Physiological Reviews, Vol 75, 473-486, Copyright © 1995 by American Physiological Society

JOURNAL ARTICLE

Pathophysiology of insulin resistance in human disease

G. M. Reaven
Department of Medicine, Stanford University School of Medicine and Geriatric Research, Department of Veterans Affairs Medical Center, Palo Alto, California, USA.

The ability of insulin to stimulate glucose uptake varies widely from person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as diseases of Western civilization. Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presented. However, the ability to maintain the degree of compensatory hyperinsulinemia necessary to prevent loss of glucose tolerance in insulin-resistant individuals does not represent an unqualified homeostatic victory. In contrast, evidence is presented supporting the view that the combination of insulin resistance and compensatory hyperinsulinemia predisposes to the development of a cluster of abnormalities, including some degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistance has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disease. Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease.

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				E. Aasum, D. D. Belke, D. L. Severson, R. A. Riemersma, M. Cooper, M. Andreassen, and T. S. Larsen Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H949 - H957. [Abstract] [Full Text] [PDF]

				M. Haidari, N. Leung, F. Mahbub, K. D. Uffelman, R. Kohen-Avramoglu, G. F. Lewis, and K. Adeli Fasting and Postprandial Overproduction of Intestinally Derived Lipoproteins in an Animal Model of Insulin Resistance. EVIDENCE THAT CHRONIC FRUCTOSE FEEDING IN THE HAMSTER IS ACCOMPANIED BY ENHANCED INTESTINAL DE NOVO LIPOGENESIS AND ApoB48-CONTAINING LIPOPROTEIN OVERPRODUCTION J. Biol. Chem., August 23, 2002; 277(35): 31646 - 31655. [Abstract] [Full Text] [PDF]

				M. M. Buijs, J. Burggraaf, J. G. Langendonk, R. C. Schoemaker, M. Frolich, J.-W. Arndt, A. F. Cohen, J. A. Romijn, M. T. Ackermans, H. P. Sauerwein, et al. Hyposomatotropism Blunts Lipolysis in Abdominally Obese Women J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3851 - 3858. [Abstract] [Full Text] [PDF]

				K. A. Virtanen, P. Lonnroth, R. Parkkola, P. Peltoniemi, M. Asola, T. Viljanen, T. Tolvanen, J. Knuuti, T. Ronnemaa, R. Huupponen, et al. Glucose Uptake and Perfusion in Subcutaneous and Visceral Adipose Tissue during Insulin Stimulation in Nonobese and Obese Humans J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3902 - 3910. [Abstract] [Full Text] [PDF]

				L.-y. Qiao, R. Zhande, T. L. Jetton, G. Zhou, and X. J. Sun In Vivo Phosphorylation of Insulin Receptor Substrate 1 at Serine 789 by a Novel Serine Kinase in Insulin-resistant Rodents J. Biol. Chem., July 12, 2002; 277(29): 26530 - 26539. [Abstract] [Full Text] [PDF]

				J. C Chatham and A.-M. L Seymour Cardiac carbohydrate metabolism in Zucker diabetic fatty rats Cardiovasc Res, July 1, 2002; 55(1): 104 - 112. [Abstract] [Full Text] [PDF]

				T. Ogihara, T. Asano, K. Ando, H. Sakoda, M. Anai, N. Shojima, H. Ono, Y. Onishi, M. Fujishiro, M. Abe, et al. High-Salt Diet Enhances Insulin Signaling and Induces Insulin Resistance in Dahl Salt-Sensitive Rats Hypertension, July 1, 2002; 40(1): 83 - 89. [Abstract] [Full Text] [PDF]

				R. Sreekumar, P. Halvatsiotis, J. C. Schimke, and K. S. Nair Gene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment Diabetes, June 1, 2002; 51(6): 1913 - 1920. [Abstract] [Full Text] [PDF]

				M. A Pereira, D. R Jacobs Jr, J. J Pins, S. K Raatz, M. D Gross, J. L Slavin, and E. R Seaquist Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults Am. J. Clinical Nutrition, May 1, 2002; 75(5): 848 - 855. [Abstract] [Full Text] [PDF]

				H. E. Lebovitz, M. Kreider, and M. I. Freed Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials: Evidence that rosiglitazone does not cause hepatic dysfunction Diabetes Care, May 1, 2002; 25(5): 815 - 821. [Abstract] [Full Text] [PDF]

				N. Rodondi, R. Darioli, A.-A. Ramelet, D. Hohl, V. Lenain, J. Perdrix, V. Wietlisbach, W. F. Riesen, T. Walther, L. Medinger, et al. High Risk for Hyperlipidemia and the Metabolic Syndrome after an Episode of Hypertriglyceridemia during 13-cis Retinoic Acid Therapy for Acne: A Pharmacogenetic Study Ann Intern Med, April 16, 2002; 136(8): 582 - 589. [Abstract] [Full Text] [PDF]

				K. Winkler, I. Friedrich, M. W Baumstark, H. Wieland, and W. Marz Pioglitazone reduces atherogenic dense low density lipoprotein (LDL) particles in patients with type 2 diabetes mellitus The British Journal of Diabetes & Vascular Disease, March 1, 2002; 2(2): 143 - 148. [Abstract] [PDF]

				F. de Beer, A. F.H. Stalenhoef, N. Hoogerbrugge, J. J.P. Kastelein, J. A. Gevers Leuven, C. M. van Duijn, L. M. Havekes, and A. H.M. Smelt Expression of Type III Hyperlipoproteinemia in Apolipoprotein E2 (Arg158->Cys) Homozygotes Is Associated With Hyperinsulinemia Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 294 - 299. [Abstract] [Full Text] [PDF]

				K. Hara, P. Boutin, Y. Mori, K. Tobe, C. Dina, K. Yasuda, T. Yamauchi, S. Otabe, T. Okada, K. Eto, et al. Genetic Variation in the Gene Encoding Adiponectin Is Associated With an Increased Risk of Type 2 Diabetes in the Japanese Population Diabetes, February 1, 2002; 51(2): 536 - 540. [Abstract] [Full Text] [PDF]

				C. Wu, D. A. Okar, C. B. Newgard, and A. J. Lange Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E38 - E45. [Abstract] [Full Text] [PDF]

				C. J. Tanner, T. R. Koves, R. L. Cortright, W. J. Pories, Y.-B. Kim, B. B. Kahn, G. L. Dohm, and J. A. Houmard Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in middle-aged men Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E147 - E153. [Abstract] [Full Text] [PDF]

				L. Maianu, S. R. Keller, and W. T. Garvey Adipocytes Exhibit Abnormal Subcellular Distribution and Translocation of Vesicles Containing Glucose Transporter 4 and Insulin-Regulated Aminopeptidase in Type 2 Diabetes Mellitus: Implications Regarding Defects in Vesicle Trafficking J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5450 - 5456. [Abstract] [Full Text] [PDF]