Families with hyperproinsulinemia may be considered a model of excess secretion of insulin by pancreatic beta cells, and those with mutant insulin receptors as a model of insulin resistance. We evaluated members of two families, one with hyperproinsulinemia (His65-proinsulin) and the other with mutant insulin receptors (His252-insulin receptor), employing the oral glucose tolerance test (OGTT) and other parameters of glucose metabolism. Alterations in glucose tolerance were observed over a five-year period. Genotypes of relevant mutations were reflected by the fasting serum CPR/IRI molar ratio in the family with hyperproinsulinemia, and by the degree of abnormality in serum IRI on OGTT in the family with mutant insulin receptors. In both families, a low insulin secretory response, indicating pancreatic beta cell dysfunction, might exacerbate glucose intolerance. We conclude that not only the mutations, but also other genetic or environmental factors, may contribute to glucose intolerance in both families.
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