Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control

Destruction and dysfunction of pancreatic beta-cells, resulting in absolute and relative insulin deficiency, represent key abnormalities in the pathogenesis of type 1 and type 2 diabetes, respectively. Following the discovery of amylin, a second beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli, it was realized that diabetes represents a state of bihormonal beta cell deficiency and that lack of amylin action may contribute to abnormal glucose homeostasis. Experimental studies show that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects. These include a suppression of postprandial glucagon secretion and a vagus-mediated regulation of gastric emptying, thereby helping to control the influx of endogenous and exogenous glucose, respectively. In animal studies, amylin has also been shown to reduce food intake and body weight, consistent with an additional satiety effect. Pramlintide is a soluble, non-aggregating, injectable, synthetic analog of human amylin currently under development for the treatment of type 1 and insulin-using type 2 diabetes. Long-term clinical studies have consistently demonstrated that pre-prandial s.c. injections of pramlintide, in addition to the current insulin regimen, reduce HbA(1c) and body weight in type 1 and type 2 diabetic patients, without an increase in insulin use or in the event rate of severe hypoglycemia. The most commonly observed side effects were gastrointestinal-related, mainly mild nausea, which typically occurred upon initiation of treatment and resolved within days or weeks. Amylin replacement with pramlintide as an adjunct to insulin therapy is a novel physiological approach toward improved long-term glycemic and weight control in patients with type 1 and type 2 diabetes.     

Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus

As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged-the dipeptidyl peptidase IV (DPP-IV) inhibitors. Unlike conventional oral antidiabetic agents, these agents promote glucose homeostasis through inhibition of DPP-IV, the enzyme responsible for degradation of two key glucoregulatory hormones: glucagon-like peptide-1 (GLP-1), which extends the action of insulin while also suppressing the release of glucagon, and glucose-dependent insulinotropic peptide (GIP). Other proposed mechanisms of action of GLP-1 and thus DPP-IV inhibitors include satiety, increased beta-cell production, and inhibition of apoptosis of beta cells. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying, and stimulate insulin release. The DPP-IV inhibitors appear to have excellent therapeutic potential in the management of type 2 diabetes as monotherapy or in combination with existing agents, such as metformin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with sustainable reductions in glycosylated hemoglobin levels and relatively few adverse effects. Their distinctive mechanism of action and adverse-event profiles may offer advantages over existing therapies, including low risk for hypoglycemia and possible augmentation of pancreatic beta-cell regeneration.     

Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes

Type 2 diabetes is a chronic metabolic disease characterized by the presence of both fasting and postprandial hyperglycemia which is a result of pancreas beta-cell dysfunction, deficiency in insulin secretion, insulin resistance and/or increased hepatic glucose production. More recently, the role of other glucoregulatory hormones, including glucagon, amylin, and the gut peptide glucagon-like peptide (GLP)-1, and an increase in the rate of postmeal carbohydrate absorption have also been included as important pathophysiologic defects. Existing anti-diabetes medications are often unefficient at achieving sustained glycemic control because they predominantly address only a single underlying defect. A number of alternative therapies for type 2 diabetes are currently under development that take advantage of the actions of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide on the pancreatic beta-cell. One such approach is based on the inhibition of dipeptidyl peptidase IV (DPP-IV), the major enzyme responsible for degrading the incretins in vivo. DPP-IV exhibits characteristics that have allowed the development of specific inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes and type 2 diabetic patients. While enhancement of insulin secretion, resulting from blockade of incretin degradation, has been proposed to be the major mode of inhibitor action, there is also evidence that inhibition of gastric emptying, reduction in glucagon secretion, peripheral insulin sensitization and important effects on beta-cell differentiation and survival can potentially preserve beta-cell mass, and improve insulin secretory function and glucose handling in diabetic patients. The present article focuses on the preclinical and clinical data of DPP-IV inhibitors that make it unique therapeutic agents representing the next generation of antidiabetes drugs.     

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.     

降糖药利拉鲁肽及其临床评价

利拉鲁肽(Iiraglutide)是新一代以肠促胰素为基础的降糖药,具有良好的降糖效果,无论单独应用还是与其他口服降糖药联用,均能迅速、高效地降低血糖和糖化血红蛋白(HbA1c)水平.其降糖作用依赖于葡萄糖浓度,即仅在血糖水平升高时刺激胰岛素释放达到治疗效果,因此发生低血糖的概率非常低.此外,利拉鲁肽能改善B细胞功能,降低血压,延缓糖尿病进展,减低糖尿病心血管并发症危险.与其他大多数降糖药相比,利拉鲁肽能帮助患者减轻体重.利拉鲁肽具有超越现有糖尿病治疗药物的多种特点.     

The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide

Background:

Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared.

Data sources:

Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles.

Findings:

Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size.

Conclusions:

Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.     

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.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive beta-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive beta-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in beta-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with 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.     

