Specific alterations of the insulin-like growth factor I system in the cerebellum of diabetic rats

Abstract

Specific changes in circulating levels of insulin-like growth factor I (IGF-I) and various IGF-binding proteins are known to occur in insulin-dependent diabetic patients and laboratory animals. However, little attention has been paid to the effects of this chronic metabolic disease on the IGF system of the central nervous system. Because various types 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 changes in the cerebellar IGF-I system. Streptozotocin-induced diabetic rats were divided into two groups: 1) well controlled diabetics, which received twice daily injections of insulin and had mean glucose levels in the normal range; and 2) poorly controlled diabetic animals, which received 1 U of insulin once a day and had glucose levels above 300 mg/dl. As previously described, there were significant decreases in circulating 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 controlled diabetic animals. All these parameters were normal in well controlled diabetic rats. In addition, significant modifications in the cerebellar IGF-I system were found. Poorly controlled diabetic animals had significantly 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 levels 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 IGF-I receptor were similar in all experimental groups. These changes appear to be anatomically specific because other brain areas did not show the same alterations. The present results indicate that in the diabetic 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 modifications in the cerebellar, IGF-I system, which plays an important trophic role in postnatal life, may underlie, at least in part, specific neuronal losses known to occur in diabetic patients.