Relation of Insulin Deficiency to Impaired Insulin Action in NIDDM Adult Rats Given Streptozocin as Neonates

We assessed the impact of chronic insulin deficiency on basal and insulin-stimulated glucose utilization by the whole-body mass in vivo in female albino Wistar rats. This assessment was based on a comparison of results in rats given streptozocin (STZ) on day of birth (n0-STZ), when 2 days old (n2-STZ), or when 5 days old (n5-STZ). At 10 wk of age, the n2-STZ rats exhibited characteristics similar to those obtained in the n0-STZ rats: normal growth, modest elevation of basal plasma glucose (8.23 ± 0.24 mM), glucose intolerance, depleted pancreatic insulin stores (∼50% of normal value), and lack of insulin release in response to glucose in vivo. In contrast, the n5-STZ rats exhibited frank basal hyperglycemia (glucose 11.9 ± 1.1 mM) and glucose intolerance, increased glycosylated hemoglobins, strong reduction of the pancreatic insulin stores (10% of normal value), decreased basal plasma insulin levels (50% of normal value), and lack of insulin release in response to glucose in vivo. Changes in the sensitivity of the neonatal β-cell to STZ and the regeneration capacity of the β-cells during the 1st postnatal wk were liable factors for the contrast. In vivo insulin action was assessed with the euglycemic-hyperinsulinemic clamp technique in 10-wk-old anesthetized animals. In the n2-STZ rats compared with controls 1) endogenous glucose production was significantly higher despite a normal plasma insulin level in the basal state, 2) endogenous glucose production rate was similarly suppressed by hyperinsulinemia, and 3) glucose utilization by the whole-body mass was similarly increased by hyperglycemia. Thus, in terms of basal hepatic glucose production, a discrete alteration of insulin action, with mild insulin deficiency, was detected in this model. In the n5-STZ rats compared with controls 1) basal hepatic glucose production was significantly higher, 2) hepatic glucose production rate was less efficiently suppressed by submaximal or maximal insulin levels, and 3) glucose utilization by the whole-body mass induced by hyperinsulinemia was significantly reduced (by 35% according to submaximal or maximal insulin levels). Thus, insulin resistance was present in vivo at the level of both the peripheral tissues (probably the muscles) and the liver of the n5-STZ rat. These data confirm that when β-cell destruction is the primary insult responsible for the emergence of moderate to severe hyperglycemia in rats, insulin resistance can develop secondarily. However, the assumption that insulin deficiency is invariably followed by an overall peripheral insulin resistance is not tenable, because there was no peripheral insulin resistance in the n0-STZ and n2-STZ models. These data are consistent with the suggestion that a certain degree of insulin deficiency is necessary to induce a clear-cut decrease in insulin action.