Hepatic and peripheral insulin resistance following streptozotocin-induced insulin deficiency in the dog

Insulin resistance and insulin deficiency are both present in many patients with diabetes mellitus. We tested the hypothesis that insulin resistance can evolve from a primary lesion of the β-cell secretory function. Insulin-mediated glucose uptake (insulin clamp), endogenous glucose production, and glucose-stimulated insulin secretion (hyperglycemic clamp) were measured in awake dogs before and four to six weeks after streptozotocin-induced diabetes mellitus. Streptozotocin (30 mg/kg) resulted in a significant rise in the mean fasting plasma glucose concentration from 104 ± 2 mg/100 mL to 200 ± 34 mg/100 mL, (P < 0.05), and a slight decrease in the mean fasting plasma insulin concentration (from 21 ± 2 μU/mL to 15 ± 2 μU/mL). Under conditions of steady-state hyperglycemia (+75 mg/100 mL hyperglycemic clamp, insulin secretion was reduced by 75% in the streptozotocin-treated dogs (P < 0.025), and the total amount of glucose metabolized decreased from 13.56 ± 1.04 to 4.74 ± 0.70 mg/min · kg (P < 0.001). In the postabsorptive state, endogenous glucose production was slightly, although not significantly, higher in the diabetic dogs (3.05 ± 0.46 v 2.51 ± 0.22 mg/min · kg), while the glucose clearance rate was 35% lower (P < 0.001). When the plasma insulin concentration was increased to ∼ 45 μU/mL (insulin clamp) while holding plasma gluscose constant at the respective fasting levels (99 ± 1 and 186 ± 30 mg/100 mL), endogenous glucose production was completely suppressed in control dogs but suppressed by only 51% (1.46 ± 0.37 mg/min · kg, P < 0.025) in diabetic animals. Insulin-stimulated glucose uptake was simiilar (4.71 ± 0.44 v 5.05 ± 0.79 mg/min · kg), but glucose clearance rate was significantly reduced in diabetic compared to control dogs (3.09 ± 0.79 v 5.13 ± 0.73 mL/min · kg, P < 0.05). To account for the enhancing effect of hyperglycemia on glucose uptake in diabetic animals, another group of dogs received an insulin clamp after lowering their fasting plasma glucose to levels similar to the prestreptozotocin ones. Under these strictly comparable conditions of glycemia (106 ± 6 v 98 ± 2 mg/100 mL) and insulinemia (47 ± 3 v 42 ± 10 μU/mL), diabetic dogs took up significantly (P < 0.05) less glucose than normal animals (2.27 ± 0.19 v 4.42 ± 0.84 mg/min · kg). In diabetic dogs, the degree of impairment in glucose clearance (as determined with the insulin clamp) was strongly related to the reduction in the insulin response to the hyperglycemic clamp (r = 0.87, P < 0.01). Furthermore, the fasting plasma glucose concentration correlated directly with endogenous glucose production both in the postabsorptive and insulin-stimulated state, and correlated inversely with the glucose clearance rate under insulin-stimulated conditions. We conclude the following: (1) in the dog, experimentally induced insulin deficiency leads to the development of insulin resistance; (2) this resistance can be demonstrated in the postabsorptive as well as in the insulin-stimulated state; (3) both the liver and the peripheral tissues contribute to the insulin resistance; (4) the insulin resistance is directly related to the impairment in insulin secretion and to the degree of fasting hyperglycemia. With respect to these abnormalities, streptozotocin-induced diabetes in dogs resembles human diabetes mellitus.