RENAL HYPERTROPHY IN HYPERGLYCEMIC NONOBESE DIABETIC MICE IS ASSOCIATED WITH PERSISTENT RENAL ACCUMULATION OF INSULIN-LIKE GROWTH-FACTOR-I

The non-obese diabetic mouse is a model of spontaneous insulin-depende nt diabetes as a result of autoimmune destruction of pancreatic beta c ells, similar to the disease seen in human Type I diabetes. This mouse strain develops glomerular lesions reminiscent of those seen in human disease. The study presented here investigated the changes in renal i nsulin-like growth factor (IGF) system in hyperglycemic non-obese diab etic mice. Female non-obese diabetic mice and their age- and sex-match ed controls were euthanized 4 days, 2 wk, and 4 wk after the onset of glycosuria. Kidney weight increased in diabetic mice, beginning at 2 w k after the onset of glycosuria. This renal hypertrophy was associated with an increase in renal extractable IGF-I protein. However, a decre ase in IGF-I mRNA was observed at the same time. Serum IGF-I levels re mained stable after 2 wk of diabetes and decreased at 1 month. No chan ge was detected in renal IGF-I receptor mRNA levels. Renal cortical IG F binding protein (IGFBP)-1 mRNA levels were increased. Ligand blot an alysis revealed a significant increase in serum and renal 30-kd IGFBP and a decrease in serum and kidney IGFBP-3 and IGFBP-4 at 30 days of d iabetes. Insulin therapy prevented the increases in kidney weight, ren al IGF-I, and 30-kd IGFBP, but did not reverse the decreased serum IGF -I levels observed at 1 month of diabetes. In summary, renal hypertrop hy in non-obese diabetic mice is associated with a persistent accumula tion of renal IGF-I and. IGTFBP-1. These changes were partially revers ed with insulin therapy, which did not correct the hyperglycemia, sugg esting an important role for insulin deficiency in mediating these cha nges in the IGF system. These findings suggest that the IGF system may play a potential role in the development of diabetic nephropathy.