Lilly lecture 1995. Glucose transport: pivotal step in insulin action.
The effect of insulin to acutely stimulate glucose uptake into muscle and adipose tissue is essential for normal glucose homeostasis. The GLUT4 glucose transporter is a major mediator of this action, and insulin recruits GLUT4 from an intracellular pool to the plasma membrane. An important pathologic feature of obesity, NIDDM, and to a lesser extent IDDM is resistance to insulin-stimulated glucose uptake. Investigations of the mechanisms have revealed tissue-specific regulation of GLUT4 with decreased gene expression in adipose cells but not in skeletal muscle. This has led to the hypothesis that alterations in the trafficking of the GLUT4 vesicle or in the exposure or activation of the GLUT4 transporter may cause insulin resistance in skeletal muscle in obesity and diabetes. Exercise training increases GLUT4 expression in muscle in association with enhanced glucose tolerance in vivo. Transgenic mice have been created to investigate other approaches to improve insulin action on glucose transport. Overexpression of GLUT4 in adipocytes of transgenic mice increases the proportion of GLUT4 on the plasma membrane and enhances insulin sensitivity in vivo. Altering insulin signaling by overexpressing p21ras in adipocytes of transgenic mice results in increased GLUT4 on the plasma membrane in the absence of insulin and increases insulin sensitivity in vitro and in vivo. Thus, glucose transport is a pivotal step in whole-body insulin action. Strategies to increase the number of GLUT4 transporters that are functionally inserted in the plasma membrane in muscle and adipocytes may lead to new therapies to treat or prevent NIDDM.
Kahn
B B
BB
Department of Medicine at Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts, USA. bkahn@bih.harvard.edu
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D003920:Diabetes Mellitus / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; D005947:Glucose