Adapting the GLP-1-Signaling System to the Treatment of Type 2 Diabetes (original) (raw)
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Saudi medical journal, 2005
Glucagon-like peptide GLP-1 is an endogenous insulinotropic/glucagonostatic hormone that acts in a self-limiting mechanism. It is a multifunctional hormone that leads to insulin release stimulation, liver glucagon breakdown suppression, upregulation of islet cell proliferation, and neogenesis and retardation of gastric emptying. The short half-life and high renal clearance due to degradation via dipeptidyl peptidase-IV DPP-IV, and active glomerular filtration rate make this hormone ineffectual as an exogenous agent. More stable and long acting GLP-1 analogues and DPP-1 inhibitors have been developed with promising clinical value for the treatment of type-2 diabetes. The GLP-1 derivatives have the advantage of decreasing body weight while the DPP-IV inhibitors can be administered orally up to once daily. The mechanism of action as well as the tolerable side effect is astounding. This review article covers this new generation of anti-diabetics.
Progress in the Oral Treatment of Type 2 Diabetes: Update on DPP-IV Inhibitors
Current Diabetes Reviews, 2009
Glucagon-like peptide-1 (GLP-1) may contribute to the decreased incretin effect characterizing type 2 diabetes. Multiple actions other than insulin secretion stimulation give to GLP-1 a highly desirable profile for an antidiabetic agent. To overcome the need for continuous infusion of the native compound, which is rapidly degraded by dimetyl peptidil peptidase-IV (DPP-IV), analogues with low affinity for this protease have been developed. A second major strategy is represented by DPP-IV inhibitors that act to increase endogenous GLP-1. On the basis of the promising results in clinical trials, the incretin-based therapy may offer an useful option for diabetes management.
Journal of Postgraduate Medical Institute, 2011
The burden of diabetic patients on healthcare has increased over the period of time. Management of diabetes presents a challenge to the physician. The availability of newer drugs, tested in high quality clinical trials, has marked a new era in the treatment of diabetes. Glucagon-like peptide 1 (GLP-1) analogs act by increasing the pancreatic beta-cell mass and subsequent insulin secretion. Dipeptidase-4 (DPP-4) inhibitors inhibit the enzyme that degrades GLP-1, resulting in the augmentation of GLP-1 in the body. Hence, the two drugs can be used synergistically. It was seen that severe hypoglycemia seldom occurred with GLP-1 analogues and DPP-4 inhibitors. Gastrointestinal upset and the development of antibodies to the drug in the body was mainly attributed to GLP-1 analogs. DPP-4 inhibitors showed increased risk of nasopharyngitis, urinary tract infections and headache. There is a need for further advances in our understanding, through randomized control clinical trials in larger se...
Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived peptide secreted from gut endocrine cells in response to nutrient ingestion. The multifaceted actions of GLP-1 include the following: (1) the stimulation of insulin secretion and of its gene expression, (2) the inhibition of glucagon secretion, (3) the inhibition of food intake, (4) the proliferation and differentiation of beta cells, and (5) the protection of beta-cells from apoptosis. The therapeutic utility of the native GLP-1 molecule is limited by its rapid enzymatic degradation by a serine protease termed dipeptidyl peptidase-IV (DPP-IV). The present article reviews the research studies aimed at elucidating the biosynthesis, metabolism, and molecular characteristics of GLP-1 since it is from these studies that the development of a GLP-1-like pharmacological agent may be derived. Copyright 2005 John Wiley & Sons, Ltd.
GLP-1 based therapy for type 2 diabetes
European Journal of Pharmaceutical Sciences, 2006
Type 2 diabetes GLP-1 DPP-IV Exenatide Vildagliptin a b s t r a c t Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve -cell mass and to prevent loss of -cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.
Journal of Molecular Endocrinology, 2003
Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala 8 -substituted analogues of GLP-1, (Abu 8 )GLP-1 and (Val 8 )GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu 8 )GLP-1 and (Val 8 )GLP-1 exhibited moderate affinities (IC 50 : 4·76 and 81·1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC 50 : 0·37 nM). (Abu 8 )GLP-1 and (Val 8 )GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1·5-and 3·5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val 8 )GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu 8 )GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val 8 )GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala 8 in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val 8 )GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.
Arquivos Brasileiros de Endocrinologia & Metabologia, 2008
The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inh...
Current Opinion in Endocrinology & Diabetes, 2005
Purpose of review Current treatments for type 2 diabetes are effective, but a substantial number of patients continue to have difficulty in achieving and maintaining satisfactory control of blood glucose. The available data suggest that enhancing the action of glucagon-like peptide 1 through the use of glucagon-like peptide 1 receptor agonists, or by preventing the degradation of glucagon-like peptide 1 by inhibition of dipeptidyl peptidase IV, may be useful therapeutic approaches for the treatment of type 2 diabetes. Herein we focus on the status of current approaches, based on enhancement of incretin action, for the treatment of type 2 diabetes. Recent findings Degradation-resistant glucagon-like peptide 1 receptor agonists acutely lower blood glucose in human beings by improvement in b cell function, inhibition of gastric emptying, and reduction of glucagon secretion. Treatment with these agents added to existing diabetes therapies, as exemplified by studies of the injectable glucagon-like peptide 1 receptor agonist exenatide, demonstrates significant reduction in HbA1c, together with prevention of weight gain and, in many individuals, significant weight loss over a 30-week study period. Dipeptidyl peptidase IV inhibitors are orally available effective antidiabetic agents that seem to be well tolerated but may not produce weight loss. Less information is currently available about the consequences of long-term treatment with Dipeptidyl peptidase IV inhibitors. Summary Both glucagon-like peptide 1receptor agonists and dipeptidyl peptidase IV inhibitors represent promising new approaches for the treatment of type 2 diabetes. The long-term safety and efficacy of these agents remain to be determined, but the available evidence suggests that these new drug classes will provide novel therapeutic alternatives for the management of diabetes.
Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1
Diabetes/Metabolism Research and Reviews, 2002
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, that is, inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore, glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. Thus, continuous subcutaneous administration of the peptide for six weeks in patients with rather advanced disease greatly improved glucose profiles and lowered body weight, haemoglobin A 1C , and free fatty acids (FFA). In addition, insulin sensitivity doubled and insulin responses to glucose were greatly improved. There were no side effects. Continuous administration is necessary because of rapid degradation by the enzyme dipeptidyl peptidase-IV. Alternative approaches include the use of analogues that are resistant to the actions of the enzyme, as well as inhibitors of the enzyme. Both approaches have shown remarkable efficacy in both experimental and clinical studies. The GLP-1based therapy of type 2 diabetes, therefore, represents a new and attractive alternative.
The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism
Diabetes, 2004
Glucagon-like peptide (GLP)-1 is a gut hormone that stimulates insulin secretion, gene expression, and -cell growth. Together with the related hormone glucosedependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect, the augmentation of insulin secretion after oral as opposed to intravenous administration of glucose. Type 2 diabetic patients typically have little or no incretin-mediated augmentation of insulin secretion. This is due to decreased secretion of GLP-1 and loss of the insulinotropic effects of GIP. GLP-1, however, retains insulinotropic effects, and the hormone effectively improves metabolism in patients with type 2 diabetes. Continuous subcutaneous administration greatly improved glucose profiles and lowered body weight and HbA 1c levels. Further, free fatty acid levels were lowered, insulin resistance was improved, and -cell performance was greatly improved. The natural peptide is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), but resistant analogs as well as inhibitors of DPP IV are now under development, and both approaches have shown remarkable efficacy in experimental and clinical studies. Diabetes 53 (Suppl. 3):