Diabetes in the C57BL/KsJ(db/db) mouse is initially expressed as hyperinsulinemia, followed by hyperphagia, progressive obesity, and widespread pathologic abnormalities. This study was designed to evaluate the effects of metabolic control on the natural history of the diabetic nephropathy. Beginning at 1 mo of age and continuing for 12 wk, diabetic mice were subjected to controlled dietary restriction, such that their weight was maintained similar to that of age-matched, nondiabetic heterozygotes. Diet-restricted diabetics were compared with diabetics fed ad libitum and heterozygote nondiabetics. Significant lowering of fasting blood glucose, water intake, and plasma insulin was achieved by diet restriction. The diet-restricted diabetes demonstrated enhanced metabolic efficiency, consuming approximately half as much food as the nondiabetics, while maintaining a similar weight. Diabetics fed ad libitum evidenced well-defined renal lesions that included 3 + to 4 + immunoglobulin deposition in the glomerular mesangium, and generalized mesangial matrix expansion. These lesions were completely prevented in diet-restricted diabetes whose glomeruli were normal light microscopy, and demonstrated trace to 1 + mesangial immunoglobulin deposition, features identical in all respects to the nondiabetics. These results indicate that diabetic control achieved by preventing of obesity in the db/db mouse prevents the development of diabetic nephropathy.

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Clodronate disodium (Cl2MDP) was given intravenously in doses of 3, 6 and 10 mg/kg to six men (aged 23 to 30 yr). Volume of distribution was 0.2720 +/- 0.0255 l/kg (mean +/- SD) after 3 mg/kg dose, 0.3037 +/- 0.0445 l/kg after 6 mg/kg, and 0.2528 +/- 0.417 l/kg after 10 mg/kg. The elimination rate constant was 0.3787 +/- 0.0546 hr(-1), 0.3492 +/- 0.0616 hr(-1), adn 0.3962 +/- 0.0358 hr(-1) after 3, 6, and 10 mg/kg. Corresponding total body clearances were 0.1026 /+- 0.0149, 0.1049 +/- 0.0159, and 0.0998 +/- 0.0172 l/kg/hr. Renal clearance accounted for 73% of total body clearance; 73% of the drug was extracted unchanged in the urine in 24 hr. After Cl2MDP serum phosphate decreased approximately 13%; this was associated at the 10 mg/kg dose with a transient fall in fractional phosphate excretion. There was no significant changes in the serum concentration of fractional excretion of calcium, sodium, or uric acid. Creatinine clearance and renal concentrating ability were not altered by Cl2MDP. After short-term administration Cl2MDP is excreted primarily by the kidney but has no significant effects on renal function.

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