Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Abstract

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

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

“…Exenatide also reduced total cholesterol and triglycerides in mice; insulin concentrations were also reduced, potentially reflecting an improvement in insulin sensitivity, consistent with observations in other studies. 6,18 Consistent with the improved metabolic profile observed in mice, patients with type 2 diabetes show improvements in cardiovascular risk factors with exenatide treatment, including decreased triglycerides. 48 Potential nonhomeostatic reductions in food intake with exenatide were evaluated in the kaolin consumption and locomotor activity models.…”

“…Although dose dependent, this effect has shown to be durable in normal mice for 24 h. 31 Sustained exenatide exposure produced a persistent reduction in body weight in both mice and rats, with a maximal weight loss at 4 weeks of 16 and 11%, respectively. The demonstrated action of peripheral exenatide to reduce weight in monogenic models of obesity 6,18,27,28 can now be Exenatide reduces body weight in high-fat-fed rats CM Mack et al extended to normal rats consuming an HF diet. Comparing our findings with those from leptin-receptor-deficient models, both ZDF 6 and fa/fa rats 18,27,28 show weight reductions of similar magnitude, suggesting that exenatide effects are mediated via a leptin-independent pathway.…”

“…Unlike GLP-1, exenatide exhibits extended kinetics 5 due to resistance to proteolytic degradation by dipeptidyl peptidase IV (DPPIV), and has up to 3000-fold higher in vivo potency for glucose-lowering in some animal models. 6 Agents that activate the GLP-1 receptor possess high therapeutic potential for the treatment of diabetes; [7][8][9] exenatide is a currently marketed antidiabetic agent that is shown to improve glycemic control in patients with type 2 diabetes. [10][11][12] Glucose-lowering with exenatide, GLP-1 and GLP-1 analogs has been associated with several mechanisms of action, the first of which to be identified was an enhancement of glucose-dependent insulin secretion.…”

“…24 Exenatide reduces food intake in rodents following either central [25][26][27] or peripheral 18,27-31 administration, and repeated or chronic exposure reduces body weight. 6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects. [10][11][12] In preclinical models, body weight reductions with systemic exenatide treatment have been demonstrated in leptinreceptor-deficient rodents under low-fat dietary conditions, 6,18,27,28 and most report single-dose effects.…”

“…6,18,[26][27][28] Recent data from clinical trials have also revealed sustainable weight loss in exenatide-treated type 2 diabetic subjects. [10][11][12] In preclinical models, body weight reductions with systemic exenatide treatment have been demonstrated in leptinreceptor-deficient rodents under low-fat dietary conditions, 6,18,27,28 and most report single-dose effects. One can readily postulate that polygenic models of obesity that mimic human consumption patterns may return a more physiologic picture of potential clinical utility.…”