SPECIFIC ALTERATIONS OF THE INSULIN-LIKE GROWTH-FACTOR-I SYSTEM IN THE CEREBELLUM OF DIABETIC RATS

Specific changes in circulating levels of insulin-like grow th factor I(IGF-I) and various IGF-binding proteins are known to occur in insuli n-dependent diabetic patients and laboratory animals. However, little attention has been paid to the effects of this chronic metabolic disea se on the IGF system of the central nervous system. Because various ty pes of human cerebellar degeneration are accompanied by changes in the peripheral IGF-I system which are similar, although not identical, to those found in diabetes, we tested whether diabetes results in change s in the cerebellar IGF-I system. Streptozotocin-induced diabetic rats were divided into two groups: 1) well controlled diabetics, which rec eived twice daily injections of insulin and had mean glucose levels in the normal range; and 2) poorly controlled diabetic animals, which re ceived 1 U of insulin once a day and had glucose levels above 300 mg/d l. As previously described, there were significant decreases in circul ating levels of IGF-I and IGFBP-3 (38-42 kDa band), and an increase in the 30-kDa IGFBP (likely corresponding to IGFBP-1) in poorly controll ed diabetic animals. All these parameters were normal in well controll ed diabetic rats. In addition, significant modifications in the cerebe llar IGF-I system were found. Poorly controlled diabetic animals had s ignificantly lower levels of IGF-I protein in the cerebellum, whereas no change in cerebellar IGF-I messenger RNA (mRNA) levels was found. A significant reduction in IGFBP-2 (31 kDa-band) protein and mRNA level s was also found in poorly controlled diabetics. Well controlled rats had normal cerebellar IGF-I levels, whereas levels of IGFBP-2 protein and mRNA were still significantly low. Finally, mRNA levels for the IG F-I receptor were similar in all experimental groups. These changes ap pear to be anatomically specific because other brain areas did not sho w the same alterations. The present results indicate that in the diabe tic animal changes in circulating IGF-I and IGFBPs are accompanied by, and possibly implicated in, modifications of the IGF-I system in the cerebellum and possibly other brain regions. We suggest that modificat ions in the cerebellar IGF-I system, which plays an important trophic role in postnatal life, may underlie, at least in part, specific neuro nal losses known to occur in diabetic patients.