Genetics of insulin resistance.
Insulin resistance, defined as the decreased ability of insulin to perform its biological functions, is likely to represent the primary physiologic defect underlying the insulin resistance syndrome (IRS), which includes insulin resistance/hyperinsulinemia, glucose intolerance and/or type 2 diabetes mellitus, visceral obesity, hypertension, and dyslipidemia. This constellation of traits is a leading cause of cardiovascular mortality and morbidity. Insulin sensitivity varies widely among individuals. Although environmental provocations including physical inactivity and caloric excess play an important role in the development of obesity and thus insulin resistance, epidemiologic and family studies show that there are also moderate genetic influences on the development of insulin resistance. Extreme forms of insulin resistance may be caused rarely by mutations in the genes for the insulin receptor and peroxisome proliferator-activated receptor gamma. However, the genetic basis for common more moderate forms of insulin resistance is likely to be polygenic and heterogeneous. Evidence further suggests that gene variants may have phenotypic influences on more than one IRS trait (so-called pleiotrophy), which may explain, in part, the clustering of these traits. This article reviews the evidence that insulin resistance has a genetic basis. Progress to date toward identifying specific gene variants are reviewed. Ultimately, the identification of specific gene variants that influence insulin resistance and other IRS traits will have profound influences on our understanding of the molecular and pathophysiologic basis of these disorders, from which new and more effective preventive and therapeutic interventions will be possible.
Mercado
Maria M
MM
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 W. Redwood Street, Room 494, Baltimore, MD 21201, USA.
McLenithan
John C
JC
Silver
Kristi D
KD
Shuldiner
Alan R
AR
D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors