The aetiology of NIDDM is uncertain, although family and twin studies indicate an important role for genetic factors in disease onset. The function and position of IRS-1 within the insulin signalling pathway make it a prime candidate gene for the development of insulin resistance and NIDDM. Insulin resistant families were identified by studying unaffected first degree relatives from families with 2 or more living NIDDM subjects. Insulin sensitivity was determined in the relatives using the insulin tolerance test, and 15 families were identified as insulin resistant. One NIDDM subject from the 10 most resistant families was selected and the entire coding region of IRS-1 analysed by SSCP analysis. Four normoglycaemic subjects with no family history of diabetes served as controls. Five variant sequences of IRS-1 were identified with the NIDDM subjects; 2 silent polymorphisms at codons 235 (GGG to GGA) and 893 (CCG to CCC): 2 non-conservative mutations (Ala513Pro; Gly972Arg) and a codon deletion (Ser681-7 to Ser681-6). The influence of the non-conservative mutations alone, and in combination with other abnormalities of the insulin signalling pathway on peripheral insulin action, remains to be determined.