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This study compared the effects of nateglinide, glyburide, and placebo on postmeal glucose excursions and insulin secretion in previously diet-treated patients with type 2 diabetes.This randomized, double-blind, placebo-controlled multicenter study was conducted in 152 patients who received either nateglinide (120 mg before three meals daily, n = 51), glyburide (5 mg q.d. titrated to 10 mg q.d. after 2 weeks, n = 50), or placebo (n = 51) for 8 weeks. Glucose, insulin, and C-peptide profiles during liquid meal challenges were measured at weeks 0 and 8. At weeks −1 and 7, 19-point daytime glucose and insulin profiles, comprising three solid meals, were measured.During the liquid-meal challenge, nateglinide reduced the incremental glucose area under the curve (AUC) more effectively than glyburide (Δ = −4.94 vs. −2.71 mmol·h/l, P < 0.05), whereas glyburide reduced fasting plasma glucose more effectively than nateglinide (Δ = −2.9 vs. −1.0 mmol/l, respectively, P < 0.001). In contrast, C-peptide induced by glyburide was greater than that induced by nateglinide (Δ = +1.83 vs. +0.95 nmol·h/l, P < 0.01), and only glyburide increased fasting insulin levels. During the solid meal challenges, nateglinide and glyburide elicited similar overall glucose control (Δ 12-h incremental AUC = −13.2 vs. −15.3 mmol·h/l), but the insulin AUC induced by nateglinide was significantly less than that induced by glyburide (Δ 12-h AUC = +866 vs. +1,702 pmol·h/l, P = 0.01).This study demonstrated that nateglinide selectively enhanced early insulin release and provided better mealtime glucose control with less total insulin exposure than glyburide.