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Nurhamimah Misuan - One of the best experts on this subject based on the ideXlab platform.
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exendin 4 from heloderma suspectum venom from discovery to its latest application as type ii diabetes combatant
Basic & Clinical Pharmacology & Toxicology, 2019Co-Authors: Michelle Khai Khun Yap, Nurhamimah MisuanAbstract:Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and Incretin Mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short Incretin-Mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an Incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.
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Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant
Basic & clinical pharmacology & toxicology, 2018Co-Authors: Michelle Khai Khun Yap, Nurhamimah MisuanAbstract:Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and Incretin Mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short Incretin-Mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an Incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.
Matthias Girndt - One of the best experts on this subject based on the ideXlab platform.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes Therapy, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Introduction Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin Mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-Mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Methods Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-Mimetic therapy), group 2 (insulin therapy without Incretin Mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Results Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin Mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-Mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). Conclusion The prevalence of Incretin Mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes therapy : research treatment and education of diabetes and related disorders, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin Mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-Mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-Mimetic therapy), group 2 (insulin therapy without Incretin Mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin Mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-Mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). The prevalence of Incretin Mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in Hospitalized Type-2-Diabetics following Myocardial Revascularization: an Observational Study
2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Abstract Background: We hypothesized that the recommended Incretin-Mimetic therapy associates with a better outcome (1-year mortality after discharge, rehospitalizations within 12 months) and with less hypoglycemic events in type − 2 diabetics following myocardial revascularization. Methods: Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle), who had percutaneous coronary intervention (29.4%) or coronary artery bypass graft (70.6%) in 2016, were included in this observational study: Group 1 (Incretin-Mimetic therapy), Group 2 (insulin therapy without Incretin Mimetics) or Group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy, number of hypoglycemic episodes and rehospitalizations 2 years following discharge. In non-responders, the vital status was obtained by local registries 2.4 years after discharge. Results: 204 patients were recruited in this prospective observational study. At discharge, only 3.9% of all type-2 diabetics had an Incretin Mimetic, 39.7% were on insulin, and 56.4% on oral medication. In all patient groups together, the prevalence of Incretin-Mimetic therapy did not change (3.9% at discharge, 2.9% at follow-up). The prevalence of sodium glucose transporter-2–inhibitor therapy slightly increased from 6.8% at discharge to 9.2% at follow-up. However, 85 out of 173 patients (49.1%) did not provide follow-up questionnaires. In hospital mortality (Group 1: 0%, Group 2: 0%, Group 3: 5.2%; p = 0.092), 1-year mortality after discharge ( Group 1: 12.5%, Group 2: 13.6%, Group 3: 11.9%; p = 0.944), and number of rehospitalizations within 12 months after discharge (Group 1: 1.0 per capita, Group 2: 1.0, Group 3: 1.1; p = 0.697) were similar among groups. Hypoglycemic events 6 months prior to follow-up were highest in Group 2 (0.9 ± 2.3) in comparison to Group 1 (0 ± 0) and Group 3 (0.1 ± 0.3; p = 0.017). Conclusion: Even after adjusting for surviving patients not sending back questionnaires, the adherence to the recommendations regarding Incretin-Mimetic and sodium-glucose transporter-2–inhibitor therapy was poor. With the limitation of a low patient number, both 1-year mortality after discharge and rehospitalizations were similar among groups. Self-reported hypoglycemic events occurred more often in insulin-treated diabetics than in the ones without.
Mark Fineman - One of the best experts on this subject based on the ideXlab platform.
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The Incretin Mimetic exenatide as a monotherapy in patients with type 2 diabetes.
Diabetes technology & therapeutics, 2007Co-Authors: Patric Nelson, Xuesong Guan, Matthew Wintle, Catherine A Schnabel, Terri Poon, Mark FinemanAbstract:Background: Exenatide is an adjunctive therapy for type 2 diabetes, and preliminary evidence suggests that its glucoregulatory effects may be similar in the absence of oral therapy. Methods: Study ...
