The effects of glucagon-like peptide-1 on the beta cell

Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based therapies have now been developed: DPP-4 inhibitors and GLP-1 receptor agonists. Liraglutide and exenatide are examples of GLP-1 receptor agonists that have been developed to mimic the insulinotropic characteristics of endogenous GLP-1. Both have demonstrated improved beta-cell function in patients with type 2 diabetes, as assessed by homoeostasis model assessment-B analysis and proinsulin : insulin ratio. Additionally, liraglutide and exenatide are able to enhance first- and second-phase insulin secretion and are able to restore beta-cell sensitivity to glucose. Preclinical studies have shown that both liraglutide and exenatide treatment can increase beta-cell mass, stimulate beta-cell proliferation, increase beta-cell neogenesis and inhibit beta-cell apoptosis. Clinical studies are needed to confirm these findings in humans. Replication of these data in humans could have important clinical implications for the treatment of type 2 diabetes.     

胰高血糖素样肽-1及其类似物的降糖机制

胰高血糖素样肽-1(GLP-1)是由肠道L细胞分泌的肠促胰岛素,对调节机体葡萄糖稳态有重要作用.GLP-1与其受体结合后,促进葡萄糖依赖的胰岛素分泌、胰岛β细胞增殖和分化并抑制其凋亡、延迟胃排空、增加外周组织对胰岛素的敏感性,但不引起体重增加和低血糖,从而保护了胰岛β细胞功能.在疾病早期应用此类药物后,受损的β细胞功能和β细胞数量有逆转的可能.GLP-1及其类似物必将成为治疗糖尿病的一个新亮点.     

Biologic actions and therapeutic potential of the proglucagon-derived peptides

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.     

Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells.     

New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins

Orally ingested glucose leads to a greater insulin response compared to intravenously administered glucose leading to identical postprandial plasma glucose excursions, a phenomenon referred to as the "incretin effect". The incretin effect comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. One of the very important gastrointestinal hormones promoting this effect is glucagon-like peptide 1 (GLP-1). It only stimulates insulin secretion and normalizes blood glucose in humans under hyperglycemic conditions, therefore it does not cause hypoglycemia. Other important physiological actions of GLP-1 are the inhibition of glucagon secretion and gastric emptying. It further acts as a neurotransmitter in the hypothalamus stimulating satiety. In vitro and animal data demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. In humans, the improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity after GLP-1 infusions. GLP-1 represents an attractive therapeutic principle for type 2 diabetes. However, native GLP-1 is degraded rapidly upon exogenous administration and is therefore not feasible for routine therapy. The first long-acting GLP-1 analog ("incretin mimetic") Exenatide (Byetta) has just been approved for type 2 diabetes therapy. Other compounds are being investigated in clinical trials (e.g. liraglutide, CJC1131). Dipeptidyl-peptidase IV inhibitors (DPP-IV inhibitors; e.g. Vildagliptin, Sitagliptin) that inhibit the enzyme responsible for incretin degradation are also under study.     

Glucagon- Like Peptide-1-Based Therapies for the Treatment of Type 2 Diabetes Mellitus

The 'incretin effect' describes the phenomenon of an enhanced insulin response following oral ingestion of glucose compared with that after intravenous administration of glucose, leading to identical postprandial plasma glucose excursions. It accounts for up to 60% of the postprandial insulin secretion, but is diminished in patients with type 2 diabetes mellitus. Gastrointestinal hormones that promote the incretin effect are called incretins. Glucagon-like peptide-1 (GLP-1) is an important incretin. Under hyperglycemic conditions in humans, it stimulates insulin secretion and normalizes blood glucose levels. GLP-1 does not stimulate insulin secretion at normal glucose levels; therefore, it does not cause hypoglycemia. Furthermore, it inhibits glucagon secretion and delays gastric emptying. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting the apoptosis of islet cells. The improvement of beta-cell function due to GLP-1 can be indirectly observed from the increased insulin secretory capacity of humans receiving such treatment. GLP-1 may represent an attractive therapeutic method for patients with type 2 diabetes because of its multiple effects, including the simulation of satiety in the CNS by acting as a transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. liraglutide) and exendin-4 (exenatide) that are resistant to degradation, called 'incretin mimetics', are being investigated in clinical trials. Dipeptidyl peptidase-IV inhibitors (e.g. vildagliptin, sitagliptin, and saxagliptin) that inhibit the enzyme responsible for incretin degradation are also being studied.     

