Mathematical modeling shows exenatide improved β-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin a sulfonylurea. We assessed postprandial p-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63 % males, 55 10 years, BMI 33 6 kg/m(2), HbAlc 8.1 +/- 1.1 % ( +/- SD) randomized to 5 mu g exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 mu g twice daily, one arm escalated to 10 mu g twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n = 73). Outcome measures were the model-based P-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced post-prandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72 % (10 mu g), increased 40 % (5 mu g), or decreased 21 % (placebo) at week 30 [p = 0.015 (10 mu g); p = 0.045 (5 mu g); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53 +/- 0.10 (10 mu g; p=0.0142 vs. placebo) or 1.40 +/- 0.08 (5 mu g; p = 0.0402 vs. placebo) compared with 1.15 +/- 0.06 (placebo). Exenatide caused an upward shift of the P-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved p-cell function in patients with type 2 diabetes treated with metformin a sulfonylurea.