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exenatide augments first and second phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Frauke Fehse, Michael E. Trautmann, Loretta L. Nielsen, Dennis Kim, Mark Fineman, Jens J. Holst, Amy E. Halseth, Nuwan Nanayakkara, Michael A NauckAbstract:Context: First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The Incretin Mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. Objective: The objective of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. Design: Fasted subjects received iv insulin infusion to reach plasma glucose 4.4–5.6 mmol/liter. Subjects received iv exenatide (DM2) or saline (DM2 and healthy volunteers), followed by iv glucose challenge. Patients: Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 ± 7 yr; body mass index, 31.7 ± 2.4 kg/m2; hemoglobin A1c, 6.6 ± 0.7% (mean ± sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls included 12 healthy, weight-matched subjects with normal glucose tolerance: nine males, three females; age, 57 ± 9 yr; and...
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pharmacokinetics of an oral drug acetaminophen administered at various times in relation to subcutaneous injection of exenatide exendin 4 in healthy subjects
The Journal of Clinical Pharmacology, 2005Co-Authors: Erich K Blase, Matthew Wintle, Kristin Taylor, Hongye Gao, Mark FinemanAbstract:Exenatide is an Incretin Mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.
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effects of exenatide exendin 4 on glycemic control and weight over 30 weeks in metformin treated patients with type 2 diabetes
Diabetes Care, 2005Co-Authors: Ralph A. Defronzo, Dennis Kim, Mark Fineman, Robert E Ratner, Jenny Han, Alain D BaronAbstract:OBJECTIVE —This study evaluates the ability of the Incretin Mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS —A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 ± 10 years with BMI of 34.2 ± 5.9 kg/m 2 and HbA 1c of 8.2 ± 1.1%. After 4 weeks of placebo, subjects self-administered 5 μg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 μg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. RESULTS —At week 30, HbA 1c changes from baseline ± SE for each group were −0.78 ± 0.10% (10 μg), −0.40 ± 0.11% (5 μg), and +0.08 ± 0.10% (placebo; intent to treat; adjusted P 1c ≤7% ( P P CONCLUSIONS —Exenatide was generally well tolerated and reduced HbA 1c with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.
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effects of exenatide exendin 4 on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea
Diabetes Care, 2005Co-Authors: David M. Kendall, Mark Fineman, Matthew C. Riddle, Julio Rosenstock, Dongliang Zhuang, Dennis Dong Hwan Kim, Alain D BaronAbstract:OBJECTIVE —This study evaluated the effects of exenatide, a novel Incretin Mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy. RESEARCH DESIGN AND METHODS —A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 ± 10 years, BMI 33.6 ± 5.7 kg/m 2 , A1C 8.5 ± 1.0%; means ± SD) randomized to 5 μg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 μg b.i.d. and arm B escalated to 10 μg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea. RESULTS —Week 30 A1C changes from baseline (±SE) were −0.8 ± 0.1% (10 μg), −0.6 ± 0.1% (5 μg), and +0.2 ± 0.1% (placebo; adjusted P P P ≤ 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 μg), 19% (5 μg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. CONCLUSIONS —Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.
Loretta L. Nielsen - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.
International Journal of Pharmaceutics, 2008Co-Authors: Bronislava Gedulin, Pamela A. Smith, Carolyn M. Jodka, Kim Chen, Sunil Bhavsar, Loretta L. Nielsen, David G. Parkes, Andrew A. YoungAbstract:Exenatide is a 39-amino acid peptide Incretin Mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.
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exenatide effects on diabetes obesity cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years
Current Medical Research and Opinion, 2008Co-Authors: David C Klonoff, Loretta L. Nielsen, John B Buse, Xuesong Guan, Christopher L Bowlus, John H Holcombe, Matthew Wintle, David G MaggsAbstract:ABSTRACTBackground: Exenatide, an Incretin Mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of ≥ 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 µg exenatide, or 10 µg exenatide for 30 weeks, followed by 5 µg exenatide BID for 4 weeks, then 10 µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.Results: 217 patients (64% male, age 58 ± 10 years, weight 99 ± 18 kg, BMI 34 ± 5 kg/m2, A1C 8.2 ± 1.0% [mean ± SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (−1.1 ± 0.1% [mean ± SEM]) were sustained to 3 years (−1.0 ± 0.1%; p < 0.0001), with 46% ac...
