, Stephen C.; Seeley, Randy J.

    1998-01-01

    Glucagon-like-peptide-1 (7–36) amide (GLP-1), when infused into the third ventricle (IVT), reduces short-term food intake. In the present experiments, we assessed whether IVT administration of GLP-1 could influence long-term food intake and body weight of lean Long Evans rats and of fatty Zucker

  2. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Finan, Brian; Fischer, Katrin

    2015-01-01

    We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglut...

  3. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul

    2017-01-01

    CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS...

  4. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis

    DEFF Research Database (Denmark)

    Edholm, T; Degerblad, M; Grybäck, P

    2010-01-01

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on ins...

  5. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D.J.; ten Kulve, J.S.; Drent, M.L.; Barkhof, F.; Diamant, M.; IJzerman, R.G.

    2015-01-01

    Objective The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM),

  6. Role of GLP-1 in the Hypoglycemic Effects of Wild Bitter Gourd

    Directory of Open Access Journals (Sweden)

    Ting-ni Huang

    2013-01-01

    Full Text Available This study aimed to examine the role of GLP-1 in the hypoglycemic activity of wild bitter gourd (Momordica charantia L., BG. In vitro, the GLP-1 secretion in STC-1, a murine enteroendocrine cell line, was dose dependently stimulated by water extract (WE, its fractions (WEL, >3 kD and WES, <3 kD, and a bitter compounds-rich fraction of BG. These stimulations were partially inhibited by probenecid, a bitter taste receptor inhibitor, and by U-73122, a phospholipase Cβ2 inhibitor. These results suggested that the stimulation might involve, at least in part, certain bitter taste receptors and/or PLCβ2-signaling pathway. Two cucurbitane triterpenoids isolated from BG, 19-nor-cucurbita-5(10,6,8,22-(E,24-pentaen-3β-ol, and 5β,19-epoxycucurbita-6,24-diene-3β,23ξ-diol (karavilagenine E, showed relative high efficacy in the stimulation. In vivo, mice fed BG diet showed higher insulinogenic index in an oral glucose tolerance test. A single oral dose of WE or WES pretreatment significantly improved intraperitoneal glucose tolerance. A single oral dose of WES significantly decreased glucose and increased insulin and GLP-1 in serum after 30 min. This acute hypoglycemic effect of WES was abolished by pretreatment with exendin-9, a GLP-1 receptor antagonist. Our data provide evidence that BG stimulates GLP-1 secretion which contributes, at least in part, to the antidiabetic activity of BG through an incretin effect.

  7. GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men.

    Science.gov (United States)

    Smits, Mark M; Muskiet, Marcel H A; Tonneijck, Lennart; Kramer, Mark H H; Diamant, Michaela; van Raalte, Daniël H; Serné, Erik H

    2015-06-01

    The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m(2)). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor L-N(G)-monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant L-N(G)-monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=-5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=-0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors. © 2015 American Heart Association, Inc.

  8. Protection against cardiac hypertrophy by geniposide involves the GLP-1 receptor / AMPKα signalling pathway.

    Science.gov (United States)

    Ma, Zhen-Guo; Dai, Jia; Zhang, Wen-Bin; Yuan, Yuan; Liao, Hai-Han; Zhang, Ning; Bian, Zhou-Yan; Tang, Qi-Zhu

    2016-05-01

    Activation of glucagon-like peptide-1 (GLP-1) receptor exerts a range of cardioprotective effects. Geniposide is an agonist of GLP-1 receptor, but its role in cardiac hypertrophy remains completely unknown. Here, we have investigated its protective effects and clarified the underlying molecular mechanisms. The transverse aorta was constricted in C57/B6 mice and then geniposide was given orally for 7 weeks. Morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers were used to evaluate hypertrophy. Geniposide inhibited the hypertrophic response induced by constriction of the transverse aorta or by isoprenaline. Activation of 5'-AMP-activated protein kinase-α (AMPKα) and inhibition of mammalian target of rapamycin, ERK and endoplasmic reticulum stress were observed in hypertrophic hearts that were treated with geniposide. Furthermore, Compound C (CpC) or knock-down of AMPKα restricted protection of geniposide against cell hypertrophy and activation of mammalian target of rapamycin and ERK induced by hypertrophic stimuli. CpC or shAMPKα also abolished the protection of geniposide against endoplasmic reticulum stress induced by thapsigargin or dihtiothreitol. The cardio-protective effects of geniposide were ablated in mice subjected to CpC. GLP-1receptor blockade counteracted the anti-hypertrophic response and activation of AMPKα by geniposide. Knock-down of GLP-1 receptor also offset the inhibitory effects of geniposide on cardiac hypertrophy in vivo. Geniposide protected against cardiac hypertrophy via activation of the GLP-1 receptor/AMPKα pathway. Geniposide is a potential therapeutic drug for cardiac hypertrophy. © 2016 The British Pharmacological Society.

  9. GPR40 reduces food intake and body weight through GLP-1.

    Science.gov (United States)

    Gorski, Judith N; Pachanski, Michele J; Mane, Joel; Plummer, Christopher W; Souza, Sarah; Thomas-Fowlkes, Brande S; Ogawa, Aimie M; Weinglass, Adam B; Di Salvo, Jerry; Cheewatrakoolpong, Boonlert; Howard, Andrew D; Colletti, Steven L; Trujillo, Maria E

    2017-07-01

    G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss. Copyright © 2017 the American Physiological Society.

  10. Baseline ALT levels as a marker of glycemic response to treatment with GLP-1 receptor agonists.

    Science.gov (United States)

    Gimeno-Orna, Jose A; Verdes-Sanz, Guayente; Borau-Maorad, Laura; Campos-Fernández, Julia; Lardiés-Sánchez, Beatriz; Monreal-Villanueva, Marta

    2016-04-01

    This study aimed to assess if ALT levels, as a marker of non-alcoholic fatty liver disease, may predict HbA1c response to treatment with GLP-1 receptor agonists (GLP-1 RAs). A retrospective, longitudinal, analytical study was conducted including patients with type 2 diabetes mellitus continuously treated with GLP-1 agonists (85% with liraglutide) for one year. Patients were divided into two groups according to baseline ALT levels, with 24 U/L (the median of the distribution) as the cut-off point. The dependent variable was HbA1c change (one-year follow-up minus baseline). The predictive value of ALT levels above 24 U/L and ALT change was analyzed using multivariate linear regression adjusted to age, gender, diabetes duration, type and dose of GLP-1 RA, baseline HbA1c, baseline body mass index (BMI), and change in BMI. A total of 117 patients (48% females) aged 58.6 (SD 9.6) years were enrolled into the study. Treatment was associated with a change in ALT of -4.3 U/L (p=0.041) and a change in HbA1c of -1.1% (pALT (-9.25 vs 0.46 U/L; p=0.002) were significantly higher in patients with ALT levels above the median. In the multivariate analysis, both ALT>24 U/L (b=-0.74; 95%CI: -1.31 to -0.18; p=0.011) and ALT change (b=0.028; 95%CI: 0.010 to 0.046; p=0.003), were significant response predictors. Elevated baseline transaminase values and decreased transaminase levels during follow-up are associated to a favorable glycemic response to GLP-1 RAs. Copyright © 2016 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  11. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice

    DEFF Research Database (Denmark)

    Sorensen, Gunnar; Reddy, India A.; Weikop, Pia

    2015-01-01

    reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we...... report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression...... implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction....

  12. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors

    DEFF Research Database (Denmark)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium......-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L...... chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT...

  13. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women

    DEFF Research Database (Denmark)

    Iepsen, Eva Pers Winning; Lundgren, Julie Rehné; Hartmann, Bolette

    2015-01-01

    bone mass reductions. DESIGN: Randomized control study. SETTING: Out-patient research hospital clinic. PARTICIPANTS: Thirty-seven healthy obese women. BMI 34±0.5 kg/m(2), age 46±2 years. INTERVENTION: After a low-calorie diet-induced 12% weight loss, participants were randomized to treatment......CONTEXT: Recent studies indicate that glucagon-like peptide 1 (GLP-1) regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE: To investigate the role of GLP-1 RAs on bone formation and weight loss induced...... markers (CTX-1 and P1NP) were investigated before, after weight loss and after 52 weeks weight maintenance. Primary end points: Change in BMC and bone markers after 52 weeks weight maintenance with or without GLP-1 RA treatment. RESULTS: Total, pelvic and arm-leg BMC decreased during weight maintenance...

  14. GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome

    DEFF Research Database (Denmark)

    Hellström, P M; Näslund, E; Edholm, T

    2008-01-01

    with irritable bowel syndrome (IBS). Antro-duodeno-jejunal manometry was carried out during a 4-h control period with saline, followed by a 4-h period with intravenous GLP-1 (healthy: 0.7 and 1.2 pmol kg(-1) min(-1) (n = 16); IBS, 1.2 and 2.5 pmol kg(-1) min(-1) (n = 14). Plasma was analysed for GLP-1 and gut...... hormones, and gut tissue expression of GLP-1 receptor was studied. In healthy subjects, GLP-1 0.7 pmol kg(-1) min(-1) reduced the migrating motor complexes (MMCs) from a median of 2 (range 2-3) to 0.5 (0-2), and motility index from 4.9 +/- 0.1 to 4.3 +/- 0.3 ln Sigma(mmHg*s min(-1)) in jejunum, while GLP-1...

  15. Secretion of GLP-1 but not GIP is potently stimulated by luminal d-Allulose (d-Psicose) in rats.

    Science.gov (United States)

    Hayakawa, Masaki; Hira, Tohru; Nakamura, Masako; Iida, Tetsuo; Kishimoto, Yuka; Hara, Hiroshi

    2018-02-02

    Glucagon-like peptide 1 (GLP-1), an incretin gastrointestinal hormone, is secreted when stimulated by nutrients including metabolizable sugars such as glucose and fructose. d-Allulose (allulose), also known as d-psicose, is a C-3 isomer of d-fructose and a rare sugar with anti-diabetic or anti-obese effects in animal models. In the present study, we examined whether an oral administration of allulose could stimulate GLP-1 secretion in rats, and investigated the underlying mechanisms. Oral, but not intraperitoneal, administration of allulose (0.5-2.0 g/kg body weight) elevated plasma GLP-1 levels for more than 2 h in a dose-dependent manner. The effects of allulose on GLP-1 secretion were higher than that of dextrin, fructose, or glucose. In addition, oral allulose increased total and active GLP-1, but not glucose-dependent insulinotropic polypeptide (GIP), levels in the portal vein. In anesthetized rats equipped with a portal catheter, luminal (duodenum and ileum) administration of allulose increased portal GLP-1 levels, indicating the luminal effect of allulose. Allulose-induced GLP-1 secretion was abolished in the presence of xanthohumol (a glucose/fructose transport inhibitor), but not in the presence of inhibitors of the sodium-dependent glucose cotransporter 1 or the sweet taste receptor. These results demonstrate a potent and lasting effect of orally administered allulose on GLP-1 secretion in rats, without affecting GIP secretion. The potent and selective GLP-1-releasing effect of allulose holds promise for the prevention and treatment of glucose intolerance through promoting endogenous GLP-1 secretion. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight.

    Science.gov (United States)

    López-Ferreras, L; Richard, J E; Noble, E E; Eerola, K; Anderberg, R H; Olandersson, K; Taing, L; Kanoski, S E; Hayes, M R; Skibicka, K P

    2017-09-12

    Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.Molecular Psychiatry advance online publication, 12 September 2017; doi:10.1038/mp.2017.187.

  17. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents.

    Science.gov (United States)

    Zhou, June; Martin, Roy J; Tulley, Richard T; Raggio, Anne M; McCutcheon, Kathleen L; Shen, Li; Danna, Samuel Colby; Tripathy, Sasmita; Hegsted, Maren; Keenan, Michael J

    2008-11-01

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are anti-diabetes/obesity hormones secreted from the gut after meal ingestion. We have shown that dietary-resistant starch (RS) increased GLP-1 and PYY secretion, but the mechanism remains unknown. RS is a fermentable fiber that lowers the glycemic index of the diet and liberates short-chain fatty acids (SCFAs) through fermentation in the gut. This study investigates the two possible mechanisms by which RS stimulates GLP-1 and PYY secretion: the effect of a meal or glycemic index, and the effect of fermentation. Because GLP-1 and PYY secretions are stimulated by nutrient availability in the gut, the timing of blood sample collections could influence the outcome when two diets with different glycemic indexes are compared. Thus we examined GLP-1 and PYY plasma levels at various time points over a 24-h period in RS-fed rats. In addition, we tested proglucagon (a precursor to GLP-1) and PYY gene expression patterns in specific areas of the gut of RS-fed rats and in an enteroendocrine cell line following exposure to SCFAs in vitro. Our findings are as follows. 1) RS stimulates GLP-1 and PYY secretion in a substantial day-long manner, independent of meal effect or changes in dietary glycemia. 2) Fermentation and the liberation of SCFAs in the lower gut are associated with increased proglucagon and PYY gene expression. 3) Glucose tolerance, an indicator of increased active forms of GLP-1 and PYY, was improved in RS-fed diabetic mice. We conclude that fermentation of RS is most likely the primary mechanism for increased endogenous secretions of total GLP-1 and PYY in rodents. Thus any factor that affects fermentation should be considered when dietary fermentable fiber is used to stimulate GLP-1 and PYY secretion.

  18. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors.

    Science.gov (United States)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J; Holst, Jens Juul; Sorensen, Charlotte M

    2017-12-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  19. Selective beneficial cardiometabolic effects of vertical sleeve gastrectomy are predominantly mediated through glucagon-like peptide (GLP-1 in Zucker diabetic fatty rats

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    2016-12-01

    Conclusion: Enhanced GLP-1 secretion post VSG imparted beneficial cardiometabolic effects on blood glucose, insulin, total cholesterol, triglyceride, bile acids and L-PGDS levels which were abated in the presence of GLP-1 antagonist.

  20. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome.

    Science.gov (United States)

    Tzotzas, Themistoklis; Karras, Spyridon N; Katsiki, Niki

    2017-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans

    DEFF Research Database (Denmark)

    Ahrén, Bo; Holst, Jens Juul; Mari, Andrea

    2003-01-01

    OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its beta-cell effects are important to establish. Previously, beta-cell effects of GLP-1...... have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted...... meal augments insulin secretion in humans by a dose...

  2. Gastric bypass surgery: Improving psoriasis through a GLP-1-dependent mechanism?

    DEFF Research Database (Denmark)

    Faurschou, Annesofie; Zachariae, Claus; Skov, Lone

    2011-01-01

    surgery. This most likely contributes importantly to the acute remission of type 2 diabetes, which is often induced by gastric bypass operations. The hormone is not hypersecreted after the purely restrictive bariatric procedure gastric banding and no case reports exist on improvement in psoriasis......, both a direct anti-inflammatory effect of GLP-1 as well as an indirect effect through weight loss could contribute to improvement in psoriasis. A potential involvement of GLP-1 in the remission of psoriasis observed after bariatric surgery offers exciting possibilities for research and eventually...... bypass surgery in patients with psoriasis may result in complete remission of the disease. A substantial weight loss is achieved in the months following surgery, which is likely to reduce psoriasis symptoms and risk of comorbidities. Interestingly, however, it has been described that improvement...

  3. GLP-1/Exendin-4 induces β-cell proliferation via the epidermal growth factor receptor.

    Science.gov (United States)

    Fusco, Joseph; Xiao, Xiangwei; Prasadan, Krishna; Sheng, Qingfeng; Chen, Congde; Ming, Yung-Ching; Gittes, George

    2017-08-22

    Exendin-4 is a long acting glucagon-like peptide 1 (GLP-1) analogue that is an agonist for the GLP-1 receptor, a G-protein coupled receptor (GPCR). Exendin-4 is used to clinically improve glucose tolerance in diabetic patients due to its ability to enhance insulin secretion. In rodents, and possibly in humans, exendin-4 can stimulate β-cell proliferation. The exact mechanism of action to induce β-cell proliferation is not well understood. Here, using a β-cell specific epidermal growth factor receptor (EGFR) null mouse, we show that exendin-4 induced an increase in proliferation and β-cell mass through EGFR. Thus, our study sheds light on the role of EGFR signaling in the effects of exendin-4 on the control of blood glucose metabolism and β-cell mass.

  4. GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight.

    Science.gov (United States)

    Vogel, Heike; Wolf, Stefanie; Rabasa, Cristina; Rodriguez-Pacheco, Francisca; Babaei, Carina S; Stöber, Franziska; Goldschmidt, Jürgen; DiMarchi, Richard D; Finan, Brian; Tschöp, Matthias H; Dickson, Suzanne L; Schürmann, Annette; Skibicka, Karolina P

    2016-11-01

    The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1-estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  5. Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.

    Science.gov (United States)

    Melhorn, Susan J; Tyagi, Vidhi; Smeraglio, Anne; Roth, Christian L; Schur, Ellen A

    2014-11-01

    Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24.7 kg/m(2), age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    DEFF Research Database (Denmark)

    Scott, R A; Freitag, D. F.; Li, L

    2016-01-01

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We...... associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed...

  7. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.

    Science.gov (United States)

    Ye, Jianping; Hao, Zheng; Mumphrey, Michael B; Townsend, R Leigh; Patterson, Laurel M; Stylopoulos, Nicholas; Münzberg, Heike; Morrison, Christopher D; Drucker, Daniel J; Berthoud, Hans-Rudolf

    2014-03-01

    Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

  8. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1.

    Science.gov (United States)

    Xu, Fen; Lin, Beisi; Zheng, Xiaobin; Chen, Zonglan; Cao, Huanyi; Xu, Haixia; Liang, Hua; Weng, Jianping

    2016-05-01

    Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in weight loss. Sirtuin 1 (SIRT1) plays a vital role in the regulation of lipid metabolism. Here, we investigated the contribution of lipolytic and oxidative changes in white adipose tissue (WAT) to the weight-lowering effect induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in mice. We also looked at the role of SIRT1 in this process. C57BL/6J mice and Sirt1 (+/-) mice were treated with exenatide (24 nmol/kg) or an NaCl solution (154 mmol/l) control i.p. for 8 weeks while receiving a high-fat diet (HFD) after a 12 week HFD challenge. Systemic phenotypic evaluations were carried out during and after the intervention. A lentivirus-mediated short hairpin (sh)RNA vector of the Sirt1 gene was transfected into differentiated 3T3-L1 adipocytes. An in vitro model system used adipocytes induced from Sirt1-null mouse embryonic fibroblasts (MEFs). Exenatide reduced fat mass and enhanced the lipolytic and oxidative capacity of WAT in diet-induced obese C57BL/6J mice. However, these effects were significantly impaired in Sirt1 (+/-) mice compared with wild-type controls. In vitro, exendin-4 increased lipolysis and fatty acid oxidation by upregulating SIRT1 expression and activity in differentiated 3T3-L1 adipocytes. Conversely, RNA interference (i)-induced knockdown of SIRT1 attenuated the lipolytic and oxidative responses to exendin-4 in differentiated 3T3-L1 adipocytes. Again, these responses were entirely abolished in Sirt1-null MEFs after induction into adipocytes. These data highlight that a GLP-1R agonist promotes brown remodelling of WAT in a SIRT1-dependent manner; this might be one of the mechanisms underlying its effect on weight loss.

  9. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

    DEFF Research Database (Denmark)

    Hagemann, Dirk; Holst, Jens Juul; Gethmann, Arnica

    2007-01-01

    INTRODUCTION: Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion of the incre...... postprandial period at supraphysiological plasma levels. Most likely, these effects are indirectly mediated through its insulinotropic action. The GLP-1-induced suppression of ghrelin secretion might be involved in its anorexic effects....

  10. Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in type 2 diabetic patients

    DEFF Research Database (Denmark)

    Nauck, M A; Weber, I; Bach, I

    1998-01-01

    Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female,...

  11. The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice

    DEFF Research Database (Denmark)

    Rolin, Bidda; Deacon, Carolyn F; Carr, Richard D

    2004-01-01

    Glucagon-like peptide-1 (GLP-1), a future treatment for type 2 diabetes, is efficiently degraded by the enzyme dipeptidyl peptidase IV (DPP IV), yielding the major metabolite GLP-1-(9-36)-amide. In this study, we examined the potential glucose lowering effect of GLP-1-(9-36)-amide in mice and fou...

  12. Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus--an adaptive response to hyperglycaemia?

    DEFF Research Database (Denmark)

    Hansen, A M K; Bödvarsdottir, T B; Nordestgaard, D N E

    2011-01-01

    of the study was to evaluate if, during the development of diabetes, alpha cells produce GLP-1 that, in turn, might trigger beta cell growth. Methods Beta cell mass, GLP-1 and insulin levels were measured in the gerbil Psammomys obesus (P. obesus), a rodent model of nutritionally induced diabetes. Furthermore...... from alpha cells is upregulated in P. obesus during the development of diabetes. A similar response is seen in islets exposed to high glucose, which supports the hypothesis that GLP-1 released from alpha cells promotes an increase in beta cell mass and function during metabolic challenge...

  13. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results

    Energy Technology Data Exchange (ETDEWEB)

    Gotthardt, Martin; Fischer, Marc; Naeher, Inga; Holz, Josefin B.; Jungclas, Hartmut; Fritsch, Hans-Walter; Behe, Martin; Joseph, Klaus; Behr, Thomas M. [Department of Nuclear Medicine, Philipps-University of Marburg (Germany); Goeke, Burkhard [Department of Internal Medicine II, Ludwig-Maximilians-University of Munich (Germany)

    2002-05-01

    The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [{sup 125}I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by {sup 252}Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [{sup 123}I]GLP-1(7-36)amide and its more stable agonist [{sup 123}I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [{sup 125}I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor

  14. No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia

    DEFF Research Database (Denmark)

    Ishøy, P L; Fagerlund, B; Broberg, B V

    2017-01-01

    OBJECTIVE: Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double...... of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients...

  15. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM

    DEFF Research Database (Denmark)

    Nauck, M A; Wollschläger, D; Werner, J

    1996-01-01

    ) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed......Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups...

  16. Lixisenatide: A New Daily GLP-1 Agonist for Type 2 Diabetes Management.

    Science.gov (United States)

    McCarty, Delilah; Coleman, Megan; Boland, Cassie L

    2017-05-01

    To review the pharmacology, pharmacokinetics, efficacy, and safety of the glucagon-like peptide-1 receptor agonist (GLP-1RA), lixisenatide, in the treatment of type 2 diabetes mellitus. A PubMed (1966-2016) search was conducted using the following keywords: lixisenatide, AVE0010, glucagon-like peptide-1 agonist, and type 2 diabetes. References were reviewed to identify additional sources. Articles written in English were included if they evaluated the pharmacology, pharmacokinetics, efficacy, or safety of lixisenatide in human subjects. Lixisenatide lowers blood glucose through a glucose-dependent increase in insulin release from pancreatic β-cells and a decreased release of glucagon from pancreatic α-cells. Additionally, lixisenatide delays gastric emptying and increases satiety. Lixisenatide has been studied head to head against exenatide and insulin glulisine. It has also been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, and insulin glargine. In the GetGoal clinical trial series, lixisenatide resulted in a hemoglobin A 1C reduction of 0.6% to 1% and a reduction in body weight of 0.2 to 2.96 kg. The adverse effect profile of lixisenatide was consistent with that of other GLP-1RAs, with nausea, vomiting, and diarrhea most commonly reported. Lixisenatide provides an additional GLP-1RA option, which may have more postprandial blood glucose-lowering effects than the other agents in the class because of its shorter half-life and effects on delaying gastric emptying.

