DEFECTS OF INSULIN AND IGF-1 ACTION AT RECEPTOR AND POSTRECEPTOR LEVEL IN A PATIENT WITH TYPE-A SYNDROME OF INSULIN-RESISTANCE

The action of insulin and IGF-1 in comparison to non-diabetic controls was studied in cultured fibroblasts of a patient with an inherited sy ndrome of insulin resistance (Type A syndrome). Insulin binding was re duced due to decreased receptor affinity, but sequence analyses reveal ed no alterations of splicing or primary insulin receptor (IR) structu re. Most likely due to the IR affinity defect analyses of signal trans duction pathways showed an impairment of insulin action on glucose upt ake, total RNA synthesis and phosphorylation as well as activity of MA P-kinase. In addition inducibility of c-fos mRNA level was strongly im paired by insulin and IGF-1, but comparable to controls by PDGF indica ting a postreceptor defect. In conclusion, we provide evidence that ge netic syndromes of insulin resistance can be associated with both, rec eptor and postreceptor defects. (C) 1991 Academic Press.