Irreversibility of nutritionally induced NIDDM in Psammomys obesus is related to beta-cell apoptosis

Psammomys lapses into fully fledged diabetes when maintained on a high-ener gy diet. Progression to diabetes has been classified into stage A of normog lycemia and normoinsulinemia (<120 mg/ml and 100 mU/L, respectively); stage B of hyperinsulinemia (100-300 mU/L) with marked insulin resistance in the face of normoglycemia; stage C of pronounced hyperinsulinemia with hypergl ycemia less than or equal to 500 mg/ml; stage D at 6-10 weeks after stage C , featuring further hyperglycemia and loss of insulin. Insulin resistance e xpressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to a ctivate muscle and liver tyrosine kinase of the insulin receptor. Diabetes at stage C, but not at stage D, was fully reversed to stage A by restrictin g the food ration of animals by half (from 14 to 7 g/day) for 10-14 days. W e examined islet beta cells of Psammomys in the four stages of progression to diabetes by staining for insulin as well as for apoptosis by the termina l deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and vi sualizing the biotin-labeled cleavage sites. Psammomys in stage A had insul in-laden beta cells. In stage B, a hypertrophy and partial insulin depletio n of beta cells was evident with negative TUNEL staining. In stage C, beta cells were markedly depleted of insulin, and their number within the islets decreased, but the TUNEL staining was virtually negative. Tn stage D, beta cells were markedly diminished within the islets, almost void of insulin, showing distinct TUNEL staining of beta cells. These results indicate that prolonged exposure of islets to in vivo hyperglycemia with beta-cell overta xation induces nuclear disintegration with irreversible damage to the insul in-secretion apparatus. This precludes the return to normalcy by restrictin g the food intake of Psammomys. The appearance of cells with TUNEL-positive staining may serve as a marker of impending irreversibility of nutritional ly induced diabetes.