  17. Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men

    DEFF Research Database (Denmark)

    Matikainen, Niina; Björnson, Elias; Söderlund, Sanni

    2016-01-01

    CONTEXT: Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified. OBJECTIVE: To explore the responses of GLP-1, GLP-2 and GIP after...... and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m2) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal. MAIN OUTCOME MEASURES: Postprandial responses (area under the curve, AUC) for glucose...... and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest. CONCLUSIONS: In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion...

  18. Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2)

    International Nuclear Information System (INIS)

    Orskov, C.; Holst, J.J.

    1987-01-01

    Gene-sequencing studies have shown that the glucagon precursor contains two additional glucagon-like sequences, the so-called glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). The authors developed radio-immunoassays against synthetic peptides corresponding to these sequences. Antisera were raised in rabbits after carbodiimide conjugation of peptides to BSA. The selected antisera showed neither mutual cross-reactivity nor cross-reacted with any other peptide of the glucagon family. Trypsin digestion experiments showed that both antisera were directed against the C-terminus of the antigen peptides. I 125 labelling was performed with chloramine T. and separation with plasma-coated charcoal. The detection limit was 7 and 25 pmol/l for GLP-1 and GLP-2. Accurate measurement of both peptides in plasma required extraction. Optimum recovery was obtained with ethanol at 75% (final concentration). The concentrations measured in fasting plasma from 10 normal subjects were 107 +- 7 pmol/l and 151 +-14 pmol/l for GLP-1 and GLP-2, respectively. After a mixed meal the concentrations rose slowly for 2 h reaching 145 +- 13 and 225 +- 15 pmol/l. (author)

  19. Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Hare, Kristine J; Knop, Filip K; Asmar, Meena

    2009-01-01

    OBJECTIVE: Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the alpha-cell is less clear. We investigated the dose-response relationship for GLP-1-induced glucagon suppression in patients with type 2 diabetes (T2DM) and healthy controls. DESIGN: Ten patients with T2DM (duration...... to d 2 (1733 +/- 193 3h x pmol/liter; P 2DM. A similar reduction in AUC for glucagon was observed in healthy controls [1122 +/- 186 (d 1) vs. 1733 +/- 312 3h x pmol/liter (d 2); P diabetic alpha-cell appears to be highly sensitive to the inhibitory...... of DM, 4 +/- 1 yr; glycosylated hemoglobin, 7.1 +/- 0.3%) were studied on 2 d, with stepwise increasing GLP-1 infusions (0.25, 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1)) (d 1) or saline (d 2) with plasma glucose (PG) clamped at fasting level. On d 3, patient PG was normalized overnight using a variable...

  20. GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging

    International Nuclear Information System (INIS)

    Mukai, Eri; Toyoda, Kentaro; Kimura, Hiroyuki; Kawashima, Hidekazu; Fujimoto, Hiroyuki; Ueda, Masashi; Temma, Takashi; Hirao, Konomu; Nagakawa, Kenji; Saji, Hideo; Inagaki, Nobuya

    2009-01-01

    We examined exendin(9-39), an antagonist of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), as a potential probe for imaging of pancreatic β-cells. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Binding assay showed competitive inhibition of [ 125 I]BH-exendin(9-39) binding by non-radioactive exendin(9-39). To assess in vivo selectivity, the biodistribution was evaluated by intravenous administration of [ 125 I]BH-exendin(9-39) to mice. Radioactivity of harvested pancreas reached highest levels at 60 and 120 min among organs examined except lung. Pre-administration of excess non-radioactive exendin(9-39) remarkably and specifically blocked the radioactivity of pancreas. After [ 125 I]BH-exendin(9-39) injection into transgenic mice with pancreatic β-cells expressing GFP, fluorescent and radioactive signals of sections of pancreas were evaluated with an image analyzer. Imaging analysis showed that the fluorescent GFP signals and the radioactive signals were correspondingly located. Thus, the GLP-1R antagonist exendin(9-39) may serve as a useful probe for pancreatic β-cell imaging.

  1. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow.

    Science.gov (United States)

    Jensen, Elisa P; Poulsen, Steen S; Kissow, Hannelouise; Holstein-Rathlou, Niels-Henrik; Deacon, Carolyn F; Jensen, Boye L; Holst, Jens J; Sorensen, Charlotte M

    2015-04-15

    Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats. Copyright © 2015 the American Physiological Society.

  2. Absence of a memory effect for the insulinotropic action of glucagon-like peptide 1 (GLP-1) in healthy volunteers

    DEFF Research Database (Denmark)

    Meier, S; Hücking, K; Ritzel, R

    2003-01-01

    BACKGROUND/AIMS: The term memory effect refers to the phenomenon that B cell stimuli retain some of their insulinotropic effects after they have been removed. Memory effects exist for glucose and sulfonylureas. It is not known whether there is a B-cell memory for incretin hormones such as GLP-1...... and appropriate post hoc tests. RESULTS: GLP-1 plasma levels during the infusion periods were elevated to 89 +/- 9, 85 +/- 13, and 89 +/- 6 pmol/l (p ... minutes after glucose with GLP-1 administered until - 30 min before the glucose load. Glucagon was suppressed by exogenous glucose, but increased significantly (p = 0.013) during the induction of reactive hypoglycemia after glucose injection during GLP-1 administration. CONCLUSION: 1). No memory effect...

  3. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    DEFF Research Database (Denmark)

    Gejl, Michael; Lerche, Susanne; Egefjord, Lærke

    2013-01-01

    In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion...... potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute...... effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with (18)F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present...

  4. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycemia in PCOS

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul

    2017-01-01

    is undetermined. SETTING: Outpatient clinic. PATIENTS AND INTERVENTIONS: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12 month treatment with OCP (150 mg desogestrel+30 microgram ethinylestradiol), metformin (2 g/day), or metformin +OCP. Five-hour oral glucose tolerance tests......CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS...... (5h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight matched healthy women were included as controls. MAIN OUTCOME MEASURES: Changes in GLP-1...

  5. GLP-1 and Exendin-4 Transiently Enhance GABA(A) Receptor-Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

    OpenAIRE

    Korol, Sergiy V.; Jin, Zhe; Babateen, Omar; Birnir, Bryndis

    2015-01-01

    GLP-1 is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the centre for memory and learning. Diabetes mellitus is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01 – 1 nmol/L) transiently...

  6. Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide

    OpenAIRE

    Pinkney, Jonathan; Fox, Thomas; Ranganath, Lakshminarayan

    2010-01-01

    Jonathan Pinkney1, Thomas Fox1, Lakshminarayan Ranganath21Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom; 2Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, United KingdomAbstract: Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Al...

  7. An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke.

    Directory of Open Access Journals (Sweden)

    Huinan Zhang

    Full Text Available Diabetes is a major risk factor for the development of stroke. Glucagon-like peptide-1 receptor (GLP-1R agonists have been in clinical use for the treatment of diabetes and also been reported to be neuroprotective in ischemic stroke. The quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert- butylaminoquinoxaline (DMB is an agonist and allosteric modulator of the GLP-1R with the potential to increase the affinity of GLP-1 for its receptor. The aim of this study was to evaluate the neuroprotective effects of DMB on transient focal cerebral ischemia. In cultured cortical neurons, DMB activated the GLP-1R, leading to increased intracellular cAMP levels with an EC50 value about 100 fold that of exendin-4. Pretreatment of neurons with DMB protected against necrotic and apoptotic cell death was induced by oxygen-glucose deprivation (OGD. The neuroprotective effects of DMB were blocked by GLP-1R knockdown with shRNA but not by GLP-1R antagonism. In C57BL/6 mice, DMB was orally administered 30 min prior to middle cerebral artery occlusion (MCAO surgery. DMB markedly reduced the cerebral infarct size and neurological deficits caused by MCAO and reperfusion. The neuroprotective effects were mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway. DMB exhibited anti-apoptotic effects by modulating Bcl-2 family members. These results provide evidence that DMB, a small molecular GLP-1R agonist, attenuates transient focal cerebral ischemia injury and inhibits neuronal apoptosis induced by MCAO. Taken together, these data suggest that DMB is a potential neuroprotective agent against cerebral ischemia.

  8. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Mentis, Nikolaos; Vardarli, Irfan; Köthe, Lars D

    2011-01-01

    , and placebo were administered over 360 min after an overnight fast (=1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined. RESULTS Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L....... Insulin secretion was stimulated (insulin, C-peptide, P

  9. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice.

    Science.gov (United States)

    Viby, Niels-Erik; Isidor, Marie S; Buggeskov, Katrine B; Poulsen, Steen S; Hansen, Jacob B; Kissow, Hannelouise

    2013-12-01

    The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P agonist-treated mice (P agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.

  10. GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose.

    Science.gov (United States)

    Iwasaki, Yusaku; Sendo, Mio; Dezaki, Katsuya; Hira, Tohru; Sato, Takehiro; Nakata, Masanori; Goswami, Chayon; Aoki, Ryohei; Arai, Takeshi; Kumari, Parmila; Hayakawa, Masaki; Masuda, Chiaki; Okada, Takashi; Hara, Hiroshi; Drucker, Daniel J; Yamada, Yuichiro; Tokuda, Masaaki; Yada, Toshihiko

    2018-01-09

    Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar D-allulose (D-psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic D-allulose administered at the light period (LP) onset ameliorates LP-specific hyperphagia, visceral obesity, and glucose intolerance. These effects are blunted by vagotomy or pharmacological GLP-1R blockade, and by genetic inactivation of GLP-1R signaling in whole body or selectively in vagal afferents. Our results identify D-allulose as prominent GLP-1 releaser that acts via vagal afferents to restrict feeding and hyperglycemia. Furthermore, when administered in a time-specific manner, chronic D-allulose corrects arrhythmic overeating, obesity and diabetes, suggesting that chronotherapeutic modulation of vagal afferent GLP-1R signaling may aid in treating metabolic disorders.

  11. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system.

    Directory of Open Access Journals (Sweden)

    Jennifer E Richard

    Full Text Available The gut/brain peptide, glucagon like peptide 1 (GLP-1, suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS, GLP-1 receptors (GLP-1R. Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

  12. Dulaglutide: the newest GLP-1 receptor agonist for the management of type 2 diabetes.

    Science.gov (United States)

    Thompson, Angela M; Trujillo, Jennifer M

    2015-03-01

    To review the pharmacology, pharmacokinetics, safety, and efficacy of the glucagon-like peptide-1 receptor agonist (GLP-1 RA), dulaglutide, in the treatment of type 2 diabetes mellitus (T2D). A PubMed search was completed to identify publications from 1947 to October 2014 using the search terms dulaglutide and LY2189265. References were reviewed to identify additional resources. Articles were included if they evaluated the pharmacology, pharmacokinetics, safety, or efficacy of dulaglutide. Dulaglutide reduces both glycosylated hemoglobin (A1C) and weight by stimulating insulin secretion and suppressing glucagon in a glucose-dependent manner, delaying gastric emptying, and promoting satiety. Dulaglutide consists of 2 GLP-1 analogues that have been modified to make it a long-acting, once-weekly agent. Dulaglutide has been studied as monotherapy and in combination with metformin, glimepiride, pioglitazone, and insulin lispro. It has demonstrated superior A1C reduction compared with placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It demonstrated noninferiority in A1C reduction to liraglutide. Dulaglutide changed A1C by -0.78% to -1.51%, and it changed weight by -0.35 kg to -3.03 kg. The most common adverse effects in clinical studies were nausea, vomiting, and diarrhea. Dulaglutide is the fifth GLP-1 RA approved for T2D in the United States. It is an attractive option because it is dosed once-weekly, provides A1C lowering similar to liraglutide, weight reduction similar to exenatide, and has an adverse effect profile similar to exenatide and liraglutide. © The Author(s) 2015.

  13. GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion.

    Science.gov (United States)

    Chepurny, Oleg G; Holz, George G; Roe, Michael W; Leech, Colin A

    2016-06-01

    GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus. AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 trisubstituted pyrimidines that exert positive glucoregulatory actions in mice. Here we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through transient receptor potential ankyrin 1 (TRPA1) cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031) and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase intracellular free calcium concentration is not replicated by GPR119 agonists (AR231453, oleoylethanolamide) unrelated in structure to AS1269574. Using human embryonic kidney-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Because we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a dual agonist at two molecular targets (GPR119/TRPA1) important to the control of L-cell function and type 2 diabetes mellitus drug discovery research.

  14. The Effect of Pumpkin on GLP-1 and HOMA-β in Hypercholesterolemic Rats

    Directory of Open Access Journals (Sweden)

    Sunarti

    2016-03-01

    Full Text Available Background and aim: High fat and fructose diet may impair β cell function through oxidative stress that is induced by subsequent hypercholesterolemia. The β cell function is usually quantified by homeostatic model assessment beta-cell function (HOMA-β. Oxidative stress may be decreased by β-carotene from pumpkin (Cucurbita maxima. This study aimed to evaluate the effects of pumpkin powder on glucagon-like peptide-1 (GLP-1 level and HOMA-β in rats with high fat and fructose diet.

  15. In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism

    DEFF Research Database (Denmark)

    Gejl, Michael; Gjedde, Albert; Egefjord, Lærke

    2016-01-01

    with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe...... in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means...

  16. Specific inhibition of bile acid transport alters plasma lipids and GLP-1

    DEFF Research Database (Denmark)

    Rudling, Mats; Camilleri, Michael; Graffner, Hans

    2015-01-01

    BACKGROUND: Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes....../L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02). CONCLUSIONS: Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans. TRIAL REGISTRATIONS: ClinicalTrial.gov: NCT01069783...

  17. GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women.

    Science.gov (United States)

    Iepsen, Eva W; Lundgren, Julie R; Hartmann, Bolette; Pedersen, Oluf; Hansen, Torben; Jørgensen, Niklas R; Jensen, Jens-Erik B; Holst, Jens J; Madsbad, Sten; Torekov, Signe S

    2015-08-01

    Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. Randomized control study. Outpatient research hospital clinic. Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.

  18. GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.

    Science.gov (United States)

    Danielpur, Liron; Sohn, Yang-Sung; Karmi, Ola; Fogel, Chen; Zinger, Adar; Abu-Libdeh, Abdulsalam; Israeli, Tal; Riahi, Yael; Pappo, Orit; Birk, Ruth; Zangen, David H; Mittler, Ron; Cabantchik, Zvi-Ioav; Cerasi, Erol; Nechushtai, Rachel; Leibowitz, Gil

    2016-10-01

    Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). A case report and in vitro mechanistic studies. We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of β-cell dysfunction and the effects of GLP-1-RA. Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

  19. The cardiovascular effect of incretin-based therapies among type 2 diabetes: a systematic review and network meta-analysis.

    Science.gov (United States)

    Wu, Shanshan; Cipriani, Andrea; Yang, Zhirong; Yang, Jun; Cai, Ting; Xu, Yang; Quan, Xiaochi; Zhang, Yuan; Chai, Sanbao; Sun, Feng; Zhan, Siyan

    2018-03-01

    To evaluate the comparative cardiovascular safety of incretin-based therapies in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with duration≥12 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the quality of evidence. The outcome of interest was a composite of cardiovascular death, myocardial infarction, stroke and heart failure. Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size. 281 RCTs (76.9% double-blinded) with 180,000 patients were included, comparing incretin-based therapies with other six classes of anti-diabetic drugs or placebo. A statistically significant reduction in the risk of cardiovascular events was found in favour of GLP-1RAs when compared with placebo (OR 0.89, 95%CI: 0.80-0.99) and sulfonylurea (OR 0.76, 95%CI: 0.59-0.99), whereas DPP-4 inhibitors showed a neutral effect compared with placebo (OR 0.92, 95%CI: 0.83-1.01). Incretin-based therapies show similar cardiovascular risk in comparison with metformin, insulin, thiazolidinediones, alpha-glucosidase inhibitor and sodium-glucose co-transporter 2. GLP-1RA could decrease the risk compared with sulfonylurea or placebo, while DPP-4I appears to have neutral effect on cardiovascular risk.

  20. Supplementation with a fish protein hydrolysate (Micromesistius poutassou): effects on body weight, body composition, and CCK/GLP-1 secretion.

    Science.gov (United States)

    Nobile, Vincenzo; Duclos, Elisa; Michelotti, Angela; Bizzaro, Gioia; Negro, Massimo; Soisson, Florian

    2016-01-01

    Fish protein hydrolysates (FPHs) have been reported as a suitable source of proteins for human nutrition because of their balanced amino acid composition and positive effect on gastrointestinal absorption. Here, we investigated the effect of a FPH, Slimpro(®), obtained from blue whiting (Micromesistius poutassou) muscle by enzymatic hydrolysis, on body composition and on stimulating cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) secretion. A randomized clinical study was carried out on 120, slightly overweight (25 kg/m(2) ≤ BMIBody composition (body weight; fat mass; extracellular water; and circumference of waist, thighs, and hips) and CCK/GLP-1 blood levels were measured at the beginning of the study and after 45 and 90 days of product use. CCK/GLP-1 levels were measured since they are involved in controlling food intake. Treated subjects reported an improvement of body weight composition and an increased blood concentration of both CCK and GLP-1. No differences were found between the 1.4 and 2.8 g FPH doses, indicating a plateau effect starting from 1.4 g FPH. Both 1.4 and 2.8 g of FPH were effective in improving body composition and in increasing CCK and GLP-1 blood levels.

  1. Oral glucose leads to a differential response in glucose, insulin, and GLP-1 in lean versus obese cats.

    Science.gov (United States)

    Hoenig, M; Jordan, E T; Ferguson, D C; de Vries, F

    2010-02-01

    The response to oral glucose was examined in 10 obese and 9 lean age-matched, neutered cats. In all cats, oral administration of 2g/kg glucose was followed by a prompt increase in glucose, insulin, and glucagon-like peptide (GLP)-1. There were significant differences between lean and obese cats in the areas under the curve for glucose, insulin, and GLP-1. However, the responses were variable, and a clear distinction between individual lean and obese cats was not possible. Therefore, this test cannot be recommended as a routine test to examine insulin resistance in individual cats as it is used in people. A further disadvantage for routine use is also the fact that this test requires gastric tubing for the correct administration of the glucose and associated tranquilization to minimize stress and that it was associated with development of diarrhea in 25% of the cats. GLP-1 concentrations were much lower in obese than lean cats. The low GLP-1 concentrations in obese cats might indicate a contribution of GLP-1 to the lower insulin sensitivity of obese cats, but this hypothesis needs to be further investigated. Copyright 2010 Elsevier Inc. All rights reserved.

  2. A mechanism for agonist activation of the glucagon-like peptide-1 (GLP-1) receptor through modelling & molecular dynamics.

    Science.gov (United States)

    Gómez Santiago, Carla; Paci, Emanuele; Donnelly, Dan

    2018-03-29

    The receptor for glucagon-like peptide 1 (GLP-1R) is a validated drug target for the treatment of type 2 diabetes and obesity. Recently the first three structures of GLP-1R were published - an X-ray structure of the apo transmembrane domain in the inactive conformation; an X-ray structure of the full-length receptor bound to a truncated peptide agonist; and a cryo-EM structure of the full-length receptor bound with GLP-1 and coupled to the G protein G s . Since the inactive structure was incomplete, and the two active-state structures shared significant differences, we utilised all available knowledge to build hybrid models of the full length active and inactive state receptors. The two models were simulated using molecular dynamics and the output trajectories analysed and compared to reveal insights into the mechanism for agonist-mediated receptor activation. His-7, Glu-9 and Asp-15 of GLP-1 act together to destabilise transmembrane helix 6 and extracellular loop 3 in order to generate an active conformation of GLP-1R. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Jørgensen, Christinna V; Smajilovic, Sanela

    2017-01-01

    The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1...... (GLP-1) secretion is unclear. Therefore, to probe if the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands: L-arginine and L-ornithine, and assessed GLP-1 levels...... in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion...

  4. The anorexic effect of Ex4/Fc through GLP-1 receptor activation in high-fat diet fed mice.

    Science.gov (United States)

    Liu, Rui; Ma, Duan; Li, Yiming; Hu, Renming; Peng, Yongde; Wang, Qinghua

    2014-08-01

    Exendin-4 (Ex4), a peptide initially found in the saliva of the Gila monster, can activate the signaling pathway of the incretin hormone glucagon-like peptide-1 (GLP-1) through the GLP-1 receptor (GLP-1R). We previously reported that a chimera protein consisting of Ex4 and mouse IgG heavy chain constant regions (Ex4/Fc) can exert biological effects of GLP-1, such as improving glycemic control and ameliorating manifestations in diabetic mice. The aim of this study was to determine whether Ex4/Fc is effective in modulating energy homeostasis in mice. Our results showed that in vivo expression of Ex4/Fc by intramuscular injection of the plasmid encoding Ex4/Fc followed by local electroporation effectively decreased food intake in the mice on high-fat diet (HFD) feeding. In addition, the reduced energy intake was associated with the decreased excrements from the Ex4/Fc-treated HFD mice but not the Fc control mice. Remarkably, the Ex4/Fctreated HFD mice displayed significantly lower triglyceride (TG) levels when compared with the control mice. Interestingly, while the leptin levels were not changed, the circulating ghrelin levels were higher in Ex4/Fc mice than those in the Fc control mice. These results suggested that Ex4/Fc can improve energy metabolism and lipid metabolism through GLP-1R in mice under excessive nutrition conditions.

  5. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation.

    Science.gov (United States)

    van Bloemendaal, Liselotte; Veltman, Dick J; ten Kulve, Jennifer S; Drent, Madeleine L; Barkhof, Frederik; Diamant, Michaela; IJzerman, Richard G

    2015-10-01

    The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM), promote weight loss. This study investigated the association between emotional eating and responses to food-cues in brain areas involved in satiety and reward processing, as well as GLP-1 receptor agonist-induced effects on these brain responses. T2DM patients with obesity, normoglycemic individuals with obesity, and lean individuals (n = 48) were studied in a randomized placebo-controlled crossover study. Using functional MRI, we determined the relation between emotional eating and regional brain responses to visual food stimuli and acute effects of intravenous administration of the GLP-1 receptor agonist exenatide on these responses. Emotional eating scores positively correlated with responses to food-cues in lean subjects in the insula, in normoglycemic subjects with obesity in the insula, and in T2DM patients in the amygdala, orbitofrontal cortex, and insula. Emotional eating scores negatively correlated with exenatide-induced reductions in responses to food-cues in normoglycemic subjects with obesity in the amygdala and in T2DM patients in the insula. Our findings indicate that emotional eaters have altered brain responses to food-cues and are less sensitive to the central effects of GLP-1 receptor activation. © 2015 The Obesity Society.

