The natural history of renal lesions in nonobese diabetic mice was assessed. This strain develops a spontaneous overt insulin-dependent diabetes that has a female predominance and an autoimmune pathogenesis. We compared mice that had a normal glucose tolerance test with mice that had a diabetes of 2 to 15 weeks' duration. The glomerular surface area was increased in all diabetic mice regardless of the duration of hyperglycemia. There was an increase in the albumin/creatinine ratio in the urine of diabetic mice. Finally, nonobese diabetic mice all showed mesangial sclerosis that was more pronounced in the diabetic mice. This suggests that this strain is susceptible to glomerulosclerosis and that the occurrence of hyperglycemia results in an increase of glomerular size, mesangial sclerosis, and proteinuria, soon after glycosuria is first demonstrated.