Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes

Abstract

Despite the advent of new treatments, glucose control in the type 2 diabetes population is unsatisfactory. AC2993 (synthetic exendin-4; exenatide), a novel glucose-dependent insulinotropic agent, exhibited notable antidiabetic potential in two clinical studies in patients with type 2 diabetes. In study A, 24 subjects received sc injections of study medication (0.1 micro g/kg AC2993 or placebo) twice daily with meals for 5 d. Statistically significant reductions in mean postprandial circulating concentrations of glucose, insulin, and glucagon occurred following treatment with AC2993. In study B, 13 subjects receiving a single dose of study medication (0.05, 0.1, or 0.2 micro g/kg AC2993 or placebo) following an overnight fast had reduced fasting plasma glucose concentrations during the subsequent 8-h period. The relative glucose and insulin concentration profiles were consistent with glucose-dependent insulinotropism. AC2993 was well tolerated. Mild transient headache, nausea, and vomiting were the main adverse events. In conclusion, AC2993 acutely and markedly reduces fasting and postprandial glucose concentrations in patients with type 2 diabetes. During fasting, glucose-dependent enhancement of insulin secretion and suppression of glucagon secretion are the predominant mechanisms, and postprandially, slowing of gastric emptying is additionally operative. This robust antidiabetic effect warrants further evaluation of AC2993.

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

“…13,14 The principal result of this insulinotropic effect is an acceleration of glucose disappearance into peripheral tissues. Exenatide additionally limits glucose appearance via glucose-dependent slowing of gastric emptying 15,16 and suppression of inappropriately elevated postprandial glucagon secretion. [15][16][17] More recently, exenatide has been found to promote pancreatic b-cell proliferation and islet cell neogenesis in both animal and in vitro studies.…”

“…Exenatide additionally limits glucose appearance via glucose-dependent slowing of gastric emptying 15,16 and suppression of inappropriately elevated postprandial glucagon secretion. [15][16][17] More recently, exenatide has been found to promote pancreatic b-cell proliferation and islet cell neogenesis in both animal and in vitro studies. 18,19 In addition to its role in glycemic control, GLP-1 is a shortterm regulator of food intake, [20][21][22] an effect mediated via central GLP-1 receptors.…”

Use of glucagon‐like peptide‐1 receptor agonists among individuals on basal insulin requiring treatment intensification

“…While both basal insulin and incretin therapies effectively reduce fasting glucose levels, incretin therapies also reduce PPG 17 and glucagon 18. Studies in patients with Type 1 diabetes have shown that GLP‐1RAs can improve glycaemic control even among those with little to no β‐cell function, suggesting that glucagon control may be particularly influential in those with long‐term Type 2 diabetes 19.…”

The therapeutic actions of DPP-IV inhibition are not mediated by glucagon-like peptide-1

“…This is also true for other incretin mimetics, such as exenatide [17] and liraglutide [18]. It should be noted that a decrease in the rate of gastric emptying has not been observed in clinical studies on DPP-IV inhibitors [19].…”

“…GLP-1 has glucose-lowering effects, both during and after its administration [1], as do incretin mimetics such as exenatide and liraglutide [17,18]. Based on the assumption that the effects of DPP-IV inhibition are mediated by GLP-1, one might expect that the maximum clinical effectiveness of inhibition would be reached within a few hours.…”