  6. Ghrelin suppresses cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in the intestine, and attenuates the anorectic effects of CCK, PYY and GLP-1 in goldfish (Carassius auratus).

    Science.gov (United States)

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Valenciano, Ana Isabel; Delgado, María Jesús; Unniappan, Suraj

    2017-07-01

    Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice

    DEFF Research Database (Denmark)

    Viby, Niels-Erik; Isidor, Marie Sophie; Buggeskov, Katrine B

    2013-01-01

    pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with measurement of enhanced...... pause (Penh) in a whole body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Penh increased...... dramatically at day 17 in all control mice but the increase was significantly less in the groups of GLP-1R agonist treated mice (p...

  8. Distal gastrectomy in pancreaticoduodenectomy is associated with accelerated gastric emptying, enhanced postprandial release of GLP-1, and improved insulin sensitivity

    DEFF Research Database (Denmark)

    Harmuth, Stefan; Wewalka, Marlene; Holst, Jens Juul

    2014-01-01

    resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations. RESULTS: Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0-30 min) integrated GLP-1 (AUC30; r (2) = 0.61; p = 0......OBJECTIVE: This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD). BACKGROUND: Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD......, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose...

  9. Effect of GLP-1 Receptor Agonist Treatment on Body weight in Obese Antipsychotic-treated Patients with Schizophrenia

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2017-01-01

    and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. MATERIAL AND METHODS...... with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented......AIMS: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects like obesity...

  10. Anti-inflammatory role of GLP-1 and the effect of gastric bypass on diabetes- and obesity-associated inflammation

    DEFF Research Database (Denmark)

    Bovbjerg, Kirsten Katrine Lindegaard

    , the RYGB procedure is associated with immediate improvement in glycemic control and insulin secretion. The exact mechanisms for the immediate and long-term positive effect of RYGB on glucose metabolism and obesity related co-morbidities remain unclear. Changes in inflammatory cellular and molecular...... with a set of metabolic abnormalities comprising the metabolic syndrome, such as hypertension, dyslipidemia, and insulin resistance. Although the exact causes for the onset of clinical disease remain largely unknown, emerging evidence seems to suggest that obesity-induced inflammation, especially...... body of literature reports antiinflammatory and other immunological effects of GLP-1 in animals and in humans suggesting that GLP-1 acts beyond purely glucoregulatory mechanisms. The exaggerated postprandial GLP-1 secretion following RYGB may thus be involved in the beneficial metabolic effects both...

  11. Roles of increased glycemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Tharakan, George; Behary, Preeshila; Wewer Albrechtsen, Nicolai Jacob

    2017-01-01

    Objective Roux-en-Y Gastric Bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized complication of RYGB surgery is postprandial hypoglycemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including...... nesidioblastosis, altered insulin clearance and increased glucagon-like-1 peptide (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments have been trialled ranging from acarbose, to both GLP-1 agonists and antagonists, even...... in insulin and GLP-1 concentration in patients who had hypoglycemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). There was a significantly increased glucagon secretion in the MMT Hypo group versus the Non-hypo group. No significant differences in oxyntomodulin, GIP...

  12. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Ten Kulve, Jennifer S; Veltman, Dick J; van Bloemendaal, Liselotte

    2015-01-01

    that endogenous GLP-1 has effects on CNS reward and satiety circuits. Methods This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible......-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state...... and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion...

  13. Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes.

    Science.gov (United States)

    Manell, Hannes; Staaf, Johan; Manukyan, Levon; Kristinsson, Hjalti; Cen, Jing; Stenlid, Rasmus; Ciba, Iris; Forslund, Anders; Bergsten, Peter

    2016-03-01

    Proglucagon-derived hormones are important for glucose metabolism, but little is known about them in pediatric obesity and type 2 diabetes mellitus (T2DM). Fasting and postprandial levels of proglucagon-derived peptides glucagon, GLP-1, and glicentin in adolescents with obesity across the glucose tolerance spectrum were investigated. This was a cross-sectional study with plasma hormone levels quantified at fasting and during an oral glucose tolerance test (OGTT). This study took place in a pediatric obesity clinic at Uppsala University Hospital, Sweden. Adolescents with obesity, age 10-18 years, with normal glucose tolerance (NGT, n = 23), impaired glucose tolerance (IGT, n = 19), or T2DM (n = 4) and age-matched lean adolescents (n = 19) were included. Outcome measures were fasting and OGTT plasma levels of insulin, glucagon, active GLP-1, and glicentin. Adolescents with obesity and IGT had lower fasting GLP-1 and glicentin levels than those with NGT (0.25 vs 0.53 pM, P adolescents with obesity and T2DM had higher fasting glucagon levels (18.1 vs 10.1 pM, P adolescents with obesity and NGT than in lean adolescents (P Obese adolescents with IGT have lowered fasting GLP-1 and glicentin levels. In T2DM, fasting glucagon levels are elevated, whereas GLP-1 and glicentin levels are maintained low. During OGTT, adolescents with obesity have more products of pancreatically than intestinally cleaved proglucagon (ie, more glucagon and less GLP-1) in the plasma. This shift becomes more pronounced when glucose tolerance deteriorates.

  14. The GIP receptor displays higher basal activity than the GLP-1 receptor but does not recruit GRK2 or arrestin3 effectively.

    Directory of Open Access Journals (Sweden)

    Suleiman Al-Sabah

    Full Text Available Glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are important regulators of insulin secretion, and their functional loss is an early characteristic of type 2 diabetes mellitus (T2DM. Pharmacological levels of GLP-1, but not GIP, can overcome this loss. GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic β-cells. Both the GLP-1 receptor (GLP-1R and the GIP receptor (GIPR are members of the secretin family of G protein-coupled receptors (GPCRs and couple positively to adenylate cyclase. We compared the signalling properties of these two receptors to gain further insight into why GLP-1, but not GIP, remains insulinotropic in T2DM patients.GLP-1R and GIPR were transiently expressed in HEK-293 cells, and basal and ligand-induced cAMP production were investigated using a cAMP-responsive luciferase reporter gene assay. Arrestin3 (Arr3 recruitment to the two receptors was investigated using enzyme fragment complementation, confocal microscopy and fluorescence resonance energy transfer (FRET.GIPR displayed significantly higher (P<0.05 ligand-independent activity than GLP-1R. Arr3 displayed a robust translocation to agonist-stimulated GLP-1R but not to GIPR. These observations were confirmed in FRET experiments, in which GLP-1 stimulated the recruitment of both GPCR kinase 2 (GRK2 and Arr3 to GLP-1R. These interactions were not reversed upon agonist washout. In contrast, GIP did not stimulate recruitment of either GRK2 or Arr3 to its receptor. Interestingly, arrestin remained at the plasma membrane even after prolonged (30 min stimulation with GLP-1. Although the GLP-1R/arrestin interaction could not be reversed by agonist washout, GLP-1R and arrestin did not co-internalise, suggesting that GLP-1R is a class A receptor with regard to arrestin binding.GIPR displays higher basal activity than GLP-1R but does not effectively recruit GRK2 or Arr3.

  15. Effects of microwave exposure on glucagon-like peptide-1 (GLP-1) and its receptor and the relationship with learning and memory injury

    International Nuclear Information System (INIS)

    Zhang Lei; Zhou Zhou; Zhang Guangbin; Yu Zhengping

    2007-01-01

    In order to explore the effects of microwave exposure on GLP-1 and its receptor, the relationship between the changes of GLP-1 and its receptor and learning and memory injury induced by microwave exposure has been studied in this paper. Morris water maze was used to evaluate learning and memory ability of rats. The changes of the plasma GLP-1 level were measured by ELISA assay. Alteration of the GLP-1R mRNA expression in rat hippocampus was determined by RT-PCR and Apoptosis was detected by TUNEL. Our study showed that microwave exposure injured the learning and memory abilities of rats meanwhile plasma GLP-1 level was decreased and GLP-1R expression in hippocampus was down-regulated, which can be protected by pretreatment with GLP-1. Alterations in GLP-1 and GLP-1R are, at least partially, responsible for the microwave exposure induced learning and memory dysfunction and neuronal injury. These data provide some new clues to investigate the mechanisms of microwave exposure induced neuronal injury and develop clinical approaches for treatment of microwave exposure induced injury. It can provide some new ideals for investigation of related mechanism and development of clinical treatment under exposed microwave irradiation. (authors)

  16. GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose

    OpenAIRE

    Iwasaki, Yusaku; Sendo, Mio; Dezaki, Katsuya; Hira, Tohru; Sato, Takehiro; Nakata, Masanori; Goswami, Chayon; Aoki, Ryohei; Arai, Takeshi; Kumari, Parmila; Hayakawa, Masaki; Masuda, Chiaki; Okada, Takashi; Hara, Hiroshi; Drucker, Daniel J.

    2018-01-01

    Overeating and arrhythmic feeding promote obesity and diabetes. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective anti-obesity drugs but their use is limited by side effects. Here we show that oral administration of the non-calorie sweetener, rare sugar d-allulose (d-psicose), induces GLP-1 release, activates vagal afferent signaling, reduces food intake and promotes glucose tolerance in healthy and obese-diabetic animal models. Subchronic d-allulose administered at the light p...

  17. Incretin-based therapy of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Knop, Filip K; Vilsbøll, Tina; Holst, Jens J

    2009-01-01

    secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular diabetic complications. Traditional treatment modalities--even multidrug approaches--for T2DM are often unsatisfactory at getting patients...... to glycemic goals as the disease progresses due to a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema...... on the actions of the incretin hormones have recently been approved for therapy of T2DM; injectable long-acting stable analogues of GLP-1, incretin mimetics, and orally available inhibitors of dipeptidyl peptidase 4 (DPP4; the enzyme responsible for the rapid degradation of GLP-1 and GIP), the so-called incretin...

  18. Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Marie; Jensen, David H; Tribler, Siri

    2015-01-01

    -phase responses to 15 mmol/l glucose were reduced equally for both hormones. CONCLUSIONS/INTERPRETATION: Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease......AIMS/HYPOTHESIS: We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance. METHODS: Nineteen healthy...... in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. TRIAL REGISTRATION: Clinicaltrials.gov NCT02235584....

  19. Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli.

    Science.gov (United States)

    Züger, Daniela; Forster, Karoline; Lutz, Thomas A; Riediger, Thomas

    2013-03-15

    The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of

  20. Sweet Taste Receptor Activation in the Gut Is of Limited Importance for Glucose-Stimulated GLP-1 and GIP Secretion

    DEFF Research Database (Denmark)

    Saltiel, Monika Yosifova; Kuhre, Rune Ehrenreich; Christiansen, Charlotte Bayer

    2017-01-01

    Glucose stimulates the secretion of the incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). It is debated whether the sweet taste receptor (STR) triggers this secretion. We investigated the role of STR activation for glucose-stimulated incretin...

  1. The effect of a subcutaneous infusion of GLP-1, OXM and PYY on Energy intake and Expenditure in Obese volunteers

    DEFF Research Database (Denmark)

    Tan, Tricia; Behary, Preeshila; Tharakan, George

    2017-01-01

    subcutaneously using a pump device, allowing volunteers to remain ambulatory. Ad Libitum food intake studies were performed during the infusion and energy expenditure measured using a ventilated hood calorimeter. Results: Post-prandial levels of GLP-1, OXM and PYY seen post RYGB were successfully matched using 4...

  2. The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour

    NARCIS (Netherlands)

    de Boer, Stefanie Amarens; Lefrandt, Joop Daniel; Petersen, Japke Frida; Boersma, Hendrikus Hessel; Mulder, Douwe Johannes; Hoogenberg, Klaas

    Background Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies. Objective To evaluate

  3. GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance

    DEFF Research Database (Denmark)

    Matikainen, Niina; Bogl, Leonie H; Hakkarainen, Antti

    2014-01-01

    OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for o...... Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults....... under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min...... GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS...

  4. Rationale for, Initiation and Titration of the Basal Insulin/GLP-1RA Fixed-Ratio Combination Products, IDegLira and IGlarLixi, for the Management of Type 2 Diabetes.

    Science.gov (United States)

    Valentine, Virginia; Goldman, Jennifer; Shubrook, Jay H

    2017-08-01

    Type 2 diabetes (T2D) is a progressive disease affecting glucose regulation and a major cause of morbidity and mortality globally. Many patients are not escalated up the treatment ladder appropriately despite failing to achieve glycemic control, with barriers such as fear of hypoglycemia, weight gain, and treatment burden recognized as factors. Exogenous basal insulin is titrated to address control of fasting plasma glucose and may preserve residual β-cell function, thus promoting a greater endogenous prandial insulin response. Native glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the gut in response to nutrient ingestion; it increases insulin secretion, inhibits glucagon secretion, and prolongs gastric emptying, thereby lowering overall food intake. As its glucose-lowering action is glucose dependent, a GLP-1 receptor agonist (GLP-1RA) achieves these benefits with a lower risk of hypoglycemia compared with other diabetes therapies. Two products, an insulin degludec/liraglutide combination (IDegLira) and an insulin glargine/lixisenatide combination (IGlarLixi), were approved for use in adults with T2D by the US Food and Drug Administration in 2016. The efficacy and safety of these two basal insulin/GLP-1RA combination products were studied in the DUAL program (NCTs 01336023, 01392573, 01676116, 01618162, 01952145, and 02298192) and the LixiLan program (NCTs 02058160 and 02058147). Compared with basal insulin, insulin/GLP-1RA fixed-ratio combinations are superior at reducing HbA 1c with weight neutrality or weight loss rather than weight gain, as well as reduced hypoglycemia rates, and reduced insulin-dose requirement with IDegLira. A combination of different medications may often be required to achieve glycemic control, and fixed-ratio combination products allow such therapies to be given in simple regimens. Clinical trial data for these products highlight the great potential of these agents, not merely their efficacy and safety but also their

  5. Glucagon and a glucagon-GLP-1 dual-agonist increases cardiac performance with different metabolic effects in insulin-resistant hearts

    DEFF Research Database (Denmark)

    Axelsen, Lene Nygaard; Keung, Wendy; Pedersen, Henrik D

    2012-01-01

    and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495). EXPERIMENTAL APPROACH Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function...

  6. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice

    DEFF Research Database (Denmark)

    Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens Juul

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth horm...

  7. GLP-1 inhibits VEGFA-mediated signaling in isolated human endothelial cells and VEGFA-induced dilation of rat mesenteric arteries

    DEFF Research Database (Denmark)

    Rotbøl, Cecilie Egholm; Khammy, Makhala Michell; Dalsgaard, Thomas

    2016-01-01

    to PLCγ activation, Src, and endothelial NOS (eNOS) signaling, thereby controlling endothelial vessel tone. By using RT-PCR analysis, we found mRNA for the GLP-1 receptor (GLP-1R) in human dermal microvascular endothelial cells (HDMEC), human retinal microvascular endothelial cells, and rat arteries...

  8. Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells.

    Science.gov (United States)

    Psichas, Arianna; Glass, Leslie L; Sharp, Stephen J; Reimann, Frank; Gribble, Fiona M

    2016-03-01

    Galanin is a widely expressed neuropeptide, which in the gut is thought to modulate gastrointestinal motility and secretion. We aimed to elucidate the poorly characterised mechanisms underlying the inhibitory effect of galanin and the potential involvement of G-protein coupled inwardly rectifying potassium, Kir 3, (GIRK) channels in glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) secretion. Purified murine L and K cells were analysed for expression of galanin receptors and GIRK subunits. Hormone secretion was measured from primary murine intestinal cultures. Intracellular cAMP was monitored in primary L cells derived from mice expressing the Epac2camps sensor under the control of the proglucagon promoter. Galanin receptor 1 (GAL1, Galr1) and GIRK channel 1 (Kir 3.1, Kcnj3) and 4 (Kir 3.4, Kcnj5) mRNA expression was highly enriched in K and L cells. Galanin and a selective GAL1 receptor agonist (M617) potently inhibited GLP-1 and GIP secretion from primary small intestinal cultures. In L cells, galanin significantly inhibited the forskolin-induced cAMP response. The GIRK1/4 activator ML297 significantly reduced glucose-stimulated and IBMX-stimulated GLP-1 secretion but had no effect on GIP. The GIRK blocker tertiapin-Q did not impair galanin-mediated GLP-1 inhibition. Galanin, acting via the GAL1 receptor and Gi -coupled signalling in L and K cells, is a potent inhibitor of GLP-1 and GIP secretion. Although GIRK1/4 channels are expressed in these cells, their activation does not appear to play a major role in galanin-mediated inhibition of incretin secretion. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  9. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.

    Science.gov (United States)

    Guo, Dan-yang; Li, De-wen; Ning, Meng-meng; Dang, Xiang-yu; Zhang, Li-na; Zeng, Li-min; Hu, You-hong; Leng, Ying

    2015-10-30

    G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response.

    Science.gov (United States)

    Dorton, Hilary M; Luo, Shan; Monterosso, John R; Page, Kathleen A

    2017-01-01

    Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI) scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD) response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen) and ventral striatum (nucleus accumbens). The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman's correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption. Added sugar intake

  11. Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response

    Directory of Open Access Journals (Sweden)

    Hilary M. Dorton

    2018-01-01

    Full Text Available Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1, and peptide YY (PYY, suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen and ventral striatum (nucleus accumbens. The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman’s correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption

  12. Short-term administration of the GLP-1 analog liraglutide decreases circulating leptin and increases GIP levels and these changes are associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, crossover study.

    Science.gov (United States)

    Farr, Olivia M; Tsoukas, Michael A; Triantafyllou, Georgios; Dincer, Fadime; Filippaios, Andreas; Ko, Byung-Joon; Mantzoros, Christos S

    2016-07-01

    GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics. Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues. By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (pfood cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA. We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials. Copyright © 2016 Elsevier Inc. All rights

  13. Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP-1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes.

    Science.gov (United States)

    Irwin, Nigel; Patterson, Steven; de Kort, Martin; Moffett, R Charlotte; Wisse, Jeffry A J; Dokter, Wim H A; Bos, Ebo S; Miltenburg, André M M; Flatt, Peter R

    2015-08-01

    The present study details the development of a family of novel D-Ala(8) glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Exenatide and liraglutide: different approaches to develop GLP-1 receptor agonists (incretin mimetics)--preclinical and clinical results

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2009-01-01

    , with average reductions in HbA1c of about 1.0% point, fasting plasma glucose of about 1.4 mmol l(-1), and causes a weight loss of approximately 2-3 kg after 30 weeks of treatment. The adverse effects are transient nausea and vomiting. The long-acting once-daily human GLP-1 receptor agonist liraglutide reduces...... HbA1c by about 1.0-2.0% point, weight by 1-3 kg and seems to have fewer gastrointestinal side effects than exenatide. The final place of the GLP-1 receptor agonists in the diabetes treatment algorithm will be clarified when we have long-term trials with cardiovascular end-points and data illustrating...

  15. Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36

    DEFF Research Database (Denmark)

    Iepsen, Eva W; Lundgren, Julie; Holst, Jens J

    2016-01-01

    at week 52. Glucagon levels were unaffected by weight loss. CONCLUSIONS: Meal responses of GLP-1 and PYY3-36 remained increased 1 year after weight maintenance, whereas ghrelin and GIP reverted toward before-weight loss values. Thus, an increase in appetite inhibitory mechanisms and a partly decrease...... in appetite-stimulating mechanisms appear to contribute to successful long-term weight loss maintenance.......-week very low-calorie diet (800kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY3-36, ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area...

  16. DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity

    DEFF Research Database (Denmark)

    Böhm, Anja; Wagner, Robert; Machicao, Fausto

    2017-01-01

    , inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). RESEARCH DESIGN...... determined. RESULTS: We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype......-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. CONCLUSIONS: A common variant, i...

  17. Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

    DEFF Research Database (Denmark)

    Kaas, A.; Andersen, M. L. M.; Fredheim, Siri

    2012-01-01

    Objective: Proinsulin is a marker of beta-cell distress and dysfunction in type 2 diabetes and transplanted islets. Proinsulin levels are elevated in patients newly diagnosed with type 1 diabetes. Our aim was to assess the relationship between proinsulin, insulin dose-adjusted haemoglobin A1c (IDAA......1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes. Methods: Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C = 9%. The patients had a liquid meal.......002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002). Conclusions: In type 1 diabetes, patients in partial remission have higher levels of proinsulin...

  18. Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice

    Science.gov (United States)

    Carmody, Jill S.; Muñoz, Rodrigo; Yin, Huali

    2016-01-01

    Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9–39) (2 pmol·kg−1·min−1 peripherally; 0.5 pmol·kg−1·min−1 centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation. PMID:27026085

  19. Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

    Science.gov (United States)

    Campbell, R Keith; Cobble, Michael E; Reid, Timothy S; Shomali, Mansur E

    2010-09-01

    The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

  20. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.

    Directory of Open Access Journals (Sweden)

    Shvetank Sharma

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a known outcome of hepatosteatosis. Free fatty acids (FFA induce the unfolded protein response (UPR or endoplasmic reticulum (ER stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively. Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein; the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM. Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

  1. Centrally located GLP-1 receptors modulate gastric slow waves and cardiovascular function in ferrets consistent with the induction of nausea.

    Science.gov (United States)

    Lu, Zengbing; Yeung, Chi-Kong; Lin, Ge; Yew, David T W; Andrews, P L R; Rudd, John A

    2017-10-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for the treatment of Type 2 diabetes and obesity, but can cause nausea and emesis in some patients. GLP-1 receptors are distributed widely in the brain, where they contribute to mechanisms of emesis, reduced appetite and aversion, but it is not known if these centrally located receptors also contribute to a modulation of gastric slow wave activity, which is linked causally to nausea. Our aim was to investigate the potential of the GLP-1 receptor agonist, exendin-4, administered into the 3rd ventricle to modulate emesis, feeding and gastric slow wave activity. Thermoregulation and cardiovascular parameters were also monitored, as they are disturbed during nausea. Ferrets were used as common laboratory rodents do not have an emetic reflex. A guide cannula was implanted into the 3rd ventricle for delivering a previously established dose of exendin-4 (10nmol), which had been shown to induce emesis and behaviours indicative of 'nausea'. Radiotelemetry recorded gastric myoelectric activity (GMA; slow waves), blood pressure and heart rate variability (HRV), and core temperature; food intake and behaviour were also assessed. Exendin-4 (10nmol, i.c.v.) decreased the dominant frequency of GMA, with an associated increase in the percentage of bradygastric power (lasting ~4h). Food intake was inhibited in all animals, with 63% exhibiting emesis. Exendin-4 also increased blood pressure (lasting ~24h) and heart rate (lasting ~7h), decreased HRV (lasting ~24h), and caused transient hyperthermia. None of the above parameters were emesis-dependent. The present study shows for the first time that gastric slow waves may be modulated by GLP-1 receptors in the brain through mechanisms that appear independent from emesis. Taken together with a reduction in HRV, the findings are consistent with changes associated with the occurrence of nausea in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Increased Postprandial GIP and Glucagon Responses, But Unaltered GLP-1 Response after Intervention with Steroid Hormone, Relative Physical Inactivity, And High-Calorie Diet in Healthy Subjects

    DEFF Research Database (Denmark)

    Hansen, Katrine B; Vilsbøll, Tina; Bagger, Jonatan I

    2011-01-01

    Objective:Increased postprandial glucose-dependent insulinotropic polypeptide (GIP) and glucagon responses and reduced postprandial glucagon-like peptide-1 (GLP-1) responses have been observed in some patients with type 2 diabetes mellitus. The causality of these pathophysiological traits...... postprandial GLP-1 responses as observed in some individuals with type 2 diabetes mellitus....... is unknown. We aimed to determine the impact of insulin resistance and reduced glucose tolerance on postprandial GIP, GLP-1, and glucagon responses in healthy subjects. Research Design and Methods:A 4-h 2200 KJ-liquid meal test was performed in 10 healthy Caucasian males without family history of diabetes...

