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

Abstract

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/m2; hemoglobin A1c, 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/m2.

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 first-phase 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-treated DM2 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.