Blood chemistry profiles (glucose, insulin, and triglycerides) and indirect calorimetry were performed on male Zucker diabetic fatty (ZDF) rats in a longitudinal fashion (starting at 7 weeks of age) to assess the nature and timing of specific events in the transition to overt diabetes. Peripheral (skeletal muscle) insulin resistance was clearly present at 7 weeks of age in ZDF rats, yet circulating glucose was only slightly above normal as a result of compensatory hyperinsulinemia. At a crucial stage from 7 to 8 weeks, a reduction in insulin levels instigated several deleterious changes resulting in reduced whole-body carbohydrate utilization and increased glycemia. In subsequent weeks, an inability to sustain peripheral glucose disposal as a consequence of a continuous decline in insulin levels further reduced carbohydrate utilization (increased lipid utilization) and enhanced the overt hyperglycemia. These observations document in a systematic fashion the alterations that define diabetic progression in ZDF rats.