  3. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    Energy Technology Data Exchange (ETDEWEB)

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming, E-mail: dr_dongming@126.com

    2016-08-05

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.

  4. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    International Nuclear Information System (INIS)

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

    2016-01-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.

  5. The Antidiabetic Mechanisms of Polyphenols Related to Increased Glucagon-Like Peptide-1 (GLP1) and Insulin Signaling.

    Science.gov (United States)

    Domínguez Avila, J Abraham; Rodrigo García, Joaquín; González Aguilar, Gustavo A; de la Rosa, Laura A

    2017-05-30

    Type-2 diabetes mellitus (T2DM) is an endocrine disease related to impaired/absent insulin signaling. Dietary habits can either promote or mitigate the onset and severity of T2DM. Diets rich in fruits and vegetables have been correlated with a decreased incidence of T2DM, apparently due to their high polyphenol content. Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. The present review describes the antidiabetic effects of polyphenols, specifically related to the secretion and effects of insulin and glucagon-like peptide 1 (GLP1), an enteric hormone that stimulates postprandial insulin secretion. The evidence suggests that polyphenols from various sources stimulate L-cells to secrete GLP1, increase its half-life by inhibiting dipeptidyl peptidase-4 (DPP4), stimulate β-cells to secrete insulin and stimulate the peripheral response to insulin, increasing the overall effects of the GLP1-insulin axis. The glucose-lowering potential of polyphenols has been evidenced in various acute and chronic models of healthy and diabetic organisms. Some polyphenols appear to exert their effects similarly to pharmaceutical antidiabetics; thus, rigorous clinical trials are needed to fully validate this claim. The broad diversity of polyphenols has not allowed for entirely describing their mechanisms of action, but the evidence advocates for their regular consumption.

  6. The Antidiabetic Mechanisms of Polyphenols Related to Increased Glucagon-Like Peptide-1 (GLP1 and Insulin Signaling

    Directory of Open Access Journals (Sweden)

    J. Abraham Domínguez Avila

    2017-05-01

    Full Text Available Type-2 diabetes mellitus (T2DM is an endocrine disease related to impaired/absent insulin signaling. Dietary habits can either promote or mitigate the onset and severity of T2DM. Diets rich in fruits and vegetables have been correlated with a decreased incidence of T2DM, apparently due to their high polyphenol content. Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. The present review describes the antidiabetic effects of polyphenols, specifically related to the secretion and effects of insulin and glucagon-like peptide 1 (GLP1, an enteric hormone that stimulates postprandial insulin secretion. The evidence suggests that polyphenols from various sources stimulate L-cells to secrete GLP1, increase its half-life by inhibiting dipeptidyl peptidase-4 (DPP4, stimulate β-cells to secrete insulin and stimulate the peripheral response to insulin, increasing the overall effects of the GLP1-insulin axis. The glucose-lowering potential of polyphenols has been evidenced in various acute and chronic models of healthy and diabetic organisms. Some polyphenols appear to exert their effects similarly to pharmaceutical antidiabetics; thus, rigorous clinical trials are needed to fully validate this claim. The broad diversity of polyphenols has not allowed for entirely describing their mechanisms of action, but the evidence advocates for their regular consumption.

  7. COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.

    Directory of Open Access Journals (Sweden)

    Marie Boutant

    Full Text Available The control of the functional pancreatic β-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how β-cell mass is determined.Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1 gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal β-cell proliferation and apoptosis, this suggests decreased β-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the β-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1 via β-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced β-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2 in human islets and rat β-cells providing a feedback loop.Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases β-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the β-catenin-dependent pathway and its expression is under the control of TCF7L2.

  8. Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes

    DEFF Research Database (Denmark)

    Rhee, N A; Vilsbøll, T; Knop, F K

    2012-01-01

    Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM...... antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB......-induced remission of T2DM are lacking. This article critically evaluates the current evidence for a role of GLP-1 in RYGB-induced remission of T2DM....

  9. At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Rungby, Jørgen; Brock, Birgitte

    2014-01-01

    and Maud Menten described the steady-state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose-dependent impact of GLP-1 on blood-brain glucose transfer and metabolism. This MiniReview examines......Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with pancreatic and extrapancreatic effects. Studies reveal significant effects in regions of brain tissue that regulate appetite and satiety. The effects cause that mimetics of GLP-1 serves as treatment of type 2 diabetes...... the potential of GLP-1 as a molecule of interest to the understanding of brain energy metabolism and notes the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders, among others. These effects can be understood only by reference to the original...

  10. Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes

    DEFF Research Database (Denmark)

    Rhee, Nicolai Alexander; Vilsbøll, T; Knop, F K

    2012-01-01

    antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB......Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM....... Interestingly, the majority of remissions occur almost immediately following the operation and long before significant weight loss has taken place. Following RYGB, dramatic increases in postprandial plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1) have been recorded, and the known...

  11. Long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Knop, Filip K

    2008-01-01

    Type 2 diabetes mellitus is characterized by insulin resistance, impaired glucose-induced insulin secretion, and inappropriately elevated glucagon levels which eventually result in hyperglycemia. The currently available treatment modalities for type 2 diabetes are often unsatisfactory in getting...... patients to glycemic goals, even when used in combination, and therefore many patients develop microvascular and macrovascular diabetic complications. Additionally, these treatment modalities are often limited by inconvenient dosage regimens and safety and tolerability issues, the latter including...... for the treatment of type 2 diabetes has become available in the US (since October 2005) and in Europe (since May 2007): the incretin-based therapies. The incretin-based therapies fall into two different classes: (i) incretin mimetics, i.e. injectable peptide preparations with actions similar to the natural...

  12. GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jiyoung; Kim, Ki-Suk; Kim, Kang-Hoon; Lee, In-Seung; Jeong, Hyeon-soo; Kim, Yumi; Jang, Hyeung-Jin, E-mail: hjjang@khu.ac.kr

    2015-12-04

    Glucagon-like peptide-1 (GLP-1) hormone is known to regulate blood glucose by an insulinotropic effect and increases proliferation as and also prevents apoptosis of pancreatic β cells. We know that GLP-1 is secreted by nutrients such as fatty acids and sweet compounds but also bitter compounds via stimulation of G-protein coupled receptors (GPCRs) in the gut. Among these, bitter compounds are multiply-contained in phytochemicals or artificial materials and perceived as ligands of various bitter taste receptors. We hypothesized that GLP-1 hormone is secreted through stimulation of a single bitter taste receptor by 1,10-phenanthroline which is known agonist of taste receptor type 2 member 5 (T2R5). To prove this hypothesis, we used the representatively well-known 1,10-phenanthroline as ligand of single receptor and evaluated the existence of T2R5 by double-labeling immunofluorescence and then 1,10-phenanthroline is able to secrete GLP-1 hormone through stimulation of T2R5 in human enteroendocrine cells. Consequently, we verify that GLP-1 hormone is colocalized with T2R5 in the human duodenum and ileum tissue and is secreted by 1,10-phenanthroline via T2R5 signal transduction in differentiated human enteroendocrine L cells. - Highlights: • Taste receptor type 2 member 5 (T2R5) is colocalized with GLP-1 hormone in human enteroendocrine cells. • GLP-1 secretion is stimulated by 1,10-phenanthroline via stimulation of T2R5. • Inhibition of the bitter taste pathway reduce GLP-1 secretion.

  13. Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity.

    Science.gov (United States)

    Thombare, Ketan; Ntika, Stelia; Wang, Xuan; Krizhanovskii, Camilla

    2017-01-01

    Fatty acids acutely stimulate GLP-1 secretion from L-cells in vivo. However, a high fat diet has been shown to reduce the density of L-cells in the mouse intestine and a positive correlation has been indicated between L-cell number and GLP-1 secretion. Thus, the mechanism of fatty acid-stimulated GLP-1 secretion, potential effects of long-term exposure to elevated levels of different fatty acid species, and underlying mechanisms are not fully understood. In the present study, we sought to determine how long-term exposure to saturated (16:0) and unsaturated (18:1) fatty acids, by direct effects on GLP-1-producing cells, alter function and viability, and the underlying mechanisms. GLP-1-secreting GLUTag cells were cultured in the presence/absence of saturated (16:0) and unsaturated (18:1) fatty acids (0.125 mM for 48 h, followed by analyses of viability and apoptosis, as well as involvement of fatty acid oxidation, free fatty acid receptors (FFAR1) and ceramide synthesis. In addition, effects on the expression of proglucagon, prohormone convertase 1/3 (PC1/3), free fatty acid receptors (FFAR1, FFAR3), sodium glucose co-transporter (SGLT) and subsequent secretory response were determined. Saturated (16:0) and unsaturated (18:1) fatty acids exerted opposing effects on the induction of apoptosis (1.4-fold increase in DNA fragmentation by palmitate and a 0.5-fold reduction by oleate; punsaturated (18:1), fatty acids induce ceramide-mediated apoptosis of GLP-1-producing cells. Further, unsaturated fatty acids confer lipoprotection, enhancing viability and function of GLP-1-secreting cells. These data provide potential mechanistic insight contributing to reduced L-cell mass following a high fat diet and differential effects of saturated and unsaturated fatty acids on GLP-1 secretion in vivo.

  14. Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and type 2-diabetic patients using exendin [9-39] as a GLP-1 receptor antagonist

    DEFF Research Database (Denmark)

    Nauck, Michael A; Kind, J; Köthe, Lars D

    2016-01-01

    under the curve (AUCs) of integrated insulin secretion rates (total AUC(ISR)) and glucose (total AUC(glucose)) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC(ISR......)/AUC(glucose) in healthy subjects. Vildagliptin significantly increased this ratio by 10.5% in patients with type 2 diabetes, and exendin [9-39] reduced it (both P ISR)/AUC(glucose) ratio achieved with exendin [9-39] was significantly smaller after vildagliptin treatment than...

  15. GLP-1 receptor regulates cell growth through regulating IDE expression level in Aβ1-42-treated PC12 cells.

    Science.gov (United States)

    Li, Huajie; Cao, Liping; Ren, Yi; Jiang, Ying; Xie, Wei; Li, Dawen

    2017-12-20

    This study aimed to validate whether glucagon-like peptide-1 receptor (GLP-1R) /cyclic adenosine monophosphate (cAMP) /protein kinase (PKA) / insulin-degrading enzyme (IDE) signaling pathway was associated with neuronal apoptosis.We developed an animal model presenting both Alzheimer's disease (AD) and type 2 diabetes (T2D), bycrossing APP/PS1 mice (AD model) with streptozotocin(STZ)-treated mice (a T2D model). Neuronal apoptosis was detected by TUNEL staining and the expression levels of apoptosis-related proteins were examined by Western blotting. The viability of PC12 cells was analyzed by MTT assay and apoptosis of PC12 cells was detected by flow cytometry. The mRNA expression level was detected by qRT-PCR.T2D contributes to AD progress by prompting neuronal apoptosis and increasing expression of pro-apoptotic protein. β-amyloid peptide1-42 (Aβ1-42) was shown to exerteffects on inhibiting cell viability and prompting cell apoptosis of PC12 cells. However, GLP-1R agonist geniposide(Gen) significantly reversed them, exerting a protective role on PC12 cells. And insulin-degrading enzyme (IDE)antagonistbacitracin (Bac) markedly reversed the protective effects of Gen on Aβ1-42-treated PC12 cells. Besides, Gensignificantly reversed the effects of Aβ1-42 treatment on IDEexpression, and the inhibitor of cAMP/PKA signaling pathway markedly reversed the effects of Gen on IDE expression level in Aβ1-42-treated PC12 cells.In conclusion,GLP-1R regulates cellgrowth, at least partially,through regulating cAMP/PKA/IDE signaling pathway in Aβ1-42-treated PC12 cells. ©2017 The Author(s).

  16. Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators.

    Science.gov (United States)

    Decara, Juan; Arrabal, Sergio; Beiroa, Daniel; Rivera, Patricia; Vargas, Antonio; Serrano, Antonia; Pavón, Francisco Javier; Ballesteros, Joan; Dieguez, Carlos; Nogueiras, Rubén; Rodríguez de Fonseca, Fernando; Suárez, Juan

    2016-11-12

    To investigate the role of glucagon-like-peptide-1 receptor (GLP-1R) in peripheral lipid metabolism. Both lean and high-fat diet (HFD)-induced obesity (DIO) rats were used to compare the peripheral effects of the subcutaneous and repeated administration of the GLP-1R agonist liraglutide on the expression of key regulators involved in lipid metabolism, β-oxidation and thermogenesis in liver, abdominal muscle, and epididymal white adipose tissue (eWAT). We observed that liraglutide reduced caloric intake, body weight, and plasma levels of triglycerides and VLDL in a diet-independent manner. However, changes in liver fat content and the expression of lipid metabolism regulators were produced in a diet and tissue-dependent manner. In lean rats, liraglutide increased the gene/protein expression of elements involved in lipogenesis (ChREBP, Acaca/ACC, Fasn/FAS, Scd1/SCD1, PPARα/γ), β-oxidation (CPT1b), and thermogenesis (Cox4i1, Ucp1/UCP1) in eWAT and muscle, which suggest an increase in fatty-acid flux and utilization to activate energy expenditure. Regarding DIO rats, the specific reduction of liver lipid content by liraglutide was associated with a decreased expression of main elements involved in lipogenesis (phospho-ACC), peroxisomal β-oxidation (ACOX1), and lipid flux/storage (Pparγ/PPARγ) in liver, which suggest a recovery of lipid homeostasis. Interestingly, the muscle of DIO rats treated with liraglutide showed a decreased expression of PPARγ and the thermogenic factor UCP1. These results help us to better understand the peripheral mechanisms regulating lipid metabolism that underlay the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity. © 2016 BioFactors, 42(6):600-611, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  17. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model.

    Directory of Open Access Journals (Sweden)

    Vadivel Parthsarathy

    Full Text Available Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers. Moreover, numbers of immature neurons (DCX were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker. A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(TM, increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.

  18. Niveles de GLP-1 tras el test de sobrecarga oral de glucosa en mujeres con antecedentes de diabetes mellitus gestacional

    OpenAIRE

    Maraver Selfa, Silvia María

    2017-01-01

    Se ha descrito una reducción significativa del efecto incretina en pacientes con DM2 que puede deberse a la secreción alterada de las hormonas incretinas y/o a una acción insulinotrópica defectuosa de las mismas. Podría plantearse que este efecto incretina deteriorado en pacientes con trastornos del metabolismo hidrocarbonado, fuese un defecto primario precoz que preceda al desarrollo de la DM2, o secundario a la propia hiperglucemia. Objetivos. Estudiar el patrón de secreción de GLP-1 ...

  19. Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes

    DEFF Research Database (Denmark)

    Albèr, Anders; Brønden, Andreas; Knop, Filip K

    2017-01-01

    , which is associated with well-described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because...... of their glucagonostatic and extrapancreatic effects. So far, the focus has mainly been on the long-acting GLP-1RAs, but the risk-benefit ratio emerging from studies evaluating the effect of long-acting GLP-1RAs as adjunctive therapy to insulin therapy in patients with type 1 diabetes has been disappointing. This might...... be attributable to a lack of glucagonostatic effect of these long-acting GLP-1RAs in type 1 diabetes, alongside development of tachyphylaxis to GLP-1-induced retardation of gastric emptying. In contrast, the short-acting GLP-1RAs seem to have a preserved and sustained effect on glucagon secretion and gastric...

  20. Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues.

    Science.gov (United States)

    Ten Kulve, Jennifer S; Veltman, Dick J; Gerdes, Victor E A; van Bloemendaal, Liselotte; Barkhof, Frederik; Deacon, Carolyn F; Holst, Jens J; Drent, Madeleine L; Diamant, Michaela; IJzerman, Richard G

    2017-11-01

    It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and weight reduction, mediated via effects on the central nervous system (CNS). Secretion of GLP-1 is greatly enhanced after RYGB. We hypothesized that postoperative elevated GLP-1 levels contribute to the improved satiety regulation after RYGB via effects on the CNS. Effects of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus placebo before and after RYGB. After RYGB, CNS activation was reduced in the rolandic operculum and caudate nucleus in response to viewing food pictures ( P = 0.03) and in the insula in response to consumption of palatable food ( P = 0.003). GLP-1 levels were significantly elevated postoperatively ( P RYGB, GLP-1 receptor blockade resulted in a larger increase in activation in the caudate nucleus in response to food pictures ( P = 0.02) and in the insula in response to palatable food consumption ( P = 0.002). We conclude that the effects of RYGB on CNS activation in response to visual and gustatory food cues may be mediated by central effects of GLP-1. Our findings provide further insights into the mechanisms underlying the weight-lowering effects of RYGB. © 2017 by the American Diabetes Association.

  1. Roux-en-Y gastric bypass in rats increases sucrose taste-related motivated behavior independent of pharmacological GLP-1-receptor modulation

    Science.gov (United States)

    Mathes, C. M.; Bueter, M.; Smith, K. R.; Lutz, T. A.; le Roux, C. W.

    2012-01-01

    Roux-en-Y gastric bypass (RYGB) surgery has been shown to decrease consummatory responsiveness of rats to high sucrose concentrations, and genetic deletion of glucagon-like peptide-1 receptors (GLP-1R) has been shown to decrease consummatory responsiveness of mice to low-sucrose concentrations. Here we assessed the effects of RYGB and pharmacological GLP-1R modulation on sucrose licking by chow-fed rats in a brief-access test that assessed consummatory and appetitive behaviors. Rats were tested while fasted presurgically and postsurgically and while nondeprived postsurgically and 5 h after intraperitoneal injections with the GLP-1R antagonist exendin-3(9–39) (30 μg/kg), agonist exendin-4 (1 μg/kg), and vehicle in 30-min sessions during which a sucrose concentration series (0.01–1.0 M) was presented in 10-s trials. Other rats were tested postsurgically or 15 min after peptide or vehicle injection while fasted and while nondeprived. Independent of food-deprivation state, sucrose experience, or GLP-1R modulation, RYGB rats took 1.5–3× as many trials as sham-operated rats, indicating increased appetitive behavior. Under nondeprived conditions, RYGB rats with presurgical sucrose experience licked more to sucrose relative to water compared with sham-operated rats. Exendin-4 and exendin-3(9–39) impacted 0.3 M sucrose intake in a one-bottle test, but never interacted with surgical group to affect brief-access responding. Unlike prior reports in both clearly obese and relatively leaner rats given RYGB and in GLP-1R knockout mice, we found that neither RYGB nor GLP-1R blockade decreased consummatory responsiveness to sucrose in our less obese chow-fed rats. Collectively, these results highlight the fact that changes in taste-driven motivated behavior to sucrose after RYGB and/or GLP-1R modulation are very model and measure dependent. PMID:22170618

  2. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates.

    Science.gov (United States)

    Henderson, S J; Konkar, A; Hornigold, D C; Trevaskis, J L; Jackson, R; Fritsch Fredin, M; Jansson-Löfmark, R; Naylor, J; Rossi, A; Bednarek, M A; Bhagroo, N; Salari, H; Will, S; Oldham, S; Hansen, G; Feigh, M; Klein, T; Grimsby, J; Maguire, S; Jermutus, L; Rondinone, C M; Coghlan, M P

    2016-12-01

    To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months. MEDI0382 potently activated rodent, cynomolgus and human GLP-1 and glucagon receptors and exhibited a fivefold bias for activation of GLP-1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP-1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor-mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP-1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys. Repeated administration of MEDI0382 elicits profound weight loss in DIO mice and non-human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP-1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  3. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes

    Science.gov (United States)

    Sikirica, Mirko V; Martin, Alan A; Wood, Robert; Leith, Andrea; Piercy, James; Higgins, Victoria

    2017-01-01

    Aim Nonadherence to glucagon-like peptide-1 receptor agonists (GLP1 RAs) is relatively common among patients with type 2 diabetes mellitus (T2DM). This study sought to identify reasons why patients discontinue GLP1 RAs. Materials and methods Retrospective data from the Adelphi Diabetes Disease Specific Programme were used. Physicians managing patients with T2DM were surveyed via face-to-face interviews, and patients treated for T2DM were surveyed via self-completed questionnaires. Patient data were stratified by current versus prior GLP1 RA use. Results Physicians (n=443) most frequently reported inadequate blood glucose control (45.6%), nausea/vomiting (43.8%), and gastrointestinal (GI) side effects (36.8%) as reasons for GLP1 RA discontinuation. Patients (n=194) reported the GI-related issues “Made me feel sick” (64.4%) and “Made me throw up” (45.4%) as their top reasons for discontinuation. The most common problems reported (excluding cost) for those currently using GLP1 RAs were “Prefer oral medication over injections” (patients 56%, physicians 32.6%), “Made me feel sick” (patients 38.1%, physicians 16.3%), and “Did not help lose weight” (patients 25.4%, physicians 18%). The most bothersome problems for patients globally (frequency reporting very/extremely bothersome) (excluding cost) were “Difficult to plan meals around” (55.6%), “Made me throw up” (51.6%), and “Caused weight gain” (50%). Conclusion Both patients and physicians reported GI-related issues as a prominent factor, but disparities between patient experiences and physician perceptions were revealed, suggesting gaps in physician–patient communication. Understanding patients’ expectations of GLP1 RAs and physicians’ patient-management practices may help increase GLP1 RA adherence and thereby potentially enhance diabetes care. PMID:29033597

  4. No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.

    Science.gov (United States)

    Ishøy, P L; Fagerlund, B; Broberg, B V; Bak, N; Knop, F K; Glenthøj, B Y; Ebdrup, B H

    2017-07-01

    Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens J; 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......, 4, 6, 8, and 12 mg x kg(-1) x min(-1) over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1). GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 +/- 51 to 975 +/- 198 pmol/kg in the patients with type 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...

