The aim of this study was to determine the mechanism by which a high-fat diet exacerbates the diabetes produced by a low dose of streptozotocin (STZ). The glucose clamp technique was used to determine hepatic glucose production (HGP) and the disappearance rate (Rd) of glucose, basally and during insulin infusions of 1.0 and 3.0 mU/kg/min in control of STZ-treated rats fed either a low-fat or high-fat diet. Fasting plasma glucose in the high fat-STZ (HFS) group was significantly higher than in any of the other groups: low fat-STZ (LFS), high-fat controls (HFC), or low-fat controls (LFC) (18.1 +/- 1.6 v 8.1 +/- 0.8 mmol/L, P less than .001; 6.0 +/- 0.2 mmol/L, P less than .001; 5.4 +/- 0.1 mmol/L, P less than .001, respectively). Basal HGP was markedly higher in the HFS group compared with each of the other three groups (98.8 +/- 5.9 v 61.4 +/- 3.7, P less than .001; 42.9 +/- 1.6, P less than .001; 39.6 +/- 1.3 mumol/kg/min, P less than .001; HFS v LFS, HFC, and LFC, respectively). Following insulin infusion, no differences were observed in HGP between the LFC and LFS groups at either insulin dose. However, HGP was not suppressed to control levels in either of the high-fat diet groups, and this defect was more marked in the HFS group. It is concluded that a high-fat diet exacerbates mild STZ diabetes primarily by increasing HGP.