Obese diabetic SHR/N-(cp/cp) rats are a genetic model for non-insulin-dependent diabetes mellitus. When SHR/N-cp rats are overtly diabetic, they are hyperinsulinemic and hyperglycemic in the fed state when consuming commercial chow or semipurified high-carbohydrate diets. Obese SHR/N-cp rats were hyperinsulinemic by 4 wk of age, although hyperglycemia did not appear until 3–4 wk later and was exacerbated by a high-sucrose diet (mean ± SE 1488 ± 238 (μ/ml insulin and 425 ± 51 mg/dl glucose). The control SHR/N-cp rats (+ /?) on the sucrose diet remained lean and normoglycemic. The obese diabetic SHR/N-cp rats showed three alterations in pancreas perfusion data (not present in control rats): 7) paradoxically high insulin secretion at low glucose levels (2.5 mM), 2) secretion of insulin in response to arginine (10 mM) in the absence of glucose, and 3) impaired response of insulin secretion to high glucose (16.7 mM). To determine whether hyperglycemia was responsible for the abnormalities of insulin secretion, perfusion studies were conducted in obese nondiabetic LA/N-cp rats and compared with the SHR/N-cp rats. The obese LA/N-cp rats resembled the corpulent SHR/N-cp rats in every way, except that they were normoglycemic on the sucrose diet. The obese LA/N-cp rats had two of the three alterations in insulin secretion shown by obese SHR/N-cp rats, lacking only the impaired response to high glucose, suggesting that hyperglycemia was required for that defect to occur. This finding is supported by the partial reversal of this defect in the obese SHR/N-cp rats after fasting for 48–72 h, when plasma glucose levels had been close to normal for >24–48 h. Additional evidence was obtained in younger, prediabetic obese SHR/N-cp rats that also showed the first two of the three defects and showed only a slightly abnormal response to high glucose. Paradoxically, high insulin secretion at low glucose levels and hypersecretion of insulin in response to arginine without glucose are early abnormalities associated with the development of obesity in these models, whereas decreased maximal response to high glucose develops later and is associated with hyperglycemia.

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