  6. CORRELATION BETWEEN PRE AND POSTOPERATIVE LEVELS OF GLP-1/GLP-2 AND WEIGHT LOSS AFTER ROUX-EN-Y GASTRIC BYPASS: A PROSPECTIVE STUDY

    Science.gov (United States)

    CAZZO, Everton; GESTIC, Martinho Antonio; UTRINI, Murillo Pimentel; PAREJA, José Carlos; CHAIM, Elinton Adami; GELONEZE, Bruno; BARRETO, Maria Rita Lazzarini; MAGRO, Daniéla Oliveira

    2016-01-01

    ABSTRACT Background: The role of gut hormones in glucose homeostasis and weight loss achievement and maintenance after bariatric surgery appears to be a key point in the understanding of the beneficial effects observed following these procedures. Aim: To determine whether there is a correlation between the pre and postoperative levels of both GLP-1 and GLP-2 and the excess weight loss after Roux-en-Y gastric bypass (RYGB). Methods: An exploratory prospective study which enrolled 11 individuals who underwent RYGB and were followed-up for 12 months. GLP-1 and GLP-2 after standard meal tolerance test (MTT) were determined before and after surgery and then correlated with the percentage of excess loss (%EWL). Results: GLP-2 AUC presented a significant postoperative increase (945.3±449.1 vs.1787.9±602.7; p=0.0037); GLP-1 AUC presented a non-significant trend towards increase after RYGB (709.6±320.4 vs. 1026.5±714.3; p=0.3808). Mean %EWL was 66.7±12.2%. There was not any significant correlation between both the pre and postoperative GLP-1 AUCs and GLP-2 AUCs and the %EWL achieved after one year. Conclusion: There was no significant correlation between the pre and postoperative levels of the areas under the GLP-1 and GLP-2 curves with the percentage of weight loss reached after one year. PMID:28076481

  7. Dietary sweet potato (Ipomoea batatas L.) leaf extract attenuates hyperglycaemia by enhancing the secretion of glucagon-like peptide-1 (GLP-1).

    Science.gov (United States)

    Nagamine, Rika; Ueno, Shiori; Tsubata, Masahito; Yamaguchi, Kazuya; Takagaki, Kinya; Hira, Tohru; Hara, Hiroshi; Tsuda, Takanori

    2014-09-01

    'Suioh', a sweet potato (Ipomoea batatas L.) cultivar developed in Japan, has edible leaves and stems. The sweet potato leaves contain polyphenols such as caffeoylquinic acid (CQA) derivatives. It has multiple biological functions and may help to regulate the blood glucose concentration. In this study, we first examined whether sweet potato leaf extract powder (SP) attenuated hyperglycaemia in type 2 diabetic mice. Administration of dietary SP for 5 weeks significantly lowered glycaemia in type 2 diabetic mice. Second, we conducted in vitro experiments, and found that SP and CQA derivatives significantly enhanced glucagon-like peptide-1 (GLP-1) secretion. Third, pre-administration of SP significantly stimulated GLP-1 secretion and was accompanied by enhanced insulin secretion in rats, which resulted in a reduced glycaemic response after glucose injection. These results indicate that oral SP attenuates postprandial hyperglycaemia, possibly through enhancement of GLP-1 secretion.

  8. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog

    DEFF Research Database (Denmark)

    Gydesen, Sofie; Andreassen, Kim Vietz; Hjuler, Sara Toftegaard

    2017-01-01

    Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089....... Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every....../kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance (P GLP-1 on food intake and body weight. Furthermore, on escalation, KBP...

  9. Development of a UHPLC-MS/MS (SRM) method for the quantitation of endogenous glucagon and dosed GLP-1 from human plasma.

    Science.gov (United States)

    Howard, James W; Kay, Richard G; Jones, Ben; Cegla, Jaimini; Tan, Tricia; Bloom, Steve; Creaser, Colin S

    2017-05-01

    The performance of glucagon and GLP-1 immunoassays is often poor, but few sensitive LC-MS/MS methods exist as alternatives. A multiplexed LC-MS/MS method using a 2D extraction technique was developed. The method was established for the quantitation of endogenous glucagon (LLOQ: 15 pg/ml) and dosed GLP-1 (LLOQ: 25 pg/ml) in human plasma, and is the first such method avoiding immunoenrichment. Specificity of endogenous glucagon quantitation was assured using a novel approach with a supercharging mobile phase additive to access a sensitive qualifier SRM. Endogenous glucagon concentrations were within the expected range, and showed good reproducibility after extended sample storage. A cross-validation against established immunoassays using physiological study samples demonstrated some similarities between methods. The LC-MS/MS method offers a viable alternative to immunoassays for quantitation of endogenous glucagon, dosed glucagon and/or dosed GLP-1.

  10. The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2018-01-01

    of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a randomized, placebo......-controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg...... was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions. CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally...

  11. [Impact of anti-diabetic therapy based on glucagon-like peptide-1 receptor agonists on the cardiovascular risk of patients with type 2 diabetes mellitus].

    Science.gov (United States)

    Camafort-Babkowski, Miguel

    2013-08-17

    Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  12. Acute peripheral GLP-1 receptor agonism or antagonism does not alter energy expenditure in rats after Roux-en-Y gastric bypass.

    Science.gov (United States)

    Abegg, Kathrin; Schiesser, Marc; Lutz, Thomas A; Bueter, Marco

    2013-09-10

    Compared to traditional weight loss strategies, the compensatory decrease in energy expenditure in response to body weight loss is markedly attenuated after Roux-en-Y gastric bypass surgery (RYGB). Because basal and postprandial levels of glucagon-like peptide-1 (GLP-1) are increased after RYGB surgery, and because GLP-1 has been shown to increase energy expenditure, we investigated if increased GLP-1 levels are involved in the alterations in energy expenditure after RYGB. Adult male Wistar rats were randomized for RYGB (n=8) or sham surgery (n=17). Part of the sham-operated rats were food restricted and body weight-matched (n=8) to the RYGB animals. The effects of acute subcutaneous administration of the GLP-1 antagonist Exendin (9-39) (Ex-9, 30μg/kg) or the GLP-1 agonist Exendin-4 (Ex-4, 5μg/kg), respectively, on energy expenditure were tested using indirect calorimetry. We found that Ex-9 increased food intake in RYGB, but not in sham-operated rats. Energy expenditure was lower in RYGB and sham-operated body weight-matched rats compared to sham-operated ad libitum fed rats, but significantly higher in RYGB rats compared to sham-operated body weight-matched rats. There was no effect of Ex-9 treatment on energy expenditure in either group of animals. Similarly, Ex-4 decreased food intake more in RYGB than in sham-operated rats, but Ex-4 did not modulate energy expenditure in any surgical group. We conclude that acute modulation of GLP-1 signaling is not directly involved in altered energy expenditure after RYGB surgery in rats. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Insulin sensitizers improve the GLP-1 secretion and the amount of intestinal L cells on high-fat-diet-induced catch-up growth.

    Science.gov (United States)

    Zheng, Juan; Xiao, Kang-Li; Chen, Lulu; Wu, Chaodong; Hu, Xiang; Zeng, Tianshu; Chen, Xiao-Qian; Li, Wen-Juan; Deng, Xiuling; Li, Huiqing; Li, Yu-Ming

    The aim of this study was to investigate whether insulin resistance can result in impaired glucagon-like peptide (GLP)-1 secretion and to determine whether insulin-sensitizing drugs could improve the secretion of GLP-1 in catch-up growth rats. Male Sprague Dawley rats were used to establish a catch-up growth model. At the end of weeks 6 and 14, these rats were euthanized to measure energy intake, body weight, plasma triacylglycerol, and nonesterified fatty acid. Fat mass percentage was analyzed by dual-energy x-ray absorptiometry scan. The GLP-1 concentrations were measured by enzyme-linked immunosorbent assay, the glucose infusion rates were measured by hyperinsulinemic-glucose clamp experiment. Quantification of the GLP-1 positive cells in distal ileum was done by immunohistochemical staining method. The L cell line NCI-H716 cells were treated in vitro with palmitate acid, the cells' viability, the carnitine palmitoyl transferase-1, and the insulin signaling pathway were detected. Rats fed a high-fat diet rats had rapidly developed insulin resistance, impaired incretin effect, and a reduction in the number of intestinal L cells. The insulin sensitizers, metformin and pioglitazone, improved insulin resistance and the concentration of circulating GLP-1, increased the relative number of intestinal L cells to a certain degree. In vitro, the NCI-H716 cell viability was decreased and impaired insulin signaling pathway with palmitate acid treatment, metformin treatment could reverse these effects, whereas pioglitazone could not. Insulin resistance caused by a high-fat diet could result in reduced GLP-1 secretion; the insulin sensitizing drugs were able to improve the incretin effect in catch-up growth rats. Copyright © 2017. Published by Elsevier Inc.

  14. A bitter pill for type 2 diabetes? The activation of bitter taste receptor TAS2R38 can stimulate GLP-1 release from enteroendocrine L-cells.

    Science.gov (United States)

    Pham, Hung; Hui, Hongxiang; Morvaridi, Susan; Cai, Jiena; Zhang, Sanqi; Tan, Jun; Wu, Vincent; Levin, Nancy; Knudsen, Beatrice; Goddard, William A; Pandol, Stephen J; Abrol, Ravinder

    2016-07-01

    The bitter taste receptor TAS2R38 is a G protein coupled receptor (GPCR) that has been found in many extra-oral locations like the gastrointestinal (GI) system, respiratory system, and brain, though its function at these locations is only beginning to be understood. To probe the receptor's potential metabolic role, immunohistochemistry of human ileum tissues was performed, which showed that the receptor was co-localized with glucagon-like peptide 1 (GLP-1) in L-cells. In a previous study, we had modeled the structure of this receptor for its many taste-variant haplotypes (Tan et al. 2011), including the taster haplotype PAV. The structure of this haplotype was then used in a virtual ligand screening pipeline using a collection of ∼2.5 million purchasable molecules from the ZINC database. Three compounds (Z7, Z3, Z1) were purchased from the top hits and tested along with PTU (known TAS2R38 agonist) in in vitro and in vivo assays. The dose-response study of the effect of PTU and Z7 on GLP-1 release using wild-type and TAS2R38 knockout HuTu-80 cells showed that the receptor TAS2R38 plays a major role in GLP-1 release due to these molecules. In vivo studies of PTU and the three compounds showed that they each increase GLP-1 release. PTU was also chemical linked to cellulose to slow its absorption and when tested in vivo, it showed an enhanced and prolonged GLP-1 release. These results suggest that the GI lumen location of TAS2R38 on the L-cell makes it a relatively safe drug target as systemic absorption is not needed for a TAS2R38 agonist drug to effect GLP-1 release. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, Lasse Bremholm; Andersen, Ulrik B; Hornum, Mads

    2017-01-01

    arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [P = 0.0162], time [P = 0.0038], and injection × time [P = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-19-36amide [P stroke volume compared to GLP-19-36 amide...... subcutaneous injections of GLP-1, GLP-19-36 amide (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured...

  16. A modulação crônica do receptor de GLP-1 altera aos níveis pressóricos, a estrutura e a função renal de ratos espontaneamente hipertensos

    OpenAIRE

    Gabriela Cozin Aragão

    2016-01-01

    O peptídeo-1 semelhante ao glucagon (GLP-1) é um hormônio incretina intestinal que exerce primariamente ações anti-hiperglicemiantes. Afim de viabilizar o emprego clínico deste peptídeo para o tratamento do diabetes mellitus tipo 2, foram criadas as terapias baseadas em incretinas que incluem as gliptinas, drogas que aumentam a meia-vida circulante do GLP-1 endógeno por meio da inibição da enzima dipeptidil peptidase-4 e agonistas exógenos do receptor de GLP-1 (GLP-1R). Demonstrou-se clínica ...

  17. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

    LENUS (Irish Health Repository)

    Hogan, A E

    2011-11-01

    The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.

  18. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    DEFF Research Database (Denmark)

    Iepsen, E W; Lundgren, J; Dirksen, C

    2015-01-01

    of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor.......3 kg (95% CI=-0.6 to -4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=-0.6 to -1)), P....3±0.1 mmol l(-1) to the level before weight loss (-0.5mmol l(-1) (95% CI=-0.1 to -0.9)), PMeal response of peptide PYY3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P

  19. Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion

    DEFF Research Database (Denmark)

    Mingrone, G; Nolfe, G; Gissey, G Castagneto

    2009-01-01

    AIMS/HYPOTHESIS: We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones. METHODS: Ten morbidly obese participants, five with normal glucose tolerance......(-1)). CONCLUSIONS/INTERPRETATION: An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes....... On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role in insulin resistance and diabetes....

  20. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice

    DEFF Research Database (Denmark)

    Rolin, Bidda; Larsen, Marianne O; Gotfredsen, Carsten F

    2002-01-01

    NN2211 is a long-acting, metabolically stable glucagon-like peptide-1 (GLP-1) derivative designed for once daily administration in humans. NN2211 dose dependently reduced the glycemic levels in ob/ob mice, with antihyperglycemic activity still evident 24 h postdose. Apart from an initial reduction...... in food intake, there were no significant differences between NN2211 and vehicle treatment, and body weight was not affected. Histological examination revealed that beta-cell proliferation and mass were not increased significantly in ob/ob mice with NN2211, although there was a strong tendency...... for increased proliferation. In db/db mice, exendin-4 and NN2211 decreased blood glucose compared with vehicle, but NN2211 had a longer duration of action. Food intake was lowered only on day 1 with both compounds, and body weight was unaffected. beta-Cell proliferation rate and mass were significantly...

  1. The impact of short chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon

    DEFF Research Database (Denmark)

    Christiansen, Charlotte Bayer; Gabe, Maria Buur Nordskov; Svendsen, Berit

    2018-01-01

    chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L-cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects...... of the predominant SCFAs formed: acetate, propionate and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP......, the KATP-channel opener diazoxide and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate and butyrate, compared to CFMB which is a full agonist with around 750-fold higher potency than...

  2. Effect of exendin (exenatide)--GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model.

    Science.gov (United States)

    Bulchandani, Deepti; Nachnani, Jagdish S; Herndon, Betty; Molteni, Agostino; Pathan, Muhammad H; Quinn, Tim; Hamdan, Hana A; Alba, Laura M; Graves, Leland

    2012-09-15

    Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (PParathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro.

    Science.gov (United States)

    Rosenstock, Julio; Fonseca, Vivian A; Gross, Jorge L; Ratner, Robert E; Ahrén, Bo; Chow, Francis C C; Yang, Fred; Miller, Diane; Johnson, Susan L; Stewart, Murray W; Leiter, Lawrence A

    2014-08-01

    GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. Patients taking basal insulin (with or without oral agents) with HbA1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA1c change from baseline at week 26. At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (-0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  4. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

    Science.gov (United States)

    Korol, Sergiy V.; Jin, Zhe; Birnir, Bryndis

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 μM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons. PMID:25927918

  5. Grape powder attenuates the negative effects of GLP-1 receptor antagonism by exendin-3 (9-39) in a normoglycemic mouse model.

    Science.gov (United States)

    Haufe, T C; Gilley, A D; Goodrich, K M; Ryan, C M; Smithson, A T; Hulver, M W; Liu, D; Neilson, A P

    2016-06-15

    Prediabetes is a condition affecting 35% of US adults and about 50% of US adults age 65+. Foods rich in polyphenols, including flavanols and other flavonoids, have been studied for their putative beneficial effects on many different health conditions including type 2 diabetes mellitus and prediabetes. Studies have shown that some flavanols increase glucagon-like peptide 1 (GLP-1) secretion. GLP-1 is a feeding hormone that increases insulin secretion after carbohydrate consumption, and increased GLP-1 secretion may be responsible for some of the beneficial effects on glycemic control after flavanol consumption. The present study explored the effects of grape powder consumption on metrics of glycemic health in normoglycemic and prediabetic C57BL/6J mice; additionally, the mechanism of action of grape powder polyphenols was investigated. Grape powder significantly reduced (p Grape powder was employed in acute (1.6 g grape powder per kg bodyweight) and long-term high fat diet (grape powder incorporated into treatment diets at 5% w/w) feeding studies in normoglycemic and prediabetic (diet-induced obesity) mice; grape powder did not impove glycemic control in these studies versus sugar-matched control. The mechanisms by which grape powder ameliorates the deleterious effects of GLP-1 receptor antagonism warrant further study.

  6. Elevated postoperative endogenous GLP-1 levels mediate effects of roux-en-Y gastric bypass on neural responsivity to food cues

    NARCIS (Netherlands)

    Ten Kulve, Jennifer S.; Veltman, Dick J.; Gerdes, Victor E.A.; Van Bloemendaal, Liselotte; Barkhof, Frederik; Deacon, Carolyn F.; Holst, Jens J.; Drent, Madeleine L.; Diamant, Michaela; IJzerman, Richard G.

    2017-01-01

    OBJECTIVE: It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite and

  7. Pancreatic beta-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia V; Deacon, Carolyn F

    2010-01-01

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...

  8. Pancreatic ß-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia; Deacon, Carolyn F.

    2010-01-01

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...

  9. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    L. Tonneijck (Lennart); M.M. Smits (Mark M.); M.H.A. Muskiet (Marcel H. A.); T. Hoekstra (Trynke); M.H.H. Kramer (Mark); A.H.J. Danser (Jan); M. Diamant (Michaela); J.A. Joles (Jaap); D.H. van Raalte (Daniël H.)

    2016-01-01

    textabstractAims/hypothesis: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods: We included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes

  10. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients : a randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Tonneijck, Lennart; Smits, Mark M.; Muskiet, Marcel H A; Hoekstra, Trynke; Kramer, Mark H H; Danser, A. H Jan; Diamant, Michaela; Joles, Jaap A.; van Raalte, Daniël H.

    2016-01-01

    Aims/hypothesis: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. Methods: We included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c

  11. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients : a randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Tonneijck, Lennart; Smits, Mark M; Muskiet, Marcel H A; Hoekstra, T.; Kramer, Mark H H; Danser, A H Jan; Diamant, Michaela; Joles, Jaap A; van Raalte, Daniël H

    AIMS/HYPOTHESIS: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients. METHODS: We included overweight (BMI 25-40 kg/m(2)) men and postmenopausal women, aged 35-75 years with type 2 diabetes (HbA1c

  12. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

    Directory of Open Access Journals (Sweden)

    Sergiy V Korol

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM, an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM plus diazepam (1 μM, only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

  13. Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients : an acute and 12-week randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Smits, Mark M; Tonneijck, Lennart; Muskiet, Marcel H A; Hoekstra, T.; Kramer, Mark H H; Diamant, Michaela; van Raalte, Daniël H

    OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. DESIGN: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. METHODS: In total, 57 type 2 diabetes patients

  14. The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Kaji, Takao

    2016-10-01

    The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, did not require functional leptin receptor, serotonin, and hypothalamic proopiomelanocortin and cocaine amphetamine regulated transcript activities in mice, although decrease in functional hypothalamic orexin activity might be involved in the acute anorexic effect of liraglutide. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. The placebo response of injectable GLP-1 receptor agonists vs. oral DPP-4 inhibitors and SGLT-2 inhibitors: a systematic review and meta-analysis

    NARCIS (Netherlands)

    Wit, H.M. de; Groen, M.; Rovers, M.M.; Tack, C.J.J.

    2016-01-01

    AIMS: The size of the placebo response in type 2 diabetes (T2DM) treatment and its relation to the route of drug administration have not been systematically reviewed. We aimed to determine weight loss, change in HbA1c and incidence of adverse events after treatment with injectable placebo GLP-1

  16. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Krarup, Thure; Madsbad, Sten

    2003-01-01

    Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both incretin hormones regulating postprandial insulin secretion. Their relative importance in this respect under normal physiological conditions is unclear, however, and the aim of the present investigatio...

  17. Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Kaji, Takao

    2018-01-01

    A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

  18. Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice

    Directory of Open Access Journals (Sweden)

    Katsunori Nonogaki

    2018-01-01

    Full Text Available A recent report suggested that brain-derived serotonin (5-HT is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1 receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph inhibitor p-chlorophenylalanine (PCPA for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

  19. Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues

    DEFF Research Database (Denmark)

    Ten Kulve, Jennifer S; Veltman, Dick J; Gerdes, Victor E A

    2017-01-01

    of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus...

  20. Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

    DEFF Research Database (Denmark)

    Grunddal, Kaare Villum; Ratner, Cecilia F; Svendsen, Berit

    2016-01-01

    increasingly multi-hormonal, i.e. co-expressing PYY and neurotensin as they move up the villus. Pro-glucagon promoter and pertussis toxin receptor driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY and neurotensin positive...

  1. GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Plamboeck, Astrid; Møller, Søren

    2002-01-01

    Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been i...

  2. Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Kaji, Takao

    2015-12-01

    Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. The effects of aerobic exercises and 25(OH D supplementation on GLP1 and DPP4 level in Type II diabetic patients

    Directory of Open Access Journals (Sweden)

    Naser Rahimi

    2017-01-01

    Full Text Available Background: The purpose of this study was to investigate the effects of an 8-week aerobic exercise and supplementation of 25(OHD3 on GLP1 and DDP4 levels in men with type II diabetes. Methods: In this semiexperimental research, among 40–60-year-old men with type II diabetes who were referred to the diabetic center of Isabn-E Maryam hospital in Isfahan; of whom, 48 patients were voluntarily accepted and then were randomly divided into 4 groups: aerobic exercise group, aerobic exercise with 25(OH D supplement group, 25(OH D supplement group, and the control group. An aerobic exercise program was conducted for 8 weeks (3 sessions/week, each session 60 to75 min with 60–80% HRmax. The supplement user group received 50,000 units of oral Vitamin D once weekly for 8 weeks. The GLP1, DPP4, and 25(OH D levels were measured before and after the intervention. At last, the data were statistically analyzed using the ANCOVA and post hoc test of least significant difference. Results: The results of ANCOVA showed a significant difference between the GLP1 and DPP4 levels in aerobic exercise with control group while these changes were not statistically significant between the 25(OH D supplement group with control group (P < 0.05. Conclusions: Aerobic exercises have resulted an increase in GLP1 level and a decrease in DPP4 level. However, consumption of Vitamin D supplement alone did not cause any changes in GLP1and DPP4 levels but led to an increase in 25-hydroxy Vitamin D level.

  4. Direct effects of exendin-(9,39) and GLP-1-(9,36)amide on insulin action, β-cell function, and glucose metabolism in nondiabetic subjects.

    Science.gov (United States)

    Sathananthan, Matheni; Farrugia, Luca P; Miles, John M; Piccinini, Francesca; Dalla Man, Chiara; Zinsmeister, Alan R; Cobelli, Claudio; Rizza, Robert A; Vella, Adrian

    2013-08-01

    Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-(3)H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 ± 4 10(-4) dL/kg[min per μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 10(-14) dL/kg/min(2) per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans.

