OBJECTIVE: We have previously shown in an acute inpatient setting that dietary substitution of 77.5% of fat kcal as medium chain triglycerides (MCT) increased insulin-mediated glucose metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM), and that this effect appeared to be mediated by increases in insulin-mediated glucose disposal. The purpose of this study was to test the application of dietary substitution of medium chain triglycerides as an adjunctive tool in ambulatory therapy of NIDDM. METHODS: Five subjects with NIDDM underwent a baseline 6 hour insulin/glucose euglycemic clamp study, with simultaneous 3H-glucose infusion for calculation of glucose disposal rate and hepatic glucose output. Subjects were then randomized to begin one of two 30-day experimental diets, with long chain (LCT) or medium chain triglycerides (MCT), and subsequent crossover to the other diet. A 6 hour euglycemic clamp was repeated after each diet phase. RESULTS: Diet records and urinary organic acid excretion indicated a high level of dietary compliance by the study participants. Postprandial blood glucose excursions were less after one month on the diet with MCT than after the LCT diet (p = 0.004). However, fasting serum glucose, serum fructosamine (a measure of glycemia), fasting insulin, hepatic glucose output, and insulin-mediated glucose metabolism were not improved by the dietary substitution of MCT. CONCLUSION: These data indicate that supplementation of a tolerable amount of MCT in a conventional diabetic exchange diet has little impact on glycemic control in subjects with NIDDM in an ambulatory setting.