OBJECTIVE: Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and beta-cell dysfunction. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 +/- 8.6 years, A1C 6.5 +/- 1.0%, and BMI 29.8 +/- 3.8 kg/m(2)[mean +/- SD]) using either oral hypoglycemic agents (OHAs) (n = 34) or diet alone (nonusers). As a measure of glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring data recorded over 3 consecutive days. The relationships between MAGE, beta-cell function, and clinical parameters were assessed by including postprandial beta-cell function (PBCF) and basal beta-cell function (BBCF) obtained by a model-based method from plasma C-peptide and plasma glucose during a mixed-meal test as well as homeostasis model assessment of insulin sensitivity, clinical factors, carbohydrate intake, and type of OHA. RESULTS: MAGE was nonlinearly correlated with PBCF (r = 0.54, P < 0.001) and with BBCF (r = 0.31, P = 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P = 0.21 and BBCF P = 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R(2) = 0.50, P < 0.010), whereas insulin sensitivity, carbohydrate intake, and nonglycemic parameters failed to contribute. CONCLUSIONS: PBCF appears to be an important target to reduce glucose fluctuations in OHA-treated type 2 diabetes.