  5. Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    1999-01-01

    inhibition of gastrointestinal motility and secretion in the presence of nutrients in the lower small intestine). However, because of these same actions, the hormone can normalise the blood glucose of patients with Type 2 diabetes mellitus, and, in contradistinction to insulin and sulphonylurea, it does...... not cause hypoglycaemia. Therefore, treatment of Type 2 diabetes based on GLP-1 is currently being investigated. As a peptide, it must be administered parenterally, and, in addition, it is metabolised extremely rapidly. However, several methods to circumvent these problems have already been developed. A GLP......-1- based therapy of diabetes mellitus and perhaps also obesity is therefore likely to become a realistic alternative to current therapies of these disorders....

  6. Why Are Incretin-Based Therapies More Efficient in East Asians? Perspectives from the Pathophysiology of Type 2 Diabetes and East Asian Dietary Habits

    Directory of Open Access Journals (Sweden)

    Daisuke Yabe

    2015-11-01

    Full Text Available Type 2 diabetes mellitus (T2D is one of the most serious global health problems. This is partly a result of its drastic increase in East Asia, which now comprises more than a quarter of the global diabetes population. Ethnicity and lifestyle factors are two determinants in the aetiology of T2D, and changes such as increased animal fat intake and decreased physical activity link readily to T2D in East Asians, which is characterised primarily by β-cell dysfunction that is evident immediately after ingestion of glucose or a meal, and less adiposity compared with T2D in Caucasians. These pathophysiological differences have an important impact on therapeutic approaches. Incretin-based therapies, such as dipeptidyl peptidase-4 inhibitors (DPP-4i and glucagon-like peptide-1 receptor agonists (GLP-1RA, have become widely available for the management of T2D. Incretins, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 are secreted from the gut in response to the ingestion of various nutrients, including carbohydrates, proteins, and fats, and enhance insulin secretion via a glucose-dependent pathway to exert their glucose-lowering effects. Recent meta-analyses of clinical trials of DPP-4i and GLP-1RA found the drugs to be more effective in East Asians, most likely due to amelioration of the primary β-cell dysfunction by increased stimulation through incretin activity. In addition, our finding that the glycosylated haemoglobin-lowering effects of DPP-4i are enhanced by fish intake, and possibly worsened by animal fat intake, suggests that dietary habits such as eating more fish and less meat can affect the secretion of incretins, and supports the greater efficacy of incretin-based therapies in East Asians.

  7. CORRELATION BETWEEN PRE AND POSTOPERATIVE LEVELS OF GLP-1/GLP-2 AND WEIGHT LOSS AFTER ROUX-EN-Y GASTRIC BYPASS: A PROSPECTIVE STUDY.

    Science.gov (United States)

    Cazzo, Everton; Gestic, Martinho Antonio; Utrini, Murillo Pimentel; Pareja, José Carlos; Chaim, Elinton Adami; Geloneze, Bruno; Barreto, Maria Rita Lazzarini; Magro, Daniéla Oliveira

    2016-01-01

    The role of gut hormones in glucose homeostasis and weight loss achievement and maintenance after bariatric surgery appears to be a key point in the understanding of the beneficial effects observed following these procedures. To determine whether there is a correlation between the pre and postoperative levels of both GLP-1 and GLP-2 and the excess weight loss after Roux-en-Y gastric bypass (RYGB). An exploratory prospective study which enrolled 11 individuals who underwent RYGB and were followed-up for 12 months. GLP-1 and GLP-2 after standard meal tolerance test (MTT) were determined before and after surgery and then correlated with the percentage of excess loss (%EWL). GLP-2 AUC presented a significant postoperative increase (945.3±449.1 vs.1787.9±602.7; p=0.0037); GLP-1 AUC presented a non-significant trend towards increase after RYGB (709.6±320.4 vs. 1026.5±714.3; p=0.3808). Mean %EWL was 66.7±12.2%. There was not any significant correlation between both the pre and postoperative GLP-1 AUCs and GLP-2 AUCs and the %EWL achieved after one year. There was no significant correlation between the pre and postoperative levels of the areas under the GLP-1 and GLP-2 curves with the percentage of weight loss reached after one year. O papel de hormônios gastrointestinais sobre a homeostase glicêmica e a obtenção e manutenção da perda de peso após a cirurgia bariátrica parece ser elemento fundamental na compreensão dos benefícios observados após estes procedimentos. Determinar se há correlação entre os níveis pré e pós-operatórios de GLP-1 e GLP-2 com a perda do excesso de peso após o bypass gástrico em Y-de-Roux. Estudo prospectivo exploratório que envolveu 11 indivíduos submetidos ao bypass gástrico, acompanhados por 12 meses. Os níveis GLP-1 e GLP-2 após um teste de refeição padrão foram determinados antes e 12 meses após a operação e então foram correlacionados com o percentual de perda do excesso de peso. Houve aumento

  8. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials.

    Science.gov (United States)

    DeFronzo, Ralph A; Buse, John B; Kim, Terri; Burns, Colleen; Skare, Sharon; Baron, Alain; Fineman, Mark

    2016-08-01

    postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc.

  9. Long-term Cost-effectiveness of Two GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus in the Italian Setting: Liraglutide Versus Lixisenatide.

    Science.gov (United States)

    Hunt, Barnaby; Kragh, Nana; McConnachie, Ceilidh C; Valentine, William J; Rossi, Maria C; Montagnoli, Roberta

    2017-07-01

    Maintaining glycemic control is the key treatment target for patients with type 2 diabetes mellitus. In addition, the glucagon-like peptide-1 (GLP-1) receptor agonists may be associated with other favorable treatment characteristics, such as reduction in body weight and reduced risk of hypoglycemia compared with traditional diabetes interventions. The aim of the present analysis was to compare the long-term cost-effectiveness of 2 GLP-1 receptor agonists, liraglutide 1.8 mg and lixisenatide 20 μg (both administered once daily), in the treatment of patients with type 2 diabetes failing to achieve glycemic control with metformin monotherapy in the Italian setting. The IMS CORE Diabetes Model was used to project long-term clinical outcomes and subsequent costs (in 2015 Euros [€]) associated with liraglutide 1.8 mg versus lixisenatide 20 μg treatment in a cohort with baseline characteristics derived from the open-label LIRA-LIXI trial (Efficacy and Safety of Liraglutide Versus Lixisenatide as Add-on to Metformin in Subjects With Type 2 Diabetes; NCT01973231) over patient lifetimes from the perspective of a health care payer. Efficacy data were taken from the 26-week end points of the same trial, including changes in glycated hemoglobin, body mass index, serum lipid levels, and hypoglycemic event rates. Outcomes projected included life expectancy, quality-adjusted life expectancy, cumulative incidence and time to onset of diabetes-related complications, and direct medical costs. Outcomes were discounted at 3% annually, and sensitivity analyses were performed. Liraglutide 1.8 mg was associated with improved discounted life expectancy (14.07 vs 13.96 years) and quality-adjusted life expectancy (9.18 vs 9.06 quality-adjusted life years [QALYs]) compared with lixisenatide 20 μg. These improvements were mostly attributable to a greater reduction in glycated hemoglobin level with liraglutide 1.8 mg versus lixisenatide 20 μg, leading to reduced incidence and

  10. Can DPP-IV Inhibitors or GLP-1 Analogs be Tomorrow’s Therapy for Diabetic Retinopathy?

    OpenAIRE

    Gonçalves, Andreia Fernandes Dâmaso

    2016-01-01

    Tese de doutoramento em Engenharia Biomédica, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra A retinopatia diabética é uma das complicações associadas à diabetes e uma das principais causas de perda de visão na população em idade ativa em todo o mundo. No entanto, os tratamentos disponíveis para esta doença são escassos, invasivos, não eficazes para todos os doentes, apresentam alguns riscos adversos e são normalmente administrados nas fases tardias da retinopa...

  11. Glucagon-Like Peptide-1 Gene Therapy

    Directory of Open Access Journals (Sweden)

    Anne M. Rowzee

    2011-01-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

  12. Pancreatic ß-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia; Deacon, Carolyn F.

    2010-01-01

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...... characterizing T2DM....... glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (P

  13. Cell-Based Therapy

    Directory of Open Access Journals (Sweden)

    Masaaki Kitada

    2012-01-01

    Full Text Available Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease.

  14. Incretin-based therapy and risk of acute pancreatitis

    DEFF Research Database (Denmark)

    Thomsen, Reimar Wernich; Pedersen, Lars; Møller, Niels

    2015-01-01

    OBJECTIVE: To investigate whether the use of incretin-based drugs (GLP-1 receptor agonists and dipeptidyl peptidase 4 [DPP4] inhibitors) is associated with acute pancreatitis. RESEARCH DESIGN AND METHODS: The study was a nationwide population-based case-control study using medical databases...... in Denmark. Participants were 12,868 patients with a first-time hospitalization for acute pancreatitis between 2005 and 2012 and a population of 128,680 matched control subjects. The main outcome measure was the odds ratio (OR) for acute pancreatitis associated with different antihyperglycemic drugs. We...... adjusted for history of gallstones, alcoholism, obesity, and other pancreatitis-associated comorbidities and medications. RESULTS: A total of 89 pancreatitis patients (0.69%) and 684 control subjects (0.53%) were ever users of incretins. The crude OR for acute pancreatitis among incretin users was 1.36 (95...

  15. Ghrelin, CCK, GLP-1, and PYY(3-36): Secretory Controls and Physiological Roles in Eating and Glycemia in Health, Obesity, and After RYGB.

    Science.gov (United States)

    Steinert, Robert E; Feinle-Bisset, Christine; Asarian, Lori; Horowitz, Michael; Beglinger, Christoph; Geary, Nori

    2017-01-01

    The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials. Copyright © 2017 the American Physiological Society.

  16. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion

    DEFF Research Database (Denmark)

    Dirksen, Carsten; Hansen, Dorte L; Madsbad, Sten

    2010-01-01

    OBJECTIVE: To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism. RESEARCH DESIGN AND METHODS: A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day into the ...... metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight loss, and caloric restriction....

  17. Effect of GLP-1 on the expression of NADPH oxidase subunits in the kidney of type 1 diabetic rats

    Directory of Open Access Journals (Sweden)

    Jin-jin LIU

    2013-09-01

    Full Text Available Objective To observe the effect of exenatide, a glucagon-like peptide-1 (GLP-1 receptor agonist, on the expression of NADPH oxidase subunits NOX4 and p22phox and connective tissue growth factor (CTGF in the kidney of streptozotocin (STZ-induced type 1 diabetic rats, and explore the protective effects and mechanisms of exenatide on the kidney of diabetic rats. Methods Thirty male Sprague-Dawley (SD rats were divided into control group (group A, n=7 and diabetic model group (n=23. Type 1 diabetic model was reproduced by intraperitoneal injection of streptozotocin. It was successful in 19 rats. Diabetic rats were randomly divided into diabetic control group (group B, n=10 and diabetic with treatment of exenatide group (group C, n=9. Rats in group C were injected subcutaneously with exenatide in dose of 5μg/kg twice daily. Rats in group A and B were given equivalent volume of normal saline by subcutaneous injection. All rats were sacrificed after eight weeks. The mRNA expression of renal p22phox and NOX4 were detected by real-time fluorescence quantitative PCR. The protein expression of CTGF was detected by immunohistochemical staining. Results The levels of blood glucose, lipids, creatinine, and urea nitrogen, the albumin excretion rate, kidney index, the mRNA expressions of renal NOX4 and p22phox, and the protein expression of renal CTGF were significantly increased in group B compared with that in group A (P0.05. Conclusion Exenatide can decrease the expressions of renal NOX4, p22phox and CTGF, decline the index of urinary protein, and alleviate the kidney hypertrophy in type 1 diabetic rats, implying that exenatide exerted a protective effect on the kidney.

  18. Serum lipase activity and concentration during intravenous infusions of GLP-1 and PYY3-36 and after ad libitum meal ingestion in overweight men

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Sjödin, Anders Mikael; Stevner, Lene Susanne

    2016-01-01

    -blinded, placebo-controlled 4-arm crossover study (Body Mass Index (BMI): 29 ± 3 kg/m(2), age: 33 ± 9 years). On separate days, the subjects received a 150-min intravenous infusion of either (1) 0.8 pmol/kg/min PYY3-36, (2) 1.0 pmol/kg/min GLP-1, (3) 1 + 2, or (4) placebo. Samples were collected throughout......To examine the effect on serum lipase activity and protein concentration of intravenous infusions of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY3-36) and of an ad libitum meal in healthy overweight men. Twenty-five healthy, male subjects participated in this randomized, double...... the infusion and after intake of an ad libitum meal for measurement of serum lipase. Serum lipase levels measured by enzyme-linked immunosorbent assay (ELISA) following mono-infusions of GLP-1 and PYY3-36 were comparable to serum lipase levels following placebo (P = 0.054 and P = 0.873, respectively...

  19. Optimization of tolerability and efficacy of the novel dual amylin and calcitonin receptor agonist KBP-089 through dose escalation and combination with a GLP-1 analog.

    Science.gov (United States)

    Gydesen, Sofie; Andreassen, Kim Vietz; Hjuler, Sara Toftegaard; Hellgren, Lars I; Karsdal, Morten Asser; Henriksen, Kim

    2017-11-01

    Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study we investigated how to optimize tolerability while maintaining efficacy of a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in food intake at every escalation step, with reducing magnitude over time, and the following treatment with 2.5, 10, and 40 µg/kg resulted in an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance ( P GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent. Copyright © 2017 the American Physiological Society.

  20. Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.

    Science.gov (United States)

    Patel, Kartikkumar Navinchandra; Joharapurkar, Amit Arvind; Patel, Vishal; Kshirsagar, Samadhan Govind; Bahekar, Rajesh; Srivastava, Brijesh Kumar; Jain, Mukul R

    2014-12-01

    Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

  1. GLP-1 receptor agonist increases the expression of CTRP3, a novel adipokine, in 3T3-L1 adipocytes through PKA signal pathway.

    Science.gov (United States)

    Li, X; Jiang, L; Yang, M; Wu, Y; Sun, S; Sun, J

    2015-01-01

    To investigate the effects of Exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, on the expression of C1q/TNF-related protein-3 (CTRP3), a novel adipokine, in 3T3-L1 adipocytes. The role of protein kinase A (PKA) signal pathway in the effects was also investigated. The mRNA and protein expressions of CTRP3 in 3T3-L1 adiocytes were detected by real-time polymerase chain reaction and western blot, respectively. Exendin-fragment 9-39 (Ex-9), a specific GLP-1 receptor antagonist, and H89, a selective antagonist of PKA, were used to confirm the signal pathway of Ex-4 on CTRP3. 2.5 or 5.0 nmol/l Ex-4 treatment for 8 h increased the expressions of CTRP3 mRNA and protein as well as PKA protein in 3T3-L1 adipocytes significantly, while Ex-9 or H89 blocked the up-regulation of CTRP3 expression induced by Ex-4 completely. GLP-1 receptor agonist increases the expression of CTRP3 mRNA and protein in 3T3-L1 adipocytes via PKA signal pathway.

  2. GLP-1 Receptor Agonists

    Science.gov (United States)

    ... Center Pacientes y Cuidadores Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ... an Endocrinologist Clinical Trials Hormones and Health The Endocrine System Hormones Endocrine Disrupting Chemicals (EDCs) Steroid and Hormone ...

  3. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis.

    Science.gov (United States)

    Sun, Feng; Wu, Shanshan; Guo, Shuxia; Yu, Kai; Yang, Zhirong; Li, Lishi; Zhang, Yuan; Quan, Xiaochi; Ji, Linong; Zhan, Siyan

    2015-10-01

    To evaluate current evidence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood pressure, heart rate, and hypertension in patients with type 2 diabetes. Medline, Embase, the Cochrane library, and the website www.clinicaltrials.gov were searched on April 5th, 2014. Randomized-controlled trials with available data were included if they compared GLP-1RAs with placebo and traditional antidiabetic drugs in patients with type 2 diabetes with duration ≥ 12 weeks. Weighted mean difference for blood pressure and heart rate, odds ratio (OR) for hypertension were calculated by random-effect model. Network meta-analysis was performed to supplement direct comparisons. Sixty trials with 14 treatments were included. Compared with placebo, insulin, and sulfonylureas, GLP-1RAs decreased systolic blood pressure with range from -1.84 mmHg (95% CI: -3.48 to -0.20) to -4.60 mmHg (95% CI: -7.18 to -2.03). Compared with placebo, a reduction in diastolic blood pressure was detected significantly only for exenatide-10 μg-twice-daily (-1.08 mmHg, 95% CI: -1.78 to -0.33). Exenatide (2 mg once weekly), liraglutide 1.2 mg once daily), and liraglutide (1.8 mg once daily) increased heart rate by 3.35 (95% CI: 1.23-5.50), 2.06 (95% CI: 0.43, 3.74), and 2.35 (95% CI: 0.94-3.76) beats/min versus placebo. This effect was evident compared with active control (range: 2.22-3.62). No significant association between incident hypertension and GLP-1RAs was detected, except for the association between exenatide-10 μg-twice-daily and sulfonylureas (OR, 0.40, 95% CI: 0.16, 0.82). GLP-1RAs were associated with modest reduction on blood pressure, a slight increase in heart rate, yet no significant association with hypertension. Further investigation to explore mechanisms is warranted. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes?

    Science.gov (United States)

    Muskiet, Marcel H A; Smits, Mark M; Morsink, Linde M; Diamant, Michaela

    2014-02-01

    Diabetic nephropathy is the leading cause of end-stage renal disease worldwide, and is associated with a high risk of cardiovascular morbidity and mortality. Intensive control of glucose levels and blood pressure is currently the mainstay of both prevention and treatment of diabetic nephropathy. However, this strategy cannot fully prevent the development and progression of diabetic nephropathy, and an unmet need remains for additional novel therapies. The incretin-based agents--agonists of glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades glucagon-like peptide 1--are novel blood-glucose-lowering drugs used in the treatment of type 2 diabetes mellitus (T2DM). Therapeutic agents from these two drug classes improve pancreatic islet function and induce extrapancreatic effects that ameliorate various phenotypic defects of T2DM that are beyond glucose control. Agonists of GLP-1R and inhibitors of DPP-4 reduce blood pressure, dyslipidaemia and inflammation, although only GLP-1R agonists decrease body weight. Both types of incretin-based agents inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in rodents and humans. In rodents, incretin-based therapies also prevent onset of the morphological abnormalities of diabetic nephropathy.

  5. Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

    DEFF Research Database (Denmark)

    Torekov, S S; Ma, L; Grarup, N

    2011-01-01

    The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits....

  6. The C-terminal extension of exendin-4 provides additional metabolic stability when added to GLP-1, while there is minimal effect of truncating exendin-4 in anaesthetized pigs

    DEFF Research Database (Denmark)

    Simonsen, L; Holst, Jens Juul; Madsen, K

    2013-01-01

    The most striking sequence difference between glucagon-like peptide-1 (GLP-1)(2) and the longer-acting GLP-1 receptor agonist, exendin-4 (Ex-4),(3) is the nine-amino acid COOH-terminal extension of Ex-4. We investigated the contribution of this extension to the survival time of Ex-4. We assessed...... the overall metabolism of GLP-1, Ex-4, a COOH-terminally extended GLP-1 peptide (GLP-1+Ex(31-39); GLP-Ex),(4) and a COOH-terminally truncated exendin peptide (Ex(1-30)) in anaesthetized, catheterized pigs, with focus on the extraction across the kidneys and a peripheral tissue (a hindleg, representing muscle......, adipose- and connective tissue). Peptide analysis was carried out with assays against the mid-region of the peptides, whereby the role of dipeptidyl peptidase-4 (DPP-4)(5) mediated NH(2)-terminal degradation could be disregarded. The half-life of GLP-1 was significantly increased when the COOH...

  7. Glucagon-Like Peptide-1 (GLP-1) Response to Oral Glucose is Reduced in Pre-diabetes, Screen-detected Type 2 Diabetes and Obesity, and Influenced by Sex

    DEFF Research Database (Denmark)

    Færch, Kristine; Torekov, Signe S; Vistisen, Dorte

    2015-01-01

    The role of glucose-stimulated release of glucagon-like peptide-1 (GLP-1) in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating...... with NGT, women with pre-diabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with pre-diabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had 20% reduced GLP-1 response to oral...... concentrations of glucose, insulin and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT, n=774), pre-diabetes (n=523) or screen-detected type 2 diabetes (n=163) who attended the Danish ADDITION-PRO study (n=1,462). Compared with individuals...

  8. Role of rs6923761 gene variant in glucagon-like peptide 1 receptor in basal GLP-1 levels, cardiovascular risk factor and serum adipokine levels in naïve type 2 diabetic patients.

    Science.gov (United States)

    de Luis, D A; Aller, R; Izaola, O; Bachiller, R

    2015-02-01

    Role of GLP-1 variants on basal GLP-1 levels, body weight and cardiovascular risk factors remains unclear in patients with diabetes mellitus type 2. Our aim was to analyze the effects of rs6923761 GLP-1 receptor polymorphism on body weight, cardiovascular risk factors, basal GLP-1 levels and serum adipokine levels in naïve patients with diabetes mellitus type 2. A sample of 104 naïve patients with diabetes mellitus type 2 was enrolled in a prospective way. Basal fasting glucose, c-reactive protein (CRP), insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides concentration, basal GLP-1, HbA1c and adipokines (leptin, adiponectin, resistin) levels were determined. Weights, body mass index, waist circumference, fat mass by bioimpedance and blood pressure measures were measured. Forty-nine patients (47.1%) had the genotype GG and 55 (52.9%) diabetic subjects had the next genotypes; GA (44 patients, 42.3%) or AA (11 study subjects, 10.6%) (second group). In A allele carriers, basal GLP-1 levels were higher than non-carriers (2.9 ± 2.1 ng/ml; p patients with diabetes mellitus type 2.

  9. Agavins from Agave angustifolia and Agave potatorum affect food intake, body weight gain and satiety-related hormones (GLP-1 and ghrelin) in mice.

    Science.gov (United States)

    Santiago-García, Patricia Araceli; López, Mercedes G

    2014-12-01

    Agavins act as a fermentable dietary fiber and have attracted attention due to their potential for reducing the risk of disease. Therefore, we evaluated the effect of supplementation using 10% agavins with a short-degree of polymerization (SDP) from Agave angustifolia Haw. (AASDP) or Agave potatorum Zucc. (APSDP) along with chicory fructans (RSE) as a reference for 5 weeks, on the energy intake, body weight gain, satiety-related hormones from the gut and blood (GLP-1 and ghrelin), blood glucose and lipids, and short-chain fatty acids (SCFAs) from the gut of ad libitum-fed mice. We evaluated the energy intake daily and weight gain every week. At the end of the experiment, portal vein blood samples as well as intestinal segments and the stomach were collected to measure glucagon-like peptide-1 (GLP-1) and ghrelin using RIA and ELISA kits, respectively. Colon SCFAs were measured using gas chromatography. The energy intake, body weight gain, and triglycerides were lower in the fructan-fed mice than in the STD-fed mice. The AASDP, APSDP, and RSE diets increased the serum levels of GLP-1 (40, 93, and 16%, respectively vs. STD) (P ≤ 0.05), whereas ghrelin was decreased (16, 38, and 42%, respectively) (P ≤ 0.05). Butyric acid increased significantly in the APSDP-fed mice (26.59 mmol g(-1), P ≤ 0.001) compared with that in the AASDP- and RSE-fed mice. We concluded that AASDP and APSDP are able to promote the secretion of the peptides involved in appetite regulation, which might help to control obesity and its associated metabolic disorder.

