Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß-cell function in nondiabetic, morbidly obese patients

Aims: To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis, and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. Materials and methods: Patients were assigned to exenatide 10 µg twice daily (EXE, n=15) or control (CT, n=15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS). Results: Post-treatment the EXE group showed a significant reduction in body weight (p<0.001). The postmeal time-course of glucose, insulin, and ISR showed a lower peak between 60-180 min in phase with a reduction in RaO (p<0.01). After an initial similar suppression, EGP resumed at higher rates between 60-180 min (p=0.02) in EXE vs CT, while total RaO and EGP throughout the MTT were similar. In EXE, the postmeal glucagon, GLP1, and GIP responses were reduced (p<0.05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR, and IS were all improved after exenatide treatment (p<0.05). Conclusions: In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement of hepatic, adipose tissue, and whole body insulin sensitivity with no influence on post-prandial lipolysis.