To determine whether whole body insulin sensitivity differs between a rat strain that does not (S 5B/Pl) and a strain that does [Osborne-Mendel (OM)] become obese when eating a high-fat diet, we performed euglycemic clamp studies in animals from each strain during low- and high-fat feeding. Clamps were performed after 2 days ("initial clamp") and 9 days ("final clamp") on each diet. Plasma glucose and insulin levels during the final 60 min of initial and final clamps were similar in S 5B/Pl and OM rats regardless of diet. Insulin sensitivity, measured as the glucose clearance rate during the final 60 min of the clamp, averaged 35 +/- 3 ml.kg-1.min-1 in S 5B/Pl rats after 2 days on a low-fat diet. This did not change significantly during an additional 7 days on the low-fat diet. The high-fat diet was associated with a 13% reduction in insulin sensitivity after 2 days and a 30% reduction after 9 days in S 5B/Pl rats. OM rats exhibited similar patterns of insulin sensitivity during low- and high-fat diets, albeit at lower insulin sensitivity overall (P < 0.0005 vs. S 5B/Pl). Mean glucose clearance after 2 days on the low-fat diet was 27 +/- 2 mg.kg-1.min-1 and did not change significantly during seven more days of low-fat feeding. The high-fat diet was associated with a 19% reduction in glucose clearance after 2 days and a 38% reduction after 9 days in OM rats. The magnitude of reduction in insulin sensitivity during high-fat diets did not differ significantly between strains.(ABSTRACT TRUNCATED AT 250 WORDS)