  10. Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity

    International Nuclear Information System (INIS)

    Seo, Daniele; Faintuch, Bluma Linkowski; Aparecida de Oliveira, Erica; Faintuch, Joel

    2017-01-01

    Introduction: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. Methods: GLP-1-βAla-HYNIC and HYNIC-βAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. Results: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2 ± 8.2 mg/dl in C, 590.4 ± 23.3 mg/dl in ADC, 234.3 ± 66.7 mg/dl in DIO, and 96.6 ± 9.3 in DRO (p = 0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. 99m Tc-HYNIC-βAla-Exendin-4 demonstrated better results than GLP-1-βAla-HYNIC- 99m Tc. Conclusions: 1) Diet-induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-βAla-Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery.

  11. Anorexigenic postprandial responses of PYY and GLP1 to slow ice cream consumption: preservation in obese adolescents, but not in obese adults.

    Science.gov (United States)

    Rigamonti, A E; Agosti, F; Compri, E; Giunta, M; Marazzi, N; Muller, E E; Cella, S G; Sartorio, A

    2013-03-01

    Eating slowly increases the postprandial responses of some anorexigenic gut hormones in healthy lean subjects. As the rate of food intake is positively associated with obesity, the aim of the study was to determine whether eating the same meal at different rates evokes different postprandial anorexigenic responses in obese adolescent and adult subjects. Eighteen obese adolescents and adults were enrolled. A test meal was consumed on two different sessions by each subject, meal duration taking either 5  min (fast feeding) or 30  min (slow feeding). Circulating levels of glucagon-like peptide 1 (GLP1), peptide YY (PYY), glucose, insulin, and triglycerides were measured over 210  min. Visual analog scales were used to evaluate the subjective feelings of hunger and satiety. fast feeding did not stimulate GLP1 release in obese adolescent and adults, whereas slow feeding increased circulating levels of GLP1 only in obese adolescents. Plasma PYY concentrations increased both in obese adolescents and in adults, irrespective of the eating rate, but slow feeding was more effective in stimulating PYY release in obese adolescents than in adults. simultaneously, slow feeding evoked a higher satiety only in obese adolescents compared with fast feeding but not in obese adults. in obese adolescents, slow feeding decreased hunger (only at 210 min). irrespective of the eating rate, postprandial responses of insulin and triglycerides were higher in obese adults than in obese adolescents. Slow feeding leads to higher concentrations of anorexigenic gut peptides and favors satiety in obese adolescents, but this physiological control of food intake is lost in obese adults.

  12. Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice

    Directory of Open Access Journals (Sweden)

    Yun Wan

    2017-05-01

    Full Text Available GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks, and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS. Cold tolerance test was performed to evaluate brown-adipose tissue (BAT activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1 in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT and aspartic transaminase (AST content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that

  13. GLP-1 derivative liraglutide in rats with beta-cell deficiencies: influence of metabolic state on beta-cell mass dynamics

    DEFF Research Database (Denmark)

    Sturis, Jeppe; Gotfredsen, Carsten F; Rømer, John

    2003-01-01

    (1) Liraglutide is a long-acting GLP-1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and beta-cell mass in rat models of beta-cell deficiencies, studies were performed in male Zucker diabetic fatty (Z...... antihyperglycemic effects in rodent models of beta-cell deficiencies, and the in vivo effect of liraglutide on beta-cell mass may in part depend on the metabolic state of the animals....

  14. Differential protective effects of exenatide, an agonist of GLP-1 receptor and Piragliatin, a glucokinase activator in beta cell response to streptozotocin-induced and endoplasmic reticulum stresses.

    Directory of Open Access Journals (Sweden)

    Mi-Kyung Kim

    Full Text Available BACKGROUND: Agonists of glucagon-like peptide-1 receptor (GLP-1R and glucokinase activators (GKA act as antidiabetic agents by their ability protect beta cells, and stimulate insulin secretion. Oxidative and endoplasmic reticulum (ER stresses aggravate type 2 diabetes by causing beta cell loss. It was shown that GLP-1R agonists protect beta cells from oxidative and ER stresses. On the other hand, little is known regarding how GKAs protect beta cells. We hypothesized that GKAs protect beta cells by mechanisms distinct from those underlying GLP-1R agonist and tested our hypothesis by comparing the molecular effects of exenatide, a GLP-1R agonist, and piragliatin, a GKA, on INS-1 cells under oxidative and ER-induced stresses. METHODS: BETA CELLS WERE TREATED WITH STREPTOZOTOCIN (STZ TO INDUCE OXIDATIVE STRESS AND WITH PALMITATE OR THAPSIGARGIN (TG TO INDUCE ER STRESS RESPECTIVELY, AND THE EFFECTS OF EXENATIDE AND PIRAGLIATIN ON THESE CELLS WERE INVESTIGATED BY: a characterizing the kinases involved employing specific kinase inhibitors, and b by identifying the differentially regulated proteins in response to stresses with proteomic analysis. RESULTS: Exenatide protected INS-1 cells from both ER and STZ-induced death. In contrast, piragliatin rescued the cells only from STZ-induced stress. Akt activation by exenatide appeared to contribute to its protective effects of beta cells while enhanced glucose utilization was the contributing factor in the case of piragliatin. Also, exenatide, not piragliatin, blocked changes in proteins 14-3-3β, ε and θ, and preserved the 14-3-3θ levels under the ER stress. Isoform-specific modifications of 14-3-3, and the reduction of 14-3-3θ, commonly associated with beta cell death were assessed. CONCLUSIONS: Exenatide and piragliatin exert distinct effects on beta cell survival and thus on type 2 diabetes. This study which confirmed our hypothesis is also the first to observe specific modulation of 14-3-3 isoform

  15. Glucagon-like peptide-1 (GLP-1) receptor agonist prevents development of tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats.

    Science.gov (United States)

    Sharma, Ajaykumar N; Pise, Ashish; Sharma, Jay N; Shukla, Praveen

    2015-06-01

    Despite major advances in the understanding about ethanol actions, the precise underlying neurobiological mechanisms for ethanol dependence remain largely elusive. We recently reported that inhibition of dipeptidyl-peptidase IV (DPP-IV), an enzyme responsible for metabolism of endogenous glucagon-like peptide-1 (GLP-1), delays tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats. Intrigued with this report, present study examined the role of glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide in (1) acute anti-anxiety effect of ethanol; (2) tolerance to ethanol's anti-anxiety-effect and (3) ethanol withdrawal-induced anxiety using elevated plus maze (EPM) test in rats. Ethanol (2 g/kg, i.p.; 8 % w/v) and liraglutide (50 μg/kg, i.p.) treatments exhibited anti-anxiety effect in EPM test. Doses of ethanol (1.0 or 1.5 g/kg, i.p.) that were not effective per se elicited anti-anxiety when combined with sub-effective dose of liraglutide (25 μg/kg, i.p.). Rats consuming ethanol-diet (6 % v/v) exhibited tolerance to anti-anxiety effect of ethanol from day-7 of ethanol consumption. Peak ethanol withdrawal-induced anxiety was observed at 8-10 h upon abstinence from ethanol-diet after 15-days consumption. Rats on simultaneous once-daily liraglutide treatment (50 μg/kg, i.p.) neither had any signs of tolerance to anti-anxiety effect of ethanol nor did they exhibit withdrawal-induced anxiety. (1) GLP-1 agonist, liraglutide exhibited anti-anxiety effect per se; (2) potentiated anti-anxiety effect of ethanol; (3) prevented development tolerance to anti-anxiety effect of ethanol and (4) prevented withdrawal-induced anxiety. Further studies examining intracellular cascade of events contributing to these effects may help to improve understanding about role of GLP-1 receptors in ethanol mediated behaviors.

  16. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Krarup, Thure; Madsbad, Sten

    2003-01-01

    -1(7-36)amide (0.33 pmol/kg/min) or saline were infused for three periods of 30 min at each glucose level, with 1 h "washout" between the infusions. On a separate day, a standard meal test (566 kcal) was performed. During the meal test, peak insulin concentrations were observed after 30 min....... Total and intact incretin hormone concentrations during the clamp studies were higher compared to the meal test, but within physiological limits. Glucose infusion alone significantly inhibited glucagon secretion, which was further inhibited by GLP-1 but not by GIP infusion. We conclude that during...

  17. Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people.

    Science.gov (United States)

    Overduin, Joost; Collet, Tinh-Hai; Medic, Nenad; Henning, Elana; Keogh, Julia M; Forsyth, Faye; Stephenson, Cheryl; Kanning, Marja W; Ruijschop, Rianne M A J; Farooqi, I Sadaf; van der Klaauw, Agatha A

    2016-12-01

    There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Difference in postprandial GLP-1 response despite similar glucose kinetics after consumption of wheat breads with different particle size in healthy men.

    Science.gov (United States)

    Eelderink, Coby; Noort, Martijn W J; Sozer, Nesli; Koehorst, Martijn; Holst, Jens J; Deacon, Carolyn F; Rehfeld, Jens F; Poutanen, Kaisa; Vonk, Roel J; Oudhuis, Lizette; Priebe, Marion G

    2017-04-01

    Underlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics and metabolic response after their consumption. Ten healthy male volunteers participated in a randomized, crossover study, consuming 13 C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour was substituted with broken wheat kernels. The structure of the breads was characterized extensively. The use of stable isotopes enabled calculation of glucose kinetics: rate of appearance of exogenous glucose, endogenous glucose production, and glucose clearance rate. Additionally, postprandial plasma concentrations of glucose, insulin, glucagon, incretins, cholecystokinin, and bile acids were analyzed. Despite the attempt to obtain a bread with a low glycemic response by replacing flour by broken kernels, the glycemic response and glucose kinetics were quite similar after consumption of CB and KB. Interestingly, the glucagon-like peptide-1 (GLP-1) response was much lower after KB compared to CB (iAUC, P bread did not result in a difference in glucose response and kinetics, but in a pronounced difference in GLP-1 response. Thus, changing the processing conditions of wheat for baking bread can influence the metabolic response beyond glycemia and may therefore influence health.

  19. Analysis of the multiple roles of gld-1 in germline development: Interactions with the sex determination cascade and the glp-1 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Francis, R.; Schedl, T. [Washington Univ. School of Medicine, St. Louis, MO (United States); Maine, E. [Syracuse Univ., NY (United States)

    1995-02-01

    The Caenorhabditis elegans gene gld-1 is essential for oocyte development; in gld-1 (null) hermaphrodites, a tumor forms where oogenesis would normally occur. We use genetic epistasis analysis to demonstrate that tumor formation is dependent on the sexual fate of the germline. When the germline sex determination pathway is set in the female mode (terminal fem/fog genes inactive), gld-1 (null) germ cells exit meiotic prophase and proliferate to form a tumor, but when the pathway is et in the male mode, they develop into sperm. We conclude that the gld-1 (null) phenotype is cell-type specific and that gld-1(+) acts at the end of the cascade to direct oogenesis. We also use cell ablation and epistasis analysis to examine the dependence of tumor formation on the glp-1 signaling pathway. Although glp-1 activity promotes tumor growth, it is not essential for tumor formation by gld-1 (null) germ cells. These data also reveal that gld-1(+) plays a nonessential (and sex nonspecific) role in regulating germ cell proliferation before their entry into meiosis. Thus gld-1(+) may negatively regulate proliferation at two distinct points in germ cell development: before entry into meiotic prophase in both sexes (nonessential premeiotic gld-1 function) and during meiotic prophase when the sex determination pathway is set in the female mode (essential meiotic gld-1 function). 46 refs., 9 figs., 4 tabs.

  20. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans

    DEFF Research Database (Denmark)

    Mandøe, Mette J.; Hansen, Katrine B.; Hartmann, Bolette

    2015-01-01

    acid), olive oil [contg. long-chain fatty acids; e.g., oleic acid plus 2-oleoyl glycerol (2-OG)], and 1,3-dioctanoyl-2-oleoyl glycerol (C8-dietary oil), which is digested to form medium-chain fatty acids (i.e., octanoic acid) and 2-OG. Design: In a randomized, single-blinded crossover study, 12 healthy...... white men [mean age: 24 y; BMI (in kg/m2): 22] were given the following 4 meals on 4 different days: 200 g carrots + 6.53 g tributyrin, 200 g carrots + 13.15 g C8-dietary oil, 200 g carrots + 19 g olive oil, or 200 g carrots. All of the lipids totaled 0.0216 mol. Main outcome measures were incremental...... areas under the curve for total GLP-1, GIP, and cholecystokinin (CCK) in plasma. Results: C8-dietary oil and olive oil showed the same GLP-1 response [583 ± 101 and 538 ± 71 (pmol/L) × 120 min; P = 0.733], whereas the GIP response was higher for olive oil than for C8-dietary oil [3293 ± 404 and 1674...

  1. Detection of Impaired Cognitive Function in Rat with Hepatosteatosis Model and Improving Effect of GLP-1 Analogs (Exenatide on Cognitive Function in Hepatosteatosis

    Directory of Open Access Journals (Sweden)

    Oytun Erbaş

    2014-01-01

    Full Text Available The aims of the study were to evaluate (1 detection of cognitive function changing in rat with hepatosteatosis model and (2 evaluate the effect of GLP-1 analog (exenatide on cognitive function in hepatosteatosis. In the study group, 30% fructose was given in nutrition water to perform hepatosteatosis for 8 weeks to 18 male rats. Six male rats were chosen as control group and had normal nutrition. Fructose nutrition group were stratified into 3 groups. In first group (n=6, intracerebroventricular (ICV infusion of exenatide (n=6 was given. ICV infusion of NaCl (n=6 was given to second group. And also, the third group had no treatment. And also, rats were evaluated for passive avoidance learning (PAL and liver histopathology. Mean levels of latency time were statistically significantly decreased in rats with hepatosteatosis than those of normal rats (P<0.00001. However, mean level of latency time in rats with hepatosteatosis treated with ICV exenatide was statistically significantly increased than that of rats treated with ICV NaCl (P<0.001. Memory performance falls off in rats with hepatosteatosis feeding on fructose (decreased latency time. However, GLP-1 ameliorates cognitive functions (increased latency time in rats with hepatosteatosis and releated metabolic syndrome.

  2. The GLP-1 Analogue Exenatide Improves Hepatic and Muscle Insulin Sensitivity in Diabetic Rats: Tracer Studies in the Basal State and during Hyperinsulinemic-Euglycemic Clamp

    Directory of Open Access Journals (Sweden)

    Hui Wu

    2014-01-01

    Full Text Available Objective. Glucagon-like peptide-1 (GLP-1 analogues (e.g., exenatide increase insulin secretion in diabetes but less is known about their effects on glucose production or insulin-stimulated glucose uptake in peripheral tissues. Methods. Four groups of Sprague-Dawley rats were studied: nondiabetic (control, C; nondiabetic + exenatide (C + E; diabetic (D; diabetic + exenatide (D + E with diabetes induced by streptozotocin and high fat diet. Infusion of 3-3H-glucose and U-13C-glycerol was used to measure basal rates of appearance (Ra of glucose and glycerol and gluconeogenesis from glycerol (GNG. During hyperinsulinemic-euglycemic clamp, glucose uptake into gastrocnemius muscles was measured with 2-deoxy-D-14C-glucose. Results. In the diabetic rats, exenatide reduced the basal Ra of glucose (P<0.01 and glycerol (P<0.01 and GNG (P<0.001. During the clamp, Ra of glucose was also reduced, whereas the rate of disappearance of glucose increased and there was increased glucose uptake into muscle (P<0.01 during the clamp. In the nondiabetic rats, exenatide had no effect. Conclusion. In addition to its known effects on insulin secretion, administration of the GLP-1 analogue, exenatide, is associated with increased inhibition of gluconeogenesis and improved glucose uptake into muscle in diabetic rats, implying improved hepatic and peripheral insulin sensitivity.

  3. Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

    Science.gov (United States)

    Kramer, Caroline K; Zinman, Bernard; Choi, Haysook; Connelly, Philip W; Retnakaran, Ravi

    2017-05-01

    Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC GIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUC GLP -1 at 12 weeks ( P  endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology. © 2017 John Wiley & Sons Ltd.

  4. The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy.

    Science.gov (United States)

    Sportiello, Liberata; Rafaniello, Concetta; Scavone, Cristina; Vitale, Cristiana; Rossi, Francesco; Capuano, Annalisa

    2016-01-01

    With the recent introduction of the new European Pharmacovigilance legislation, all new drugs must be carefully monitored after admission on the European market, in order to assess the long safety profile. Currently, special attention is given to several hypoglycemic agents with recent market approval (agonists of glucagon-like peptide-1 [GLP-1] receptor and dipeptidyl peptidase 4 inhibitors [DPP-4i]), which act through the potentiation of incretin hormone signaling. Their inclusion in European additional monitoring is also due to safety problems, which seem to characterize their pharmacological class. In fact, these drugs initially showed a good tolerability profile with mainly gastrointestinal adverse events, low risk of hypoglycemia and minor effects on body weight. But, new concerns such as infections, pancreatitis, pancreatic cancer and above all cardiovascular events (especially risk of heart failure requiring hospitalization) are now arising. In this review, we highlighted aspects of the new Pharmacovigilance European dispositions, and then we investigated the tolerability profile of incretin-based therapies, in particular DPP-4 inhibitors. Notably, we focused our attention on new safety concerns, which are emerging mostly in the post-marketing period, as the cardiovascular risk profile. Evidence in literature and opinions of regulatory agencies (e.g., European Medicines Agency and Food and Drug Administration) about risks of incretin-based therapies are yet controversial, and there are many open questions in particular on cancer and cardiovascular effects. Thus, it is important to continue to monitor closely the use of these drugs in clinical practice to improve the knowledge on their long-term safety and their place in diabetes therapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. DPP-4 Inhibitors: Incretin-Based Medicine for Type 2 Diabetes

    Science.gov (United States)

    ... Another type of incretin-based medicine, called a GLP-1 receptor agonist, works in a slightly different way to achieve the same effect on blood glucose levels. What are DPP-4 ... of the DPP-4 enzyme. This makes GLP-1 last longer and increases the amount of GLP- ...

  6. Cell-based delivery of glucagon-like peptide-1 using encapsulated mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wallrapp, Christine; Thoenes, Eric; Thürmer, Frank

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) CellBeads are cell-based implants for the sustained local delivery of bioactive factors. They consist of GLP-1 secreting mesenchymal stem cells encapsulated in a spherically shaped immuno-isolating alginate matrix. A highly standardized and reproducible encapsulati...

  7. Therapeutic strategies based on glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F

    2004-01-01

    of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short......-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding...... of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation...

  8. Body weight loss, reduced urge for palatable food and increased release of GLP-1 through daily supplementation with green-plant membranes for three months in overweight women.

    Science.gov (United States)

    Montelius, Caroline; Erlandsson, Daniel; Vitija, Egzona; Stenblom, Eva-Lena; Egecioglu, Emil; Erlanson-Albertsson, Charlotte

    2014-10-01

    The frequency of obesity has risen dramatically in recent years but only few effective and safe drugs are available. We investigated if green-plant membranes, previously shown to reduce subjective hunger and promote satiety signals, could affect body weight when given long-term. 38 women (40-65 years of age, body mass index 25-33 kg/m(2)) were randomized to dietary supplementation with either green-plant membranes (5 g) or placebo, consumed once daily before breakfast for 12 weeks. All individuals were instructed to follow a three-meal paradigm without any snacking between the meals and to increase their physical activity. Body weight change was analysed every third week as was blood glucose and various lipid parameters. On days 1 and 90, following intake of a standardized breakfast, glucose, insulin and glucagon-like peptide 1 (GLP-1) in plasma were measured, as well as subjective ratings of hunger, satiety and urge for different palatable foods, using visual analogue scales. Subjects receiving green-plant membranes lost significantly more body weight than did those on placebo (p weight loss with green-plant extract was 5.0 ± 2.3 kg compared to 3.5 ± 2.3 kg in the control group. Consumption of green-plant membranes also reduced total and LDL-cholesterol (p meal tests performed on day 1 and day 90 demonstrated an increased postprandial release of GLP-1 and decreased urge for sweet and chocolate on both occasions in individuals supplemented with green-plant membranes compared to control. Waist circumference, body fat and leptin decreased in both groups over the course of the study, however there were no differences between the groups. In conclusion, addition of green-plant membranes as a dietary supplement once daily induces weight loss, improves obesity-related risk-factors, and reduces the urge for palatable food. The mechanism may reside in the observed increased release of GLP-1. Copyright © 2014 The Authors. Published by Elsevier Ltd

  9. Lower glucose-dependent insulinotropic polypeptide (GIP) response but similar glucagon-like peptide 1 (GLP-1), glycaemic, and insulinaemic response to ancient wheat compared to modern wheat depends on processing

    DEFF Research Database (Denmark)

    Bakhøj, S; Flint, A.; Holst, Jens Juul

    2003-01-01

    OBJECTIVE: To test the hypothesis that bread made from the ancient wheat Einkorn (Triticum monococcum) reduces the insulin and glucose responses through modulation of the gastrointestinal responses of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) compared...... whole grain bread elicit a reduced gastrointestinal response of GIP compared to conventional yeast bread. No differences were found in the glycaemic, insulinaemic and GLP-1 responses. Processing of starchy foods such as wheat may be a powerful tool to modify the postprandial GIP response....

  10. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes

    DEFF Research Database (Denmark)

    Lund, Asger; Vilsbøll, Tina; Bagger, Jonatan I

    2011-01-01

    Type 2 diabetes mellitus (T2DM) is associated with reduced suppression of glucagon during oral glucose tolerance test (OGTT), whereas isoglycemic intravenous glucose infusion (IIGI) results in normal glucagon suppression in these patients. We examined the role of the intestinal hormones glucose......-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) in this discrepancy. Glucagon responses were measured during a 3-h 50-g OGTT (day A) and an IIGI (day B) in 10 patients with T2DM [age (mean ± SE), 51 ± 3 yr; body mass index, 33 ± 2 kg/m(2); HbA(1c), 6.5 ± 0......, and GLP-2, may play a role in the inappropriate glucagon response to orally ingested glucose in T2DM with, especially, GIP, acting to increase glucagon secretion....

  11. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease

    DEFF Research Database (Denmark)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille

    2016-01-01

    . In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically...... injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six...... weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect...

