Exenatide can reduce glucose independent of islet hormones or gastric emptying

Abstract

Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 microg sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = +526 +/- 315 and -536 +/- 197 mg.dl(-1).min(-1) with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 +/- 1 vs. 97 +/- 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 +/- 3 and 92 +/- 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.

Fig. 1.

Glucose (A), insulin (B), glucagon (C), and acetaminophen (D) plasma concentrations (left) and area under the curve (AUC, right) during meal test with exenatide (EX; ▪, solid bars) or without exenatide (□, open bars). *P < 0.05.

Fig. 2.

Glucose (A), insulin (B), and glucagon (C) plasma concentrations (left) and 0- to 240-min AUC (right) during intraportal glucose infusion with exenatide (•, solid bars) or without exenatide (○, open bars). ***P < 0.001.

Fig. 3.

A: peripheral glycemia during exenatide (□), exenatide + antagonist (•), or saline (▴) infusion. For exenatide + antagonist, solid horizontal bar (−15 to 60 min) indicates antagonist exendin-(9-39) infusion, which was stopped at 60 min. B: glucose AUC during exenatide (solid bars) or exenatide + antagonist (gray bars) infusion from −15 to 60 min in the presence of antagonist (left) or from 60–240 min without antagonist (right). *P < 0.05.

Fig. 4.

Insulin (A), C-peptide (B), and glucagon (C) AUC during exenatide (solid bars) or exenatide + antagonist (gray bars) infusion from −15 to 60 min in the presence of antagonist (left) or from 60 to 240 min without antagonist (right).