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.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes

Sitagliptin, a novel orally-active dipeptidyl-peptidase (DPP-4) inhibitor has been introduced into type 2 diabetes therapy. Sitagliptin inhibits the degradation of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as that of other regulatory peptides important for glucose homeostasis. It reduces haemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose- dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause hypoglycemia when compared to metformin or placebo. Metformin, which has a different unique mechanism, has been used in type 2 diabetes for approximately 50 years. Metformin improves insulin resistance and is the first-line antidiabetic drug in use today. The combination of a DPP-4 inhibitor with metformin allows a broad and complementary spectrum of antidiabetic actions. This combination does not increase the risk of hypoglycaemia nor does it promote weight gain, an adverse effect of various other oral antidiabetic combinations. This article gives an overview of the data available on the combined antidiabetic effects of metformin and sitagliptin.     

Defining the role of insulin lispro in the management of postprandial hyperglycaemia in patients with type 2 diabetes mellitus

The role of postprandial hyperglycaemia in contributing to the risk of both micro- and macrovascular complications in patients with diabetes mellitus is being increasingly recognized. In type 2 diabetes, there is a progressive shift in the relative contributions of postprandial and fasting hyperglycaemia to the overall glycaemic control as the disease progresses. For patients with fairly good glycaemic control (glycosylated haemoglobin [HbA(1c)] <8.5%), postprandial hyperglycaemia makes a relatively greater contribution to the overall glycaemic load than fasting hyperglycaemia, but in patients with poorer control, the relative contribution of the two states to the overall glycaemic load is reversed. This finding, coupled with epidemiological evidence that elevated postprandial glucose concentration is an independent risk factor for cardiovascular disease (CVD), and is associated with a greater CVD risk than elevated fasting glucose, points to the need to monitor and target postprandial glucose, as well as fasting glucose and HbA(1c) levels, when optimizing insulin therapy for patients with type 2 diabetes. When insulin therapy becomes necessary in patients with type 2 diabetes who can no longer be controlled with oral antihyperglycaemic therapy, use of short-acting insulin analogues with a rapid onset of action and capable of controlling postprandial glycaemic excursions when injected immediately before a meal, has advantages over regular human insulin in that they provide a more favourable time-action profile that mimics normal physiological insulin secretion. Among the available rapid-acting insulin analogues, insulin lispro has been shown to reduce postprandial glucose concentrations to a significantly greater degree than regular human insulin in patients with type 2 diabetes. Moreover, premixed combinations of insulin lispro with the longer acting analogue neutral insulin lispro protamine suspension in 25% : 75% or 50% : 50% combinations are significantly more effective in lowering postprandial blood glucose concentrations than premixed regular human insulin plus neutral protamine Hagedorn (NPH) 30% : 70%. The premixed insulin lispro combinations offer the advantage of fewer daily injections than intensive insulin therapy, and the convenience of not having to mix insulin preparations manually. Although it has yet to be conclusively established that targeting postprandial hyperglycaemia reduces CVD risk, the potential benefits of improved postprandial and interprandial hyperglycaemia favour the use of newer insulin analogues, such as insulin lispro and insulin lispro mixes, over conventional insulin therapy, whenever insulin therapy becomes necessary in patients with type 2 diabetes.     

Exenatide

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.     

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.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control.

Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized.

Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice

We explored whether inhibition of the enzyme dipeptidyl peptidase IV (DPP IV) increases endogenous levels of glucagon-like peptide-1 (GLP-1) and improves glucose tolerance and insulin secretion in mice. Glucose (150 mg) was administered through a gastric gavage with or without the inhibitor of dipeptidyl peptidase IV, valine-pyrrolidide (100 micromol/kg), in high-fat fed glucose intolerant or control C57BL/6J mice. The increase in plasma GLP-1 after gastric glucose was potentiated by dipeptidyl peptidase IV inhibition (P<0.05). Valine-pyrrolidide also potentiated the plasma insulin response to gastric glucose and improved the glucose tolerance in both groups of mice (P<0.001). In contrast, valine-pyrrolidide did not affect glucose-stimulated insulin secretion from isolated islets. This suggests that valine-pyrrolidide improves insulin secretion and glucose tolerance through indirect action, probably through augmentation of levels of GLP-1 and other incretin hormones. Therefore, inhibition of dipeptidyl peptidase IV activity is feasible to exploit as a treatment for glucose intolerance and type 2 diabetes.     

Targeting beta-cell cyclic 3'5' adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review

Cyclic 3'5'AMP is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet beta-cell, where it is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). These hormones are secreted from the small intestine during and following a meal, and are important in producing a full insulin secretory response to nutrient stimuli. Cyclic AMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet beta-cell differentiation, growth and survival. Cyclic AMP (cAMP) itself is rapidly degraded in the pancreatic islet beta-cell by cyclic nucleotide phosphodiesterase (PDE) enzymes. This review discusses the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired. This could be achieved by the use of GLP-1 or GIP to elevate cAMP in the pancreatic islet beta-cell. However, these peptides are normally rapidly degraded by dipeptidyl peptidase IV (DPP IV). Thus longer-acting analogues of GLP-1 and GIP, resistant to enzymic degradation, and orally active inhibitors of DPP IV have also been developed, and these agents were found to improve metabolic control in experimentally diabetic animals and in patients with type 2 diabetes. The use of selective inhibitors of type 3 phosphodiesterase (PDE3B), which is probably the important pancreatic islet beta-cell PDE isoform, would require their targeting to the islet beta-cell, because inhibition of PDE3B in adipocytes and hepatocytes would induce insulin resistance.     

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

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