Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogenous disorder characterized by defects in insulin action and secretion. This study was aimed at developing a rat model in which these pathogenic factors might be studied. Male Wistar rats were injected at 2 days of age with 45 or 30 mg/kg streptozocin (STZ) or vehicle (control). Fasting plasma glucose and insulin levels were not significantly different between the two groups between 5 and 8 wk of age. At 8 wk, half of each group was randomly assigned to isocaloric diets high in either fat (59% of calories) or starch (70% of calories). After 1 wk on the diets, 45-mg/kg-STZ-administered fat-fed animals displayed significant fasting hyperglycemia (8.6 ± 0.2 mM; P < 0.01), which was exacerbated by the stress of anesthesia and/or cannulation, whereas no changes were observed in any of the other groups before (STZ starch fed, 6.7 ± 0.1 mM; control fat fed, 6.8 ± 0.1 mM; control starch fed; 6.4 ± 0.1 mM) or after anesthesia and/or cannulation. In the 30-mg/kg-STZ animals, fat feeding did not significantly elevate plasma glucose concentration, but a significant hyperglycemic response was seen with anesthesia and/or cannulation. In all STZ groups, substantial impairment of glucose-induced insulin secretion was observed, particularly early-phase insulin secretion. Further studies indicated that STZ animals on a diet conferring normal insulin sensitivity (starch) maintained basal normoglycemia and mildly impaired (i.v.) glucose tolerance despite this gross insulin secretory defect. However, addition of dietary fatinduced insulin resistance resulted in basal hyperglycemia and marked deterioration of glucose tolerance. These results highlight the interaction between diet, insulin secretion and action, and the autonomic nervous system in the development of hyperglycemia.

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