EVALUATION OF INSULIN SENSITIVITY IN OBESE OFFSPRING OF DIABETIC RATS BY HYPERINSULINEMIC-EUGLYCEMIC CLAMP TECHNIQUE

Young adult macrosomic offspring of streptozotocin-induced mildly hyperglycemic rats exhibit accelerated growth through the first 10 wk of age. At 10 wk, oral glucose loading resulted in elevated plasma insulin and glucose concentrations compared to controls. To assess the mechanism of the abnormal glucose tolerance in vivo, hyperinsulinemic-euglycemic clamp studies were performed. Ten-wk-old rats were fasted overnight, and porcine insulin was infused (2.4 mU . kg-1 . min-1). Glucose was infused concurrently at varying rates to maintain euglycemia for 40-60 min. Insulin levels were raised from a baseline value of 163 +/- 57 pmol/L (23 +/- 8-mu-U/mL) (SD) to 476 +/- 57 pmol/L (67 +/- 8-mu-U/mL) at steady state for males and from 178 +/- 43 pmol/L (25 +/- 6-mu-U/mL) to 454 +/- 43 pmol/L (64 +/- 6-mu-U/mL) for females. The results showed that the macrosomic male and female animals were significantly less sensitive to the effects of insulin than were their respective controls; this was evident by a lower increment in glucose disposal rate per unit increase in insulin (0.04 +/- 0.01 versus 0.11 +/- 0.03 for males and 0.05 +/- 0.03 versus 0.18 +/- 0.07 mg . kg-1 per mu-U/mL for females). The endogenous glucose production by the liver in the basal (fasted) state in the macrosomic group compared to controls was higher, suggesting possible hepatic insulin resistance. However, endogenous glucose production was suppressed to the same degree between the experimental and control groups during the hyperinsulinemic period, suggesting that the hepatic insulin resistance can be overcome by high insulin levels. Thus, the reduced sensitivity to the effect of insulin on glucose disposal in the macrosomic animals provides additional in vivo evidence for peripheral insulin resistance as a contributing factor for the development of glucose intolerance in obese offspring of mildly hyperglycemic dams.