ABSTRACT
Diabetic neuropathy is a common and disabling complication of diabetes mellitus whose pathogenesis remains unknown. Insulin-like growth factors (IGFs) have been recently implicated in the development and maintenance of the peripheral nervous system, and circulating IGF levels are decreased in experimental and clinical diabetes. Therefore, we tested the hypothesis that IGF gene expression is reduced in peripheral nerves early after the onset of diabetes. Sciatic nerves from nondiabetic and streptozotocin-treated rats were removed 5-7 days after the induction of diabetes. RNA was isolated and analyzed by Northern and slot blots. IGF-I mRNA content was significantly decreased per milligram wet weight nerve (P < 0.025) as well as per poly(A)+ RNA (P < 0.01) in diabetic vs nondiabetic nerves. Likewise, the amount of IGF-II mRNA was significantly decreased per milligram wet weight nerve (P < 0.01) as well as per poly(A)+ RNA (P < 0.005). These effects were selective because histone 3.3 mRNA content, as well as poly(A)+ mRNA content, per milligram nerve were unchanged. Insulin treatment partially prevented this decline in IGF-I and IGF-II mRNA levels. The diminished IGF mRNA content is one of the earliest biochemical abnormalities to be observed in the diabetic nerve, supporting the hypothesis that a reduction in IGF activity in diabetic nerves precedes and contributes to the development of neuropathy.
Subject(s)
Diabetes Mellitus, Experimental/genetics , Gene Expression , Sciatic Nerve/physiopathology , Somatomedins/genetics , Animals , Blood Glucose/analysis , Body Weight , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/pathology , Male , Organ Size , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Sciatic Nerve/pathologyABSTRACT
Circulating insulin-like growth factor I (IGF-I) concentrations are known to be reduced in experimental and clinical diabetes mellitus. The IGF-I mRNA content was measured in several tissues of rats treated with streptozotocin to determine whether a correlation with neuropathy could be found. IGF-I mRNA content was sharply reduced relative to total and poly(A)+ RNA in diabetic liver and adrenal glands. In contrast, histone 3.3 mRNA content was not significantly reduced relative to poly(A)+ RNA in liver, and alpha-tubulin mRNA content instead was increased in adrenal glands, showing that the decline in IGF-I mRNAs in these tissues was selective. In addition, spinal cord IGF-I mRNA content was significantly reduced per tissue, total RNA, and poly(A)+ RNA after 1 and 2 weeks of diabetes. This was correlated with a concurrent and significant decrease in conduction velocity in both spinal cord and peripheral nerves in a separate study. The decline in liver and spinal cord IGF-I mRNA was not due to streptozotocin toxicity, because it was significantly opposed by insulin which was continuously infused beginning the day after diabetes induction. These results, when taken together with those of others, indicate that the reduction in IGF-I mRNA content may be widespread among diabetic tissues, and might contribute in part to certain syndromes of diabetes, such as neuropathy.
