Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes

Context: First- phase insulin secretion ( within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus ( DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose- dependent enhancement of insulin secretion. Objective: The objective of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. Design: Fasted subjects received iv insulin infusion to reach plasma glucose 4.4 - 5.6 mmol/ liter. Subjects received iv exenatide ( DM2) or saline ( DM2 and healthy volunteers), followed by iv glucose challenge. Patients: Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/ m(2); hemoglobin A(1c), 6.6 +/- 0.7% ( mean +/- SD) treated with diet/ exercise ( n = 1), metformin ( n = 10), or acarbose ( n = 2). Controls included 12 healthy, weight- matched subjects with normal glucose tolerance: nine males, three females; age, 57 +/- 9 yr; and body mass index, 32.0 +/- 3.0 kg/ m(2). Setting: The study was conducted at an academic hospital. Main Outcome Measures: Plasma insulin, plasma C- peptide, insulin secretion rate ( derived by deconvolution), and plasma glucagon were the main outcome measures. Results: DM2 subjects administered saline had diminished firstphase insulin secretion, compared with healthy control subjects. Exenatide-treated DM2 subjects had an insulin secretory pattern similar to healthy subjects in both first ( 0 - 10 min) and second ( 10 - 180 min) phases after glucose challenge, in contrast to saline- treatedDM2 subjects. In exenatide- treated DM2 subjects, the most common adverse event was moderate nausea ( two of 13 subjects). Conclusions: Short- term exposure to exenatide can restore the insulin secretory pattern in response to acute rises in glucose concentrations in DM2 patients who, in the absence of exenatide, do not display a first phase of insulin secretion. Loss of first- phase insulin secretion in DM2 patients may be restored by treatment with exenatide.