Genetic Disorders of Insulin Action: Far More than Diabetes

Abstract

As obesity rates inexorably rise, so the incidence of diseases associated with insulin resistance (IR) is also surging. The tendency towards obesity-associated IR appears significantly genetically determined, but the underlying genetic determinants have proved difficult to elucidate. In contrast, genetic study of unusually severe IR, often presenting in childhood and/or in lean patients, has uncovered many examples of causative single gene defects. "IR" is usually defined by reduced ability of insulin to lower blood glucose, but study of such patients suggests the existence of IR subphenotypes, and implies that some harmful components of the "IR syndrome" actually require intact insulin action in some pathways or tissues. Recently several genetic disorders have also been identified that are due to mutations activating insulin signaling to produce hypoglycemia or overgrowth. This article will discuss these groups of disorders, emphasizing their clinical recognition, and the implications of genetic diagnosis for understanding of common disease. © 2013 Springer Science+Business Media New York.