Incretin mimetics and dipeptidyl peptidase-IV inhibitors: a review of emerging therapies for type 2 diabetes

Type 2 diabetes is thought to develop as a result of progressive beta-cell dysfunction in the setting of insulin resistance, leading to increased risks of microvascular and macrovascular complications. Type 2 diabetes is currently treated with diet and exercise, followed by oral drug therapy, and finally exogenous insulin. While this approach is known to improve glycemic control, none of the currently available therapies significantly improve beta-cell function. In addition, this approach does not address defects in hormonal secretion thought to play key roles in the pathophysiology of type 2 diabetes. Type 2 diabetes is characterized by excess glucagon secretion and insufficient secretion of the hormone amylin from the pancreatic beta-cell. In addition, individuals with type 2 diabetes demonstrate insufficient secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Novel therapies that leverage the so-called "incretin effect" of GLP-1 (including the incretin mimetics and dipeptidyl peptidase-IV (DPP-IV) inhibitors) are being actively developed for the management of type 2 diabetes. Incretin mimetics are either derivatives of GLP-1, modified to resist proteolysis, or are novel peptides that share glucoregulatory functions with GLP-1 and are naturally resistant to proteolysis. DPP-IV inhibitors enhance the concentration of endogenous GLP-1 by limiting proteolysis of native GLP-1. With the approval of exenatide- the first "incretin mimetic"-treatment of type 2 diabetes will no doubt be changed. An understanding of the effects of these compounds will be needed to enhance the clinical approach to diabetes treatment.     

Normal secretion and action of the gut incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in young men with low birth weight

CONTEXT: Low birth weight (LBW) is associated with increased risk of type 2 diabetes mellitus. An impaired incretin effect was reported previously in type 2 diabetic patients. OBJECTIVE: We studied the secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in young LBW men (n = 24) and matched normal birth weight controls (NBW) (n = 25). RESULTS: LBW subjects were 5 cm shorter but had a body mass index similar to NBW. LBW subjects had significantly elevated fasting and postprandial plasma glucose, as well as postprandial (standard meal test) plasma insulin and C-peptide concentrations, suggestive of insulin resistance. Insulin secretion in response to changes in glucose concentration ("beta-cell responsiveness") during the meal test was similar in LBW and NBW but inappropriate in LBW relative to insulin sensitivity. Fasting and postprandial plasma GLP-1 and GIP levels were similar in the groups. First- and second-phase insulin responses were similar in LBW and NBW during a hyperglycemic clamp (7 mm) with infusion of GLP-1 or GIP, respectively, demonstrating normal action of these hormones on insulin secretion. CONCLUSION: Reduced secretion or action of GLP-1 or GIP does not explain a relative reduced beta-cell responsiveness to glucose or the slightly elevated plasma glucose concentrations observed in young LBW men.     

Impact of glucagon-like peptide-1 on endothelial function

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety – which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor–dependent and –independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.     

Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function

Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a pro-satiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases beta-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.     

Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass

The "incretin effect" describes the enhanced insulin response from orally ingested glucose compared with intravenous glucose leading to identical postprandial plasma glucose excursions. It makes up to 60% of the postprandial insulin secretion but is diminished in type 2 diabetes. Gastrointestinal hormones promoting the incretin effect are called incretins. Glucagon-like peptide- 1 (GLP-1) is an important incretin. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1 or incretin mimetics that act like GLP-1. Furthermore, GLP-1 inhibits glucagon secretion and rarely causes hypoglycemia. It may represent an attractive therapeutic method for type 2 diabetes because of its multiple effects, including a slowing of gastric emptying and the simulation of satiety by acting as a transmitter in the CNS. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasable for routine therapy. Long-acting GLP-1 analogs (e.g., Liraglutide [Novo Nordisk, Copenhagen, Denmark]) and exenadin-4 (Exenatide [Eli Lilly, Indianapolis, IN]) that are resistant to degradation, called "incretin mimetics," are being investigated in clinical trials. Dipeptidyl peptidase IV inhibitors (e.g., Vildagliptin [Novartis, Basel, Switzerland]) that inhibit the enzyme responsible for incretin degradation are also under study.     

Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 in hibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.     

Incretins and other peptides in the treatment of diabetes.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially,which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However,the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes,and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1.GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion,delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV(DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are underdevelopment. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss.     

Incretins: a new treatment option for type 2 diabetes?

This article describes how the discovery of a protein almost 100 years ago led to a clinical treatment for type 2 diabetes. Food intake, but also stimulation of the sympathetic nervous system (for example physical exercise), stimulates the secretion of glucagon-like-peptide-1 (GLP-1), derived from the glucagon precursor proglucagon in the small intestine. GLP-1 stimulates the production and secretion of insulin, the release of somatostatin, glucose utilisation by increasing insulin sensitivity and in animal studies also beta-cell function and expansion (proliferation). It inhibits glucagon release, gastric emptying, appetite and food intake via the central nervous system and in animal experiments also apoptosis of beta-cells. Since GLP-1 has to be administered parenterally and its half-life is short, a long-acting GLP-1 receptor agonist (exenatide) and a long-acting GLP-1 analogue (liraglutide) have been developed as well as an inhibitor of DPP-IV (the enzyme that breaks down endogenous GLP-1). Clinical studies with exenatide and liraglutide as monotherapy show a significant increase in the postprandial insulin concentration as well as a smaller increase in the postprandial glucose values. Adding these drugs to standard oral glucose-lowering medication shows improvement in glucose and insulin concentrations and HbA1c compared with adding placebo. The effect of exenatide on HbA1c is the same as adding a long-acting insulin analogue (glargine), but the increase in weight after adding insulin is not seen after exenatide, where even a small decrease in weight is found. This is an important advantage, because most type 2 patients are already obese. Whether less beta-cell apoptosis and maintenance of beta-cell function occurs, as has been shown in animal studies, has to be awaited. Clinical studies with the oral DPPIV inhibitors sitagliptin and vildagliptin show promising results, but are only published as abstracts at scientific meetings.     

Harnessing the Therapeutic Potential of Glucagon-Like Peptide-1

Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.     

GLP-1: physiological effects and potential therapeutic applications

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 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 efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.     

Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats

Glucose homeostasis in mammals is maintained by insulin secretion from the beta-cells of the islets of Langerhans. Type 2 diabetes results either from primary beta-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7-36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the beta-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and beta-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pM/kg x min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and beta-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9-39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment. Beta-cell mass increased to 7.2 +/- 0.58 from 4.88 +/- 0.38 mg, treated vs. control, respectively, P < 0.02. Total pancreatic insulin content also increased from 0.55 +/- 0.02 to 1.32 +/- 0.11 microg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and beta-cell differentiation in the pancreas of rodents.     

The incretins: From the concept to their use in the treatment of type 2 diabetes. Part A: Incretins: Concept and physiological functions

This paper briefly reviews the concept of incretins and describes the biological effects of the two incretins identified so far: the glucose-dependent insulinotropic polypeptide (GIP); and the glucagon-like peptide-1 (GLP-1). GIP is released by the K cells of the duodenum, while GLP-1 is released by the L cells of the distal ileum, in response to nutrient absorption. GIP and GLP-1 stimulate insulin biosynthesis and insulin secretion in a glucose-dependent manner. In addition, they increase beta-cell mass. GIP has a specific effect on adipose tissue to facilitate the efficient disposal of absorbed fat and, thus, may be involved in the development of obesity. GLP-1 has specific effects on pancreatic alpha cells, the hypothalamus, and gastrointestinal and cardiovascular systems. By inhibiting glucagon secretion and delaying gastric-emptying, GLP-1 plays an important role in glucose homoeostasis and, by inhibiting food intake, prevents the increase in body weight. As the metabolic effects of GIP are blunted in type 2 diabetes, this peptide cannot be used as an efficient therapy for diabetes. In contrast, GLP-1 effects are preserved at high concentrations in type 2 diabetes, making this peptide of great interest for the treatment of diabetes, a topic that will be discussed in the second part of this review.     

Beyond glycemic control: the effects of incretin hormones in type 2 diabetes

The improved understanding of glucoregulatory hormones has driven the development of new pharmacologic agents to treat type 2 diabetes. One new class of antihyperglycemic medication is incretin mimetics (IMs). Incretin hormones potentiate insulin secretion following meal ingestion, a process that is impaired in patients with type 2 diabetes. GLP-1, a 30-amino acid peptide incretin hormone, is produced in the L cells of the ileum and colon. Studies have shown that a 6-week continuous GLP-1 infusion in patients with type 2 diabetes improved glycemic control and beta-cell function and delayed gastric emptying. Despite the rapid degradation and inactivation of GLP-1 by the enzyme dipeptidyl peptidase IV (DPP-IV), agents that mimic the actions of GLP-1 are of great clinical interest. First-in-class IM exenatide, a GLP-1 receptor agonist resistant to DPP-IV inactivation, mimics many beneficial glucoregulatory effects of GLP-1, such as suppressing glucagon secretion, regulating gastric emptying and satiety, and increasing glucose-dependent insulin secretion. Exenatide is an adjunctive therapy for patients who take metformin, a sulfonylurea, a thiazolidinedione, or a combination of these oral medications but have not achieved glycemic control. An 82-week, open-label extension trial has shown that exenatide is well tolerated and that the benefits, including improved glycemic control, weight loss, and mitigation of cardiovascular risk factors, are sustained.