Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m(2), Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique iv [3-H-3] glucose and oral [1-C-14] glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E + G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E + G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon (similar to 90 pg/ml) decreased by similar to 20% to 73 +/- 4 pg/ml in EXE P < 0.01) and was not different from CON in E + G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E + G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from similar to 36g in CON to similar to 52g in EXE and to similar to 60g in E + G (P < 0.001 vs. CON). Acetaminophen(AUC) was reduced by similar to 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by similar to 50%) and by slowing gastric emptying.