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/m², Hb A_1c 7.5 ± 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-³H]glucose and oral [1-¹⁴C]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 (∼90 pg/ml) decreased by ∼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 to 189 ± 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 ∼36g in CON to ∼52g in EXE and to ∼60g in E+G (P < 0.001 vs. CON). Acetaminophen(AUC) was reduced by ∼80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by ∼50%) and by slowing gastric emptying.