HUMAN INSULIN-RECEPTOR SUBSTRATE-1 - VARIANT SEQUENCES IN FAMILIAL NONINSULIN-DEPENDENT DIABETES-MELLITUS

The aetiology of NIDDM is uncertain, although family and twin studies indicate an important role for genetic factors in disease onset. The f unction and position of IRS-1 within the insulin signalling pathway ma ke it a prime candidate gene for the development of insulin resistance and NIDDM. Insulin resistant families were identified by studying una ffected first degree relatives from families with 2 or more living NID DM subjects. Insulin sensitivity was determined in the relatives using the insulin tolerance test, and 15 families were identified as insuli n resistant. One NIDDM subject from the 10 most resistant families was selected and the entire coding region of IRS-1 analysed by SSCP analy sis. Four normoglycaemic subjects with no family history of diabetes s erved as controls. Five variant sequences of IRS-1 were identified wit hin the NIDDM subjects; 2 silent polymorphisms at codons 235 (GGG to G GA) and 893 (CCG to CCC): 2 non-conservative mutations (Ala(513)Pro; G ly(972)Arg) and a codon deletion (Ser(681-7) to Ser(681-6)). The influ ence of the non-conservative mutations alone, and in combination with other abnormalities of the insulin signalling pathway on peripheral in sulin action, remains to be determined.