Effect of exenatide on splanchnic and peripheral glucose metabolism in type 2 diabetic subjects

Objective: Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). Study Design: Seventeen T2DM patients (44 yr; seven females, 10 males; body mass index = 33.6 kg/m2; glycosylated hemoglobin = 7.9%) received a mixed meal followed for 6 h with double-tracer technique ([1-¹⁴C]glucose orally; [3- ³H]glucose iv) before and after 2 wk of exenatide. In protocol II (n = 5), but not in protocol I (n = 12), exenatide was given in the morning of the repeat meal. Total and oral glucose appearance rates (RaT and RaO, respectively), endogenous glucose production (EGP), splanchnic glucose uptake (75 g - RaO), and hepatic insulin resistance (basal EGP x fasting plasma insulin) were determined. Results: After 2 wk of exenatide (protocol I), fasting plasma glucose decreased (from 10.2 to 7.6 mM) and mean postmeal plasma glucose decreased (from 13.2 to 11.3 mM) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.9 to 10.8 μmol/kg · min, P < 0.05), and hepatic insulin resistance declined (both P < 0.05). RaO, gastric emptying (acetaminophen area under the curve), and splanchnic glucose uptake did not change. In protocol II (exenatide given before repeat meal), fasting plasma glucose decreased (from 11.1 to 8.9 mM) and mean postmeal plasma glucose decreased (from 14.2 to 10.1 mM) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.4 to 10.7 μmol/kg · min, P = 0.05). RaT and RaO decreased markedly from 0-180 min after meal ingestion, consistent with exenatide's action to delay gastric emptying. Conclusions: Exenatide improves 1) fasting hyperglycemia by reducing basal EGP and 2) postmeal hyperglycemia by reducing the appearance of oral glucose in the systemic circulation.