  12. Glucose-Lowering Effects and Low Risk of Hypoglycemia in Patients With Maturity-Onset Diabetes of the Young When Treated With a GLP-1 Receptor Agonist

    DEFF Research Database (Denmark)

    Ostoft, Signe H; Bagger, Jonatan I; Hansen, Torben

    2014-01-01

    diabetes.RESEARCH DESIGN AND METHODS: Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 ± 0.5 kg/m(2) [mean ± SEM]; fasting plasma glucose [FPG] 9.9 ± 0.9 mmol/L; HbA1c 6.4 ± 0.2% [47 ± 3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide......) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutide was up-titrated once weekly to 1.8 mg once daily. At baseline and at the end...

  13. HOMA-S is associated with greater HbA1c reduction with a GLP-1 analogue in patients with type 2 diabetes.

    Science.gov (United States)

    Heald, A H; Narayanan, R P; Lowes, D; Jarman, E; Onyekwelu, E; Qureshi, Z; Laing, I; Anderson, S G

    2012-07-01

    Exenatide, a glucagon-like peptide-1 (GLP-1) analogue, is an effective glucoregulator for treating overweight individuals, not at target HbA1 c. This prospective study aimed to determine whether estimates of beta cell function (HOMA-B) and insulin sensitivity (HOMA-S) predict response to Exenatide treatment.Prospective data on 43 type 2 diabetes patients were collected for up to 2.8 years in UK primary care. HOMA-B and HOMA-S were estimated prior to initiating Exenatide, with monitoring of cardio-metabolic risk factors.Mean (SD) age and BMI pre-treatment were 54.1±10.5 years and 35.7±7.5 kg/m2 respectively. HbA1c decreased (mean reduction 0.9%, p=0.04; p for trend=0.01) in 61% of patients. In univariate analyses, HOMA-S as a measure of insulin sensitivity was inversely (β=- 0.41, p 0.009) related to change in HbA1c, with no relation for HOMA-B.In a random effects regression model that included age at baseline, weight, LDL-C, HDL-C and triglycerides, change in HbA1c (β= - 0.14, pHOMA-S were 45% more likely to have a fall in HbA1c with an odds ratio (OR) of 0.55 (95% CI 0.47-0.66) p<0.0001 (log likelihood ratio for the model χ2=71.6, p<0.0001).Patients with greater measured insulin sensitivity achieve greater reduction in HbA1c with Exenatide. Determination of insulin sensitivity may assist in guiding outcome expectation in overweight patients treated with GLP-1 analogues. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  14. Expression of CTRP3, a Novel Adipokine, in Rats at Different Pathogenic Stages of Type 2 Diabetes Mellitus and the Impacts of GLP-1 Receptor Agonist on It

    Directory of Open Access Journals (Sweden)

    Xin Li

    2014-01-01

    Full Text Available This study aimed to investigate the expression of C1q/TNF-related protein-3 (CTRP3 in rats at different pathogenic stages of type 2 diabetes mellitus (T2DM and the impacts of glucagon-like peptide-1 (GLP-1 receptor agonist on it. Male wistar rats were fed with high-fat diet for 10 weeks to induce insulin resistance (IR and then were given low-dose streptozotocin (STZ intraperitoneal injection to induce T2DM. Exendin-4 (Ex-4, a GLP-1 receptor agonist, was subcutaneous injected to the IR rats and T2DM rats for 4 weeks. The expression of CTRP3 mRNA and protein in epididymis adipose tissue of rats at the stage of IR was lower significantly than that of normal control (NC rats and decreased more when they were at the stage of overt T2DM (all P<0.05 or P<0.01. After the treatment with Ex-4, the mRNA and protein expressions of CTRP3 were increased by 15.5% (P<0.01 and 14.8% (P<0.05, respectively, in IR rats and increased by 20.6% (P<0.01 and 16.5% (P<0.05, respectively, in T2DM rats. Overall, this study found that the expression of CTRP3 in visceral adipose tissue was progressively decreased in a T2DM rat model from the pathogenic stage of IR to overt diabetes, while Ex-4 treatment increased its expression in such animals.

  15. GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

    Directory of Open Access Journals (Sweden)

    Brend Ray-Sea Hsu

    Full Text Available Background and aims: The aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA, exenatide, on clozapine-associated glucose dysregulation in mice. Materials and methods: We randomly separated B6 male mice into four groups (A to D. Mice in groups C and D received a daily oral dose of 13.5 mg/kg body weight of clozapine for 4 months. Mice in groups B and D received 1 μg of exenatide daily. The body weight and blood glucose before and 2 h after clozapine treatment were measured twice a week. Intraperitoneal glucose tolerance test (IPGTT scores and the amount of daily food intake were recorded. The pancreases of the mice were removed for insulin content (PIC measurement and histological examination after sacrifice. Results: The mean non-fasting blood glucose levels were not different, and the mean changes in blood glucose 2 h after oral clozapine were 0 ± 4, −40 ± 2, 25 ± 3, and −39 ± 2, in groups A to D, respectively. There was no significant difference in daily calorie intake or area under the curve of IPGTT among the four groups. At sacrifice, the PIC of mice treated with clozapine was significantly lower than that of the control mice, however the PIC was completely restored in the mice treated with exenatide. Histological examination of the pancreas revealed that exenatide treatment reversed the clozapine-induced apoptosis of islet cells. Conclusion: Our results provide preclinical evidence of a pharmaceutical role of GLP-1RA in managing glucose dysregulation in schizophrenic patients under long-term atypical antipsychotic treatments. Keywords: Clozapine, Exenatide, Glucose dysregulation, Beta cell, Apoptosis

  16. Acting on hormone receptors with minimal side effect on cell proliferation: a timely challenge illustrated with GLP-1R and GPER.

    Directory of Open Access Journals (Sweden)

    Véronique eGigoux

    2013-04-01

    Full Text Available G protein coupled receptors (GPCRs constitute a large family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. GPCR are involved in a wide variety of physiological processes, including in the neuroendocrine system. GPCR are also involved in many diseases and are the target of 30% of marketed medicinal drugs. Whereas the majority of the GPCR-targeting drugs have proved their therapeutic benefit, some of them were associated with undesired effects. We develop two examples of used drugs whose therapeutic benefits are tarnished by carcinogenesis risks. The chronic administration of glucagon-like peptide-1 (GLP-1 analogs widely used to treat type-2 diabetes was associated with an increased risk of pancreatic or thyroid cancers. The long term treatment with the estrogen antagonist tamoxifen, developed to target breast cancer overexpressing estrogen receptors ER, presents agonist activity on the G protein-coupled estrogen receptor GPER which is associated with an increased incidence of endometrial cancer and breast cancer resistance to hormonotherapy. We point out and discuss the need of pharmacological studies to understand and overcome the undesired effects associated with the chronic administration of GPCR ligands. In fact, biological effects triggered by GPCR often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling networks are engaged following GPCR activation appears to be primordial to unveil their contribution in the physiological and physiopathological processes. The development of biased agonists to elucidate the role of the different signaling mechanisms mediated by GPCR activation will allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1R biased ligands promoting insulin secretion without inducing protumoral effects would offer

  17. A novel dual GLP-1/GIP receptor agonist alleviates cognitive decline by re-sensitizing insulin signaling in the Alzheimer icv. STZ rat model.

    Science.gov (United States)

    Shi, Lijuan; Zhang, Zhihua; Li, Lin; Hölscher, Christian

    2017-06-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1 Ser1101 levels and phospho-Akt Ser473 up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Glucagon-like peptide 1 receptor agonist (GLP-1 RA): long-term effect on kidney function in patients with type 2 diabetes.

    Science.gov (United States)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter; Persson, Frederik; Rossing, Peter

    2015-07-01

    In a short-term study including 31 patients with type 2 diabetes, glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment was associated with a significant reversible decline in GFR. Twenty-three patients re-initiated GLP-1 RA treatment after the primary study, and the aim was to investigate the long-term effect on kidney function. We included 30 patients in a one-year extension study, all initially treated with liraglutide for seven weeks. During follow-up 23 were treated with liraglutide and seven untreated. Primary outcome was change in GFR ((51)Cr-EDTA plasma clearance). Patients were 61.5 (10.0) years and HbA(1c) 60.1 (13.8) mmol/mol. Baseline GFR was 100.6 (24.9) mL/min/1.73 m(2) and was reduced by 11 (95% CI: 6.6-15.7, p < 0.001) mL/min/1.73 m(2), independent of change in 24-h systolic blood pressure (SBP), weight, UAER or HbA(1c) (p≥0.33). Geometric mean (IQR) of UAER was 25.5 (9.9-50.9) mg/d and was reduced by 27 (95% CI: 5-44; p = 0.020)%, and 24-h SBP was reduced by 8.2 (p = 0.048) mmHg. No changes occurred in untreated patients. Long-term treatment with liraglutide was associated with a reduction in measured GFR similar to the effect during short-term treatment, suggesting a metabolic or haemodynamic reversible effect and not structural changes. Moreover, UAER and 24-h SBP were reduced. ClinicalTrials.gov identifier: NCT01499108. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. Copyright © 2016. Published by Elsevier B.V.

  20. Effect of Age on Blood Glucose and Plasma Insulin, Glucagon, Ghrelin, CCK, GIP, and GLP-1 Responses to Whey Protein Ingestion

    Directory of Open Access Journals (Sweden)

    Caroline Giezenaar

    2017-12-01

    Full Text Available Protein-rich supplements are used widely to prevent and manage undernutrition in older people. We have previously shown that healthy older, compared to younger, adults have less suppression of energy intake by whey protein—although the effects of age on appetite-related gut hormones are largely unknown. The aim of this study was to determine and compare the acute effects of whey protein loads on blood glucose and plasma gut hormone concentrations in older and younger adults. Sixteen healthy older (eight men, eight women; mean ± SEM: age: 72 ± 1 years; body mass index: 25 ± 1 kg/m2 and 16 younger (eight men, eight women; 24 ± 1 years; 23 ± 0.4 kg/m2 adults were studied on three occasions in which they ingested 30 g (120 kcal or 70 g (280 kcal whey protein, or a flavored-water control drink (~2 kcal. At regular intervals over 180 min, blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK, gastric inhibitory peptide (GIP, and glucagon-like peptide-1 (GLP-1 concentrations were measured. Plasma ghrelin was dose-dependently suppressed and insulin, glucagon, CCK, GIP, and GLP-1 concentrations were dose-dependently increased by the whey protein ingestion, while blood glucose concentrations were comparable during all study days. The stimulation of plasma CCK and GIP concentrations was greater in older than younger adults. In conclusion, orally ingested whey protein resulted in load-dependent gut hormone responses, which were greater for plasma CCK and GIP in older compared to younger adults.

  1. BEYOND GLYCEMIC CONTROL IN DIABETES MELLITUS: EFFECTS OF INCRETIN-BASED THERAPY ON BONE METABOLISM

    Directory of Open Access Journals (Sweden)

    ELENA eCECCARELLI

    2013-06-01

    Full Text Available Diabetes mellitus (DM and osteoporosis (OP are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM and in type 2 (T2DM diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density (BMD. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g. tiazolidinediones, insulin may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e. GLP-1 receptor agonists and DPP-4 inhibitors is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells.Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.

  2. Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young men with low birth weight

    DEFF Research Database (Denmark)

    Hagen Schou, Jakob; Pilgaard, Kasper; Vilsbøll, Tina

    2005-01-01

    Context. Low birth weight (LBW) is associated with increased risk of Type 2 diabetes mellitus. An impaired incretin effect was previously reported in type 2 diabetic patients. Objective. We studied the secretion and action of GLP-1 and GIP in young LBW men (n = 24) and matched normal birth weight...

  3. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes : A 12-week, randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Tonneijck, Lennart; Smits, Mark M.; Muskiet, Marcel H.A.; Hoekstra, Trynke; Kramer, Mark H.H.; Danser, A. H.Jan; Ter Wee, Piet M.; Diamant, Michaela; Joles, Jaap A.; Van Raalte, Daniël H.

    2016-01-01

    OBJECTIVE To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney

  4. How to implement incretin therapy.

    Science.gov (United States)

    Cobble, Michael E

    2008-09-01

    The roles of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are rapidly evolving, despite limited recommendations on their use in current guidelines. This evolution is based on data from the large number of clinical trials demonstrating the clinical efficacy and favorable safety profile of these agents in individuals with type 2 diabetes mellitus (T2DM). This article focuses on factors to consider when implementing the GLP-1 receptor agonists and DPP-4 inhibitors as monotherapy or in combination with other agents in the treatment of T2DM.

  5. Cell based therapy in Parkinsonism

    NARCIS (Netherlands)

    de Munter, J.P.J.M.; Lee, C.; Wolters, E.C.

    2013-01-01

    Parkinson's disease (PD) is a synucleinopathy-induced chronic progressive neurodegenerative disorder, worldwide affecting about 5 million humans. As of yet, actual therapies are symptomatic, and neuroprotective strategies are an unmet need. Due to their capability to transdifferentiate, to immune

  6. Exendin-4 inhibits structural remodeling and improves Ca2+homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway.

    Science.gov (United States)

    Chen, Jingjing; Wang, Dandan; Wang, Fangai; Shi, Shaobo; Chen, Yuting; Yang, Bo; Tang, Yanhong; Huang, Congxin

    2017-04-01

    The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 is a long-acting analog of GLP-1, which stimulates insulin secretion and is clinically used in the treatment of type 2 diabetes. Previous studies have demonstrated that GLP-1 agonists and analogs serve as cardioprotective factors in various conditions. Disturbances in calcium cycling are characteristic of heart failure (HF); therefore, the aim of this study was to investigate the effect of exendin-4 (a GLP-1 mimetic) on the regulation of calcium handling and to identify the underlying mechanisms in an HF rat model after myocardial infarction (MI). Rats underwent surgical ligation of the left anterior descending coronary artery or sham surgery prior to infusion with vehicle, exendin-4, or exendin-4 and exendin9-39 for 4 weeks. Exendin-4 treatment decreased MI size, suppressed chamber dilation, myocyte hypertrophy, and fibrosis and improved in vivo heart function in the rats subjected to MI. Exendin-4 resulted in an increase in circulating GLP-1 and GLP-1R in ventricular tissues. Additionally, exendin-4 activated the eNOS/cGMP/PKG signaling pathway and inhibited the Ca 2+ /calmodulin-dependent kinase II (CaMKII) pathways. Myocytes isolated from exendin-4-treated hearts displayed higher Ca 2+ transients, higher sarcoplasmic reticulum Ca 2+ content, and higher l-type Ca 2+ current densities than MI hearts. Exendin-4 treatment restored the protein expression of sarcoplasmic reticulum Ca 2+ uptake ATPase (SERCA2a), phosphorylated phospholamban (PLB) and Cav1.2 and decreased the levels of phosphorylated ryanodine receptor (RyR). Moreover, the favorable effects of exendin-4 were significantly inhibited by exendin9-39 (a GLP-1 receptor antagonist). Exendin-4 treatment of an HF rat model after MI inhibited cardiac and cardiomyocytes progressive remodeling. In addition, Ca 2+ handling and its molecular modulation were also improved by exendin-4 treatment. The beneficial effects of exendin-4 on cardiac remodeling

  7. Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report.

    Science.gov (United States)

    Horikawa, Yukio; Enya, Mayumi; Komagata, Makie; Hashimoto, Ken-Ichi; Kagami, Masayo; Fukami, Maki; Takeda, Jun

    2018-02-01

    Diabetes patients with Prader-Willi syndrome (PWS) are obese because of hyperphagia; weight control by dietary modification and medicine is required for glycemic control. There are several recent reports showing the effectiveness of GLP-1 receptor agonists (GLP-1RAs) for diabetes treatment in PWS. A 36-year-old Japanese male patient was diagnosed with PWS at 10 years of age. At age 16 years, he was diagnosed with diabetes and began to take several kinds of oral hypoglycemic agents. At age 29 years, his BMI was 39.1 kg/m 2 and he was referred to our department for diabetes and obesity treatment. In the present case, the HbA1c was not improved by GLP-1RAs despite a 28-kg BW reduction, which included a 9-kg loss of muscle. Apprehensive of further loss of muscle mass, basal insulin of insulin glargine was administered in addition to GLP-1RAs. Immediately after the addition of tofogliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, the patient's HbA1c decreased dramatically with only about an additional 3% BW reduction. We note an improvement in our case of lipid deposition in the pancreas confirmed by abdominal CT after the improvement of HbA1c. It is unknown whether this improvement of fatty pancreas was a cause or an effect of the improved glycemic control in the present case. This finding clearly supports the effectiveness of combining SGLT2 inhibitors with GLP-1RAs for treatment of patients with PWS and non-alcoholic fatty pancreas disease.

  8. Liposome based radiosensitizer cancer therapy

    DEFF Research Database (Denmark)

    Pourhassan, Houman

    Liposome-encapsulated chemotherapeutics have been used in the treatment of a variety of cancers and are feasible for use as mono-therapeutics as well as for combination therapy in conjunction with other modalities. Despite widespread use of liposomal drugs in cancer patient care, insufficient drug...... biomolecules. By modulating the liposomal membrane, liposomes can become sensitive towards enzymatically-driven destabilization and/or functionalization, thereby allowing control of the release of encapsulated therapeutics within the diseased tissue upon intrinsic stimulation from tumor-associated enzymes...... in tumor-bearing mice.The safety and efficacy of sPLA2-sensitive liposomal L-OHP was assessed in sPLA2-deficient FaDu hypopharyngeal squamous cell carcinoma and sPLA2-expressing Colo205 colorectal adenocarcinoma. Also, the feasibility of multimodal cancer therapy employing L-OHP encapsulated in MMP...

  9. Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist.

    Directory of Open Access Journals (Sweden)

    Mi-Kyung Kim

    Full Text Available Beta cell death caused by endoplasmic reticulum (ER stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1 reversed by exenatide, 2 exaggerated by exenatide, and 3 unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.

  10. A randomized controlled trial comparing the GLP-1 receptor agonist liraglutide to a sulphonylurea as add on to metformin in patients with established type 2 diabetes during Ramadan: the Treat 4 Ramadan Trial.

    Science.gov (United States)

    Brady, E M; Davies, M J; Gray, L J; Saeed, M A; Smith, D; Hanif, W; Khunti, K

    2014-06-01

    To compare a sulphonylurea with the glucagon like peptide-1 (GLP-1) receptor agonist liraglutide in combination with metformin in patients on mono/dual oral therapy with established type 2 diabetes fasting during Ramadan. Ninety-nine adults intending to fast during Ramadan [50% male, mean age 52 years, body mass index (BMI) 32 kg/m(2)] were randomized from two UK sites. Baseline data were collected ≥14 days prior to Ramadan and at 3 and 12 weeks after Ramadan. At 12 weeks, more patients in the liraglutide compared with the sulphonylurea group achieved a composite endpoint of haemoglobin A1c (HbA1c) < 7%, no weight gain and no severe hypoglycaemia but this did not reach statistical significance [odds ratio (OR) 4.08, 95% confidence interval (CI) 0.97, 17.22, p = 0.06]. From a baseline of 7.7% there was no change in HbA1c at 12 weeks in the sulphonylurea (+0.02%) compared with a 0.3% reduction in the liraglutide group (adjusted coefficient -0.41, 95% CI -0.83, 0.01, p = 0.05). Significant reductions were also observed in weight and diastolic blood pressure (BP) in the liraglutide compared with the sulphonylurea group. Treatment satisfaction was comparable across the treatment groups. There were no episodes of severe hypoglycaemia in either group, however, self-recorded episodes of blood glucose ≤3.9 mmol/l were significantly lower with liraglutide (incidence rate ratio 0.29, 95% CI 0.19, 0.41, p < 0.0001). Liraglutide compared with sulphonylurea is well tolerated and maybe an effective therapy in combination with metformin during Ramadan with more patients able to achieve target HbA1c, lose or maintain weight with no severe hypoglycaemia. This was achieved with a high level of treatment satisfaction. © 2013 John Wiley & Sons Ltd.

  11. Magnetic nanoparticle-based cancer therapy

    International Nuclear Information System (INIS)

    Yu Jing; Yousaf Muhammad Zubair; Hou Yang-Long; Huang Dong-Yan; Gao Song

    2013-01-01

    Nanoparticles (NPs) with easily modified surfaces have been playing an important role in biomedicine. As cancer is one of the major causes of death, tremendous efforts have been devoted to advance the methods of cancer diagnosis and therapy. Recently, magnetic nanoparticles (MNPs) that are responsive to a magnetic field have shown great promise in cancer therapy. Compared with traditional cancer therapy, magnetic field triggered therapeutic approaches can treat cancer in an unconventional but more effective and safer way. In this review, we will discuss the recent progress in cancer therapies based on MNPs, mainly including magnetic hyperthermia, magnetic specific targeting, magnetically controlled drug delivery, magnetofection, and magnetic switches for controlling cell fate. Some recently developed strategies such as magnetic resonance imaging (MRI) monitoring cancer therapy and magnetic tissue engineering are also addressed. (topical review - magnetism, magnetic materials, and interdisciplinary research)

  12. Magnetic nanoparticle-based cancer therapy

    Science.gov (United States)

    Yu, Jing; Huang, Dong-Yan; Muhammad Zubair, Yousaf; Hou, Yang-Long; Gao, Song

    2013-02-01

    Nanoparticles (NPs) with easily modified surfaces have been playing an important role in biomedicine. As cancer is one of the major causes of death, tremendous efforts have been devoted to advance the methods of cancer diagnosis and therapy. Recently, magnetic nanoparticles (MNPs) that are responsive to a magnetic field have shown great promise in cancer therapy. Compared with traditional cancer therapy, magnetic field triggered therapeutic approaches can treat cancer in an unconventional but more effective and safer way. In this review, we will discuss the recent progress in cancer therapies based on MNPs, mainly including magnetic hyperthermia, magnetic specific targeting, magnetically controlled drug delivery, magnetofection, and magnetic switches for controlling cell fate. Some recently developed strategies such as magnetic resonance imaging (MRI) monitoring cancer therapy and magnetic tissue engineering are also addressed.

  13. Radionuclide therapy of endocrine-related cancer; Nuklearmedizinische Therapie endokriner Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L. [Universitaetsklinikum Heidelberg, Abteilung Nuklearmedizin, Heidelberg (Germany)

    2014-10-15

    This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [German] Dieser Artikel gibt einen Ueberblick ueber die etablierten sowie weitere vielversprechende, aktuell im Rahmen von Studien eingesetzte nuklearmedizinische Therapiemoeglichkeiten diverser endokrinologischer Neoplasien. Die Radiojodtherapie ist unveraendert die Therapie der Wahl beim differenzierten, jodspeichernden Schilddruesenkarzinom. Im metastasierten Stadium sind in ca. 50 % der Faelle noch

  14. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist: Protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study – the TAO study

    DEFF Research Database (Denmark)

    Ishøy, Pelle Lau; Knop, Filip Krag; Broberg, Brian Villumsen

    Introduction: Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against...... antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight lowering effects have also been recognized in non-diabetic patients. The purpose of this trial is to examine if treatment...... with a GLP-1 receptor agonist (exenatide once-weekly) is safe and facilitates weight loss in non-diabetic schizophrenia patients with antipsychotic-associated obesity. Methods and analysis: Forty obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised...