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

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 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 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, therefore, appears very promising.     

Gut peptides in the treatment of diabetes mellitus

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPPIV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.     

Gut peptides in the treatment of diabetes mellitus

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.     

Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus

The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucosedependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies -- including the newly approved incretin mimetic exenatide -- that elicit actions similar to those of GLP-1.     

Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is a peptide hormone released from the gut mucosa in response to meal ingestion. Its actions include stimulation of all steps of insulin gene expression, as well as β-cell growth, inhibition of glucagon secretion, inhibition of hepatic glucose production, inhibition of gastrointestinal secretion and motility, and inhibition of appetite and food intake. Physiologically, therefore, GLP-1 is thought to act as an incretin hormone (intestinal hormones that enhance meal-related insulin secretion) and as one of the hormones of the ileal brake mechanism (endocrine 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.     

Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is a peptide hormone released from the gut mucosa in response to meal ingestion. Its actions include stimulation of all steps of insulin gene expression, as well as beta-cell growth, inhibition of glucagon secretion, inhibition of hepatic glucose production, inhibition of gastrointestinal secretion and motility, and inhibition of appetite and food intake. Physiologically, therefore, GLP-1 is thought to act as an incretin hormone (intestinal hormones that enhance meal-related insulin secretion) and as one of the hormones of the ileal brake mechanism (endocrine 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.     

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.     

Incretins and their analogues as new antidiabetic drugs

Glucagon-like peptide 1 (GLP-1) is a gut (incretin) hormone with multiple actions that could potentially contribute to an antidiabetic effect. This includes: (a) glucose-dependent insulinotropic actions; (b) glucagonostatic actions; (c) a reduction in appetite/promotion of satiety leading to reduced food intake and weight reduction; (d) the deceleration of gastric emptying; and (e) the stimulation of islet growth, differentiation and regeneration. Thus, multiple aspects of the type 2 diabetic phenotype can potentially be improved or even corrected by GLP-1. The native gut hormone, however, after intravenous injection or absorption from subcutaneous depots, is proteolytically degraded and eliminated from the circulation too quickly to be useful for the treatment of diabetes. GLP-1 derivatives (receptor agonists) with prolonged pharmacokinetics that promise a potential for clinical use in the near future are being developed.     

(d-Ser)Oxm[mPEG-PAL]: A novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions

Oxyntomodulin (Oxm) is a hormone which has been shown to exhibit a range of potentially beneficial actions for alleviation of obesity-diabetes. However, exploitation of Oxm-based therapies has been severely restricted due to degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV). Thus, the aim of this study was to assess the glucose-lowering, insulin-releasing and anorexigenic actions of chemically modified, enzyme-resistant analogues of Oxm. Oxm, (d-Ser²)Oxm and (d-Ser²)Oxm[mPEG-PAL], were incubated with DPP-IV to assess enzyme stability and pancreatic beta-cells to evaluate insulin secretion. cAMP production was assessed using glucagon-like peptide-1 (GLP-1) and glucagon receptor transfected cells. In vivo effects of Oxm analogues on glucose homeostasis, insulin secretion, food intake and bodyweight were examined in obese diabetic (ob/ob) mice. (d-Ser²)Oxm[mPEG-PAL] displayed enhanced DPP-IV resistance compared to (d-Ser²)Oxm and Oxm. All peptides demonstrated similar in vitro cAMP and insulin-releasing actions, which was associated with dual action at GLP-1 and glucagon receptors. Acute administration of (d-Ser²)Oxm[mPEG-PAL] and (d-Ser²)Oxm reduced plasma glucose and food intake, whilst plasma insulin levels were elevated. Once-daily administration of (d-Ser²)Oxm[mPEG-PAL] for 14 days to ob/ob mice decreased food intake, bodyweight, plasma glucose and increased plasma insulin. Furthermore, daily (d-Ser²)Oxm[mPEG-PAL] improved glucose tolerance, increased glucose-mediated insulin secretion, pancreatic insulin content, adiponectin and decreased both visfatin and triglyceride levels. The ability of enzyme-resistant (d-Ser²)Oxm[mPEG-PAL] to improve glucose homeostasis, insulin secretion, satiety, bodyweight and markers of fat metabolism suggests significant promise for Oxm-based therapies for obesity-diabetes.     

Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents

Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.     

Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.     

The potential role of glucagon-like peptide 1 in diabetes

The incretin hormone glucagon-like peptide 1 (GLP-1) has a promising potential for the treatment of type 2 diabetes due to its glucose-dependent insulinotropic and glucagonostatic properties. In addition, the peptide potently decelerates gastric emptying and inhibits appetite, thereby leading to reduced food intake. In animal studies, GLP-1 has been demonstrated to increase B-cell mass via inhibition of apoptosis and stimulation of B-cell replication and neogenesis. However, an in vivo half-life in the range of minutes limits the therapeutic use of the native peptide GLP-1. Different pharmacological approaches to overcome these problems are currently being evaluated. They include the continuous parenteral administration of the peptide via infusion pumps, the inhibition of its in vivo degradation and the generation or use of modified derivatives/analogs of GLP-1 displaying prolonged biological activity. The physiological effects of GLP-1 and its pharmacokinetic limitations will be reviewed here, and the current therapeutic approaches based on GLP-1 discussed.     

GLP-1 – Incretin and pleiotropic hormone with pharmacotherapy potential. Increasing secretion of endogenous GLP-1 for diabetes and obesity therapy

Because of the beneficial actions of the hormone glucagon-like peptide-1 on glucose metabolism and appetite, food intake and eventually body weight, and because of the observation that the similar metabolic effects of gastric bypass surgery are associated with excessive secretion of GLP-1, attempts are now being made to stimulate the endogenous secretion of this hormone. By targeting the natural cellular origin of GLP-1 it is anticipated that also the physiological pathways of hormone action (which may include neural mechanisms) would be engaged, which might generate fewer side effects. In addition, release of other products of the responsible intestinal endocrine cells, the L-cells, namely the appetite inhibitory hormone, PYY 3–36, and the dual glucagon-GLP-1 co-agonist, oxyntomodulin, would also be promoted. Here, the normal mechanisms for stimulation of L-cell secretion are reviewed, and the potential of identified secretagogues is discussed. Paracrine regulation of L-cell secretion is also discussed and the potential of somatostatin receptor antagonists is emphasized. A therapeutic approach based on stimulation of endogenous secretion of GLP-1/PYY still seems both attractive and potentially feasible.     

Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic β-cells, but also suppresses glucagon secretion from pancreatic α-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes.     

GLP-2的生物学作用的研究进展

胰高血糖素样肽-2(glucagon-like peptide-2,GLP-2)是胰高血糖素原基因转录、翻译后处理加工的33个氨基酸的多肽。GLP-2是新近发现的肠上皮特异性生长因子,对胃肠道有多方面的作用,包括促进正常小肠的生长和发育,保护和修复各种肠道疾病中损伤的肠粘膜,抑制胃酸的分泌和胃肠的运动,增加肠道的血液供应等。GLP-2通过作用于特异性G蛋白偶联受体(GLP-2受体)来保护肠道细胞。该文全面概括了GLP-2的生理、药理、治疗作用和GLP-2受体信号转导机制,重点讨论了GLP-2最新的研究进展。     

Replacing SUs with incretin-based therapies for type 2 diabetes mellitus: challenges and feasibility

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by insulin resistance, a steady decline in glucose-induced insulin secretion (most likely caused by a progressive decrease in functional beta-cell mass), and inappropriately regulated glucagon secretion; in combination, these effects result in hyperglycemia. In 1958, sulfonylurea (SU) was introduced to the market as one of the first oral treatments for T2DM. Since then, the ability of SU to stimulate the release of insulin from pancreatic beta-cells by the closure of ATP-sensitive K+-channels has been employed as one of the most widespread treatment options for T2DM. However, SUs are associated with weight gain and a risk of hypoglycemia, and the one-track antidiabetic mechanism of SUs often results in patients being treated with additional antidiabetic drugs. In recent studies, SU has proven to be associated with increased beta-cell apoptosis, suggesting that SU may actually accelerate the progressive decrease in beta-cell mass, thereby promoting the need for insulin replacement. In contrast, the newly developed incretin-based therapies for T2DM employ the beta-cell-preserving properties of incretin hormones - glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). More importantly, incretin-based therapies potentiate glucose-stimulated insulin secretion and may restore reduced glucose-induced insulin secretion in T2DM. Furthermore, the insulinotropic effects of GLP-1 and GIP are glucose-dependent, reducing the risk of hypoglycemia. GLP-1 inhibits glucagon secretion and decreases gastrointestinal motility, in turn reducing food intake and body weight. This feature review focuses on the challenges and feasibilities of replacing SU with incretin-based therapy in patients with T2DM.     

