Heritable abnormalities in the insulin gene have often been considered in terms of their potential for contributing to diabetes. It is only within the last 5 yr, however, that evidence has demonstrated the existence of insulin gene mutations in man and the secretion of abnormal human insulins in affected individuals. HPLC analysis of insulin purified from serum by immunoaffinity chromatography and detection of insulin by radioimmunoassay have documented abnormal insulins in subjects from three separate families. HPLC analysis of these natural insulins and of semisynthetic insulin analogues have identified the accompanying amino acid substitutions in two of these cases: in one, leucine replaces phenylalanine B25; in the other, serine replaces phenylalanine B24. Both substitutions occur in an invariant tetrapeptide sequence within the active site of the hormone. Studies of the biologic activities of these analogues further suggest that replacements at position B25 result in the loss of an important side chain contact between the hormone and its receptor, whereas those at position B24 result in conformational changes in the insulin molecule as a whole. Two additional individuals have been identified to secrete abnormal intermediates of proinsulin conversion in which the C-peptide remains attached to the insulin A-chain and in which Arg65 has been replaced by a nonbasic amino acid. This result emphasizes the importance of dibasic amino acid pairs at prohormone conversion sites and provides clues about the evolution of hormone precursors. Thus, studies of the products of abnormal human insulin genes have provided insights into subjects as varied as insulin biosynthesis, structure-activity relationships in insulin recognition by receptors, and the physiology of insulin action.

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