The effect of chronic twice daily exenatide treatment on β-cell function in new onset type 2 diabetes.

OBJECTIVE: To determine the effect of chronic daily exenatide treatment on β-cell function in type 2 diabetes (T2DM). BACKGROUND: Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on β-cell function can be difficult to discern by conventional measures. DESIGN: Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-μg twice daily, or placebo. All subjects had oral glucose tolerance tests (OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates (ISR), peripheral insulin sensitivity (OGIS) and hepatic insulin resistance index (Hep-IR) were calculated. RESULTS: During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in β-cell sensitivity to glucose. CONCLUSIONS: These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased β-cell sensitivity to glucose. These improvements in β-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for.