Synergistic Effects of Nateglinide and Meal Administration on Insulin Secretion in Patients with Type 2 Diabetes Mellitus

This study assessed the synergistic effects of nateglinide (a nonsulfonylurea d-phenylalanine derivative) and meals on insulin secretion in 24 patients with type 2 diabetes. Oral doses of 60 and 180 mg or 120 and 240 mg were administered to two cohorts of subjects 10 min before meals (or fasting) three times daily for 7 days, with washout intervals between treatment periods. Dose-dependent increases in plasma insulin occurred, with the peak effect within 2 h after treatment. Significantly greater insulin secretion was observed when nateglinide was taken before a meal compared to nateglinide given in the fasted state or in response to just the meal. Nateglinide lowered plasma glucose concentrations significantly vs. placebo at all doses, and doses of 120 and 240 mg were more effective than 60 mg (P < 0.05). Adverse event rates were similar for nateglinide and placebo, and no hypoglycemic episodes or serious adverse events were reported during the study. Nateglinide (120 mg) was the maximum effective dose in this study and was shown to be a safe and well tolerated therapy for control of mealtime glucose excursions in patients with type 2 diabetes. Results indicate that a synergistic interaction occurs between nateglinide and elevated mealtime plasma glucose concentrations to stimulate insulin secretion.