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Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes
Journal of the American Board of Family Medicine : JABFM, 2006Co-Authors: Deborah Hinnen, Loretta L. Nielsen, Amy Waninger, Pamela KushnerAbstract:Incretin Mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic several of the actions of Incretin hormones originating in the gut, such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. These agents seem to have multiple mechanisms of action for the treatment of type 2 diabetes mellitus (T2DM), including some or all the following: enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and decreased food intake. Exenatide (BYETTA) is the first Incretin Mimetic approved for clinical use by the US Food and Drug Administration. In phase 3 clinical trials, exenatide reduced HbA(1c) by approximately 1% and body weight by approximately 2 kg in T2DM patients failing to achieve glycemic control with metformin and/or a sulfonylurea, with mild-to-moderate nausea the most common side effect. Several GLP-1 analogues and DPP-IV inhibitors are in late-stage clinical testing and may soon become available for treating T2DM patients. The use of these agents may provide an opportunity to bring about new improvements in diabetes care.
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Incretin Mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. - eScholarship
2006Co-Authors: Deborah Hinnen, Loretta L. Nielsen, Amy Waninger, Pamela KushnerAbstract:Incretin Mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic several of the actions of Incretin hormones originating in the gut, such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. These agents seem to have multiple mechanisms of action for the treatment of type 2 diabetes mellitus (T2DM), including some or all the following: enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and decreased food intake. Exenatide (BYETTA) is the first Incretin Mimetic approved for clinical use by the US Food and Drug Administration. In phase 3 clinical trials, exenatide reduced HbA(1c) by approximately 1% and body weight by approximately 2 kg in T2DM patients failing to achieve glycemic control with metformin and/or a sulfonylurea, with mild-to-moderate nausea the most common side effect. Several GLP-1 analogues and DPP-IV inhibitors are in late-stage clinical testing and may soon become available for treating T2DM patients. The use of these agents may provide an opportunity to bring about new improvements in diabetes care.
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Investigation of exenatide elimination and its in vivo and in vitro degradation.
Current drug metabolism, 2006Co-Authors: Kathrin Copley, Loretta L. Nielsen, Andrew A. Young, Kevin Mccowen, Richard Hiles, David G. ParkesAbstract:Exenatide is a 39 amino acid Incretin Mimetic for the treatment of type 2 diabetes, with glucoregulatory activity similar to glucagon-like peptide-1 (GLP-1). Exenatide is a poor substrate for the major route of GLP-1 degradation by dipeptidyl peptidase-IV, and displays enhanced pharmacokinetics and in vivo potency in rats relative to GLP-1. The kidney appears to be the major route of exenatide elimination in the rat. We further investigated the putative sites of exenatide degradation and excretion, and identified primary degradants. Plasma exenatide concentrations were elevated and sustained in renal-ligated rats, when compared to sham-operated controls. By contrast, exenatide elimination and degradation was not affected in rat models of hepatic dysfunction. In vitro, four primary cleavage sites after amino acids (AA)-15, -21, -22 and -34 were identified when exenatide was degraded by mouse kidney membranes. The primary cleavage sites of exenatide degradation by rat kidney membranes were after AA-14, -15, -21, and -22. In rabbit, monkey, and human, the primary cleavage sites were after AA-21 and -22. Exenatide was almost completely degraded into peptide fragments
Michelle Khai Khun Yap - One of the best experts on this subject based on the ideXlab platform.
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exendin 4 from heloderma suspectum venom from discovery to its latest application as type ii diabetes combatant
Basic & Clinical Pharmacology & Toxicology, 2019Co-Authors: Michelle Khai Khun Yap, Nurhamimah MisuanAbstract:Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and Incretin Mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short Incretin-Mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an Incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.
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Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant
Basic & clinical pharmacology & toxicology, 2018Co-Authors: Michelle Khai Khun Yap, Nurhamimah MisuanAbstract:Type II diabetes mellitus (T2DM) is a chronic non-communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and Incretin Mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin-4 is a short Incretin-Mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon-like peptide 1 (GLP-1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl-peptidase-4 and has a longer half-life than the endogenous GLP-1; thus, it is further developed as an Incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N-terminal domain (NTD) of GLP-1 receptor while the C-terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto-inhibited state of the receptor to its auto-activated state. Exendin-4 enhances the physiological functions of β-cells and the up-regulation of GLP-1 receptors, thus reducing the plasma glucose levels. Moreover, exendin-4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin-4 have also been extrapolated into several clinical trials. Although exendin-4 has a reasonable subcutaneous bioavailability, its half-life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin-4 and the structure-function relationships of exendin-4 with GLP-1 receptor. The review also highlights some challenges and future directions in the improvement of exendin-4 as an anti-diabetic drug.
