Non-insulin-dependent diabetes mellitus (NIDDM) was obtained in adult female rats byneonatal administration of streptozocin (STZ). At 2 mo of age, the basal plasma glucose values inthe postabsorptive state were elevated, the glucose disappearance rate measured after intravenous(i.v.) glucose load was significantly lower in the diabetic than in control rats, and in vivo glucose-induced insulin release was drastically reduced. To quantify and characterize the in vivo insulin sensitivity in rats with NIDDM, we have used the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production, glucose utilization, and glucoseclearance (measured by using 3-3H-glucose) were studied in anesthetized diabetic or control rats while in the postabsorptive state. An inherent condition to set up a valid experimental design was to take into consideration, in the diabetics, the influence of the high blood glucose concentration on glucose uptake and glucose production, since the blood glucose concentration by itself affects these two parameters by a mass action effect independent of insulin. The issue was addressed by evaluating glucose production and utilization in three experimental groups: diabetics clamped at their basal blood glucose level (170 mg/dl), controls clamped at their basal blood glucose level (110 mg/dl), and controls clamped at high blood glucose level (170 mg/dl).
In the basal state, glucose production was significantly higher in the diabetics than in controls. When plasma insulin was clamped at submaximal levels (300 μU/ml), the suppression of glucose production was significantly more important in the diabetics than in the two control groups. A similar conclusion was drawn from experiments with maximal insulin levels (4500 μU/ml).
In the basal state, glucose utilization was significantly higher in the diabetics as comparedwith the controls. During the clamp experiments, glucose utilization induced by a submaximal insulin level was significantly more important in the diabetics than in controls maintained at euglycemia, but it was found similar to that obtained in controls maintained at hyperglycemia. At maximal insulin level, glucose utilization was similar in the three groups.
In these experiments, as well, it was found that the use of the glucose clearance is not an accurate method for the evaluation of insulin action in vivo in the rat, as glucose clearance decreases significantly in the normal rat when blood glucose concentration was increased from 110 to 170 mg/dl at plasma insulin levels of 300 μU/ml or 4500 μU/ml. Thus in the rat, the glucose clearance is not independent of blood glucose concentration.
The present results obtained in vivo show that: (1) an increased sensitivity to insulin's suppressive effect on hepatic glucose production is a characteristic feature of rats with NIDDM. In connection with previous data by us, this observation is consistent with a postreceptor modification of glucose metabolismin the liver of these rats. (2) The insulin-mediated glucose uptake by peripheral tissues seems to be unaffected in rats with NIDDM.
