Spatial compartmentalization of signal transduction in insulin action Christian A. Baumann and Alan R. Saltiel* Summary Insulin resistance is thought to be the primary defect in the pathophysiology of type 2 diabetes. Thus, under- standing the cellular mechanisms of insulin action may contribute significantly to developing new treatments for this disease. Although the effects of insulin on glucose and lipid metabolism are well documented, gaps remain in our understanding of the precise molecular mechan- isms of signal transduction for the hormone. One potential clue to understanding the unique cellular effects of insulin may lie in the compartmentalization of signaling molecules and metabolic enzymes. We review this evidence, and speculate on how PI-3 kinase-inde- pendent and -dependent signaling pathways both di- verge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action. BioEs- says 23:215±222, 2001. ß 2001 John Wiley & Sons, Inc. Introduction Diabetes mellitus is a worldwide epidemic, in some ethnic groups affecting over 10% of the population. Type 1 diabetes, defined by an absolute requirement for administration of exogenous insulin, results from the autoimmune destruction of the insulin-secreting pancreatic b cells. Type 2 diabetes usually occurs during adulthood, and is often characterized by a relative resistance to endogenous insulin. The pathophy- siology of type 2 diabetes, which accounts for over 90% of patients with the disease, involves defects in three organ systems that conspire together to produce abnormal glucose and lipid metabolism. While there is some uncertainty regarding the primary lesion, or relative importance of different tissues, metabolic defects in liver, peripheral target tissues such as fat and muscle and pancreatic b cells all contribute to the syndrome. Insulin resistance, which is defined as a state of reduced responsiveness to normal circulating concentrations of insulin, is now recognized as a characteristic trait of type 2 diabetes, and contributes to abnormalities in all of these tissues. A number of prospective epidemiological studies across several population groups have indicated that type 2 diabetes progresses over a continuum of worsening insulin action, beginning with peripheral insulin resistance and ending with a loss of insulin secretion. In most patients, insulin resistance can be detected long before the deterioration of glucose intolerance occurs. Insulin resistance is a quite common state, associated with aging, a sedentary lifestyle, as well as a genetic predisposition. The state seems to be fueled by or perhaps to a certain extent the result of obesity. The ensuing dysregulation of carbohydrate and lipid metabolism that occurs as a consequence of insulin resistance further exacer- bates its progression. Beta cells of the pancreas normally compensate for the insulin-resistant state by increasing basal and postprandial insulin secretion. At some point, the beta cells can no longer compensate, failing to respond appro- priately to glucose. This ultimately leads to the deterioration of glucose homeostasis, and the development of glucose into- lerance. Approximately 5±10% of glucose intolerant patients per year progress to frank diabetes, which continues to worsen as insulin resistance increases. Adipose cells generate more fatty acids, the liver produces more glucose in an unregulated fashion, and the beta cells undergo complete failure, resulting in the late stages of the disease, where high doses of exogenous insulin may be required. Even in the absence of diabetes, insulin resistance is a key feature of other human disease states. Impaired insulin action coupled with hyperinsulinemia leads to a variety of abnorm- alities, including elevated triglycerides, low levels of HDL, enhanced secretion of VLDL, disorders of coagulation, increased vascular resistance, changes in steroid hormone levels, attenuation of peripheral blood flow and weight gain. Thus, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipi- demia and atherosclerosis. This constellation of symptoms is often referred to as Syndrome X, or Insulin Resistance BioEssays 23:215±222, ß 2001 John Wiley & Sons, Inc. BioEssays 23.3 215 Abbreviations: CAP, c-Cbl associating protein; EGF, epidermal growth factor; IRAP, insulin-responsive aminopeptidase; GSV, Glut4 vesicle; IRS, insulin receptor substrate; PDGF, platelet-derived growth factor; PDK, phosphoinosotide dependent kinase 1; PIP3, phosphotidylino- sitol 3,4,5 triphosphate; PKB, PI 3-kinase protein kinase B; PKC, protein kinase C; SH2, src-homology 2; SH3, src-homology 3; SNARE, soluble N-ethylmaleimide sensitive factor attachment protein; Syn4, syntaxin 4. Department of Cell Biology, Parke-Davis Pharmaceutical Research and the Department of Physiology, University of Michigan. Ã Correspondence to: Dr. Alan R. Saltiel, Life Sciences Institute, Department of Internal Medicine, University of Michigan School of Medicine, MSRB1, Room 4520, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0650. E-mail: saltiel@umich.edu Review articles