Insulin stimulates both glucose and K(+) uptake, and high-fat feeding is known to decrease insulin-stimulated glucose uptake. The purpose of this study was to examine whether insulin's actions on glucose and K(+) uptake are similarly decreased by a high-fat diet. Wistar rats were fed a standard control (12.2% fat; n = 6) or high-fat (66.5% fat; n = 13) diet for 15 days. Because K(+) content was 1% in the control and 0.5% in the high-fat diet and because the rats ate less of the high-fat diet, we also compared the high-fat diet with 0.5% K(+) (HFD; n = 7) to a high-fat diet supplemented with 1.5% K(+) (HFD+K; n = 6). K(+) intake was matched between the control and HFD+K groups (246 +/- 8 vs. 224 +/- 2 mg/day), but was lower in the HFD group (78 +/- 10 mg/day; P < 0.05). Insulin-stimulated glucose and K(+) uptake were determined by hyperinsulinemic (5 mU.kg(-1).min(-1)) glucose and K(+) clamps. The HFD depressed both insulin-stimulated glucose uptake compared to the control (133 +/- 5 vs. 166 +/- 7 micromol.kg(-1).min(-1); P < 0.05) and K(+) uptake (5.5 +/- 0.9 vs. 8.9 +/- 1.0 micromol.kg(-1).min(-1); P < 0.05) compared to the control. However, insulin-stimulated K(+) uptake was unchanged in the HFD+K versus in the control group (10.0 +/- 0.6 vs. 8.9 +/- 1.0 micromol.kg(-1).min(-1); P > 0.05), whereas insulin-stimulated glucose uptake in the HFD+K group was decreased to a rate (137 +/- 9 micromol.kg(-1).min(-1)), similar to that of the HFD group. We concluded that the decrease in insulin-stimulated K(+) uptake during high-fat feeding was a result of decreased K(+) intake, and that insulin's actions on glucose uptake and K(+) uptake are independently regulated by dietary fat and K(+) content, respectively.