Undigested carbohydrates and some dietary fibers are fermented in the large intestine to form short-chain fatty acids (SCFA), including acetate, propionate, and butyrate. It has been suggested that some of the beneficial effects of high-carbohydrate, high-fiber diets on carbohydrate and lipid metabolism are mediated by the metabolism of SCFA in the liver. Propionate has been shown in vitro to decrease glucose production in rat hepatocytes. The aim of the present study was to investigate the effects of propionate on carbohydrate metabolism in normal and streptozocin (STZ)-induced diabetic male Sprague-Dawley rats. Rats were fed a high-fat diet with or without sodium propionate supplementation (either 0.5% or 5% wt/wt) for 4 weeks. At the completion of the feeding period, body weight and liver glycogen concentrations were significantly decreased in STZ-diabetic rats and were unaffected by propionate supplementation. Although STZ-diabetic animals had elevated fasting plasma glucose, cholesterol, and triglyceride levels relative to nondiabetic rats, propionate supplementation had no significant effect on these parameters in either group. Basal and insulin-stimulated carbohydrate metabolism were assessed using the euglycemic clamp technique in overnight-fasted animals with 3(H)-6-glucose infusion. As expected, basal hepatic glucose production (HGP) was higher and the metabolic clearance rate of glucose (MCR) was lower in STZ-diabetic rats. High-dose insulin infusion (3 mU.kg-1.min-1) suppressed HGP in nondiabetic and diabetic animals and increased the MCR in nondiabetic animals. However, propionate supplementation did not alter basal or insulin-stimulated HGP or the MCR in either nondiabetic or diabetic animals.(ABSTRACT TRUNCATED AT 250 WORDS)