EXCESSIVE GLUCOSE-PRODUCTION, RATHER THAN INSULIN-RESISTANCE, ACCOUNTS FOR HYPERGLYCEMIA IN RECENT-ONSET STREPTOZOTOCIN-DIABETIC RATS

Glucose production and utilization and activities of key enzymes involved in liver and muscle glucose metabolism were studied in post-absorptive streptozotocin-diabetic rats after 12 h of severe hyperglycaemia (17.5 +/- 0.5 mmol/l) and insulinopenia (5 +/- 1 mu U/ml). Basal glucose production was increased: 36.6 +/- 3.0 mg . kg . min(-1), vs 24.4 +/- 2.5 in controls (p < 0.05); liver glycogen concentration was decreased by 40 % (p < 0.05); liver phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities were increased by 375 and 156%, respectively (p < 0.001 and < 0.01). During a euglycaemic clamp at a plasma insulin level of 200 mu U/ml, glucose production was totally suppressed in controls, but persisted at 20% of basal in diabetic rats. In these rats, glucose production was suppressed at a plasma insulin level of 2500 mu U/ml. Basal whole body glucose utilization rate, 2-deoxy-1-[H-3]-D-glucose ([H-3]-2DG) uptake by muscles and muscle glycogen concentrations were similar in both groups, as well as total and active forms of pyruvate dehydrogenase and glyco-gen synthase activities. During the euglycaemic clamp, the total body glucose utilization rates and [H-3]-2DG uptake by muscles were similar in control and diabetic rats at a plasma insulin level of 200 mu U/ mi, but lower in diabetic rats at a plasma insulin level of 2500 mu U/ml. We conclude 1) in recent-onset severely insulinopenic rats, an excessive glucose production via gluconeogenesis prevailed, mainly accounting for the concomitant hyperglycaemia. This excess glucose output cannot be attributed to liver insulin resistance: the gluconeogenic pathway is physiologically less sensitive than glycogenolysis to the inhibition by insulin. 2) Glucose utilization was apparently normal under hyperglycaemic conditions and at a lower insulin plateau of the euglycaemic clamp but suboptimal in the presence of maximal insulin concentrations, suggesting an early appearance of peripheral insulin resistance.