The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management

The incretin effect is a phenomenon in which enteral glucose administration provokes greater insulin secretion than intravenous administration. The main incretins, glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1 are defective in Type 2 diabetes; whereas glucose-dependent insulinotropic peptide displays diminished effectiveness, GLP-1 secretion is decreased; thus, GLP-1 was a stronger candidate for a new class of anti-diabetic agents designed to potentiate the incretin effect. In the past decade, GLP-1 mimetics, peptidase inhibitors and GLP-1 have been developed. Early randomised trials show that these agents contribute to glucose homeostasis and enhance beta-cell function, without causing hypoglycaemia or weight gain. This review includes an historical perspective, physiology of incretins, and discussions of the pathophysiology in Type 2 diabetes, pharmacology of the main agents and randomised clinical trials published to date.     

The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management

The incretin effect is a phenomenon in which enteral glucose administration provokes greater insulin secretion than intravenous administration. The main incretins, glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1 are defective in Type 2 diabetes; whereas glucose-dependent insulinotropic peptide displays diminished effectiveness, GLP-1 secretion is decreased; thus, GLP-1 was a stronger candidate for a new class of anti-diabetic agents designed to potentiate the incretin effect. In the past decade, GLP-1 mimetics, peptidase inhibitors and GLP-1 have been developed. Early randomised trials show that these agents contribute to glucose homeostasis and enhance β-cell function, without causing hypoglycaemia or weight gain. This review includes an historical perspective, physiology of incretins, and discussions of the pathophysiology in Type 2 diabetes, pharmacology of the main agents and randomised clinical trials published to date.     

Glucagon and glucagon-like peptide receptors as drug targets

Glucagon and the glucagon-like peptides are derived from a common proglucagon precursor, and regulate energy homeostasis through interaction with a family of distinct G protein coupled receptors. Three proglucagon-derived peptides, glucagon, GLP-1, and GLP-2, play important roles in energy intake, absorption, and disposal, as elucidated through studies utilizing peptide antagonists and receptor knockout mice. The essential role of glucagon in the control of hepatic glucose production, taken together with data from studies employing glucagon antagonists, glucagon receptor antisense oligonucleotides, and glucagon receptor knockout mice, suggest that reducing glucagon action may be a useful strategy for the treatment of type 2 diabetes. GLP-1 secreted from gut endocrine cells controls glucose homeostasis through glucose-dependent enhancement of beta-cell function and reduction of glucagon secretion and gastric emptying. GLP-1 administration is also associated with reduction of food intake, prevention of weight gain, and expansion of beta-cell mass through stimulation of beta-cell proliferation, and prevention of apoptosis. GLP-1R agonists, as well as enzyme inhibitors that prevent GLP-1 degradation, are in late stage clinical trials for the treatment of type 2 diabetes. Exenatide (Exendin-4) has been approved for the treatment of type 2 diabetes in the United States in April 2005. GLP-2 promotes energy absorption, inhibits gastric acid secretion and gut motility, and preserves mucosal epithelial integrity through enhancement of crypt cell proliferation and reduction of epithelial apoptosis. A GLP-2R agonist is being evaluated in clinical trials for the treatment of inflammatory bowel disease and short bowel syndrome. Taken together, the separate receptors for glucagon, GLP-1, and GLP-2 represent important targets for developing novel therapeutic agents for the treatment of disorders of energy homeostasis.     

Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus: focus on bile acid sequestrants

Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic β-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) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. 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 to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.