Turning down insulin signaling Morris

655 In recent years, much has been written about the importance of diabetes mellitus, both as a cause of widespread morbidity and mortality and in terms of the resultant overwhelming health care costs. In an analysis of worldwide diabetes in 1994, the World Health Organization reported that the agestandardized prevalence in European populations varied from 3% to 10%, while more restricted populations demonstrated prevalence of up to 50% (1). Over the same period, approximately 10.2 million people with diagnosed diabetes mellitus resided in the US, but another 5.4 million individuals with diabetes went undiagnosed (2). Perhaps even more impressive, these numbers have been estimated to represent as much as a 50% increase over the prevalence in equivalent populations during the previous decade. In 1997, health care expenditures attributable to diabetes in the US were estimated to be $98 billion (3). Undoubtedly, this is due not only to the widespread prevalence of the disease, but also to its chronic nature and disabling complications, affecting cardiovascular, renal, visual, and neurological function. Thus, perhaps the lack of an even more intense research effort into the pathophysiology of diabetes can only be attributed to the difficulty inherent in making progress in the study of this complex, multisystem disease. For these reasons, it is particularly important that in two recent articles — one appearing in the current issue of the journal Science and the other a recent issue of the JCI — Steven Shoelson, Gerald Shulman, and their colleagues present a new hypothesis, which not only purports to explain the insulin resistance of type 2 diabetes mellitus but also offers a clear basis for the development of novel therapeutics (4, 5). Over 90% of diabetes mellitus is accounted for by what is now called the type 2 variant. Unlike type 1 diabetes, for which there is a reasonable consensus that the disease results from autoimmune destruction of insulin-secreting pancreatic β cells, the etiology of type 2 diabetes remains a bit uncertain. Most investigators and clinicians agree that genetic and environmental factors contribute and that obesity is a frequent if not essential antecedent of the disease. Perhaps the most heated debate among diabetes researchers has concerned the nature of the primary inciting metabolic event, that is, whether it represents a disturbance in the normal pattern of insulin secretion or abnormalities in the action of insulin in peripheral tissues (6). Experiments in which defects in insulin secretion or action have been selectively introduced into mice by the modification of single or multiple genes have been surprisingly unhelpful at resolving this issue. Perhaps these genetic studies only serve to emphasize the multi–organ system nature of diabetes mellitus, in which several defects are required to elicit sufficient dysfunction to overwhelm physiological compensatory mechanisms and produce diabetes. Nevertheless, investigators have postulated a reasonable series of events to explain the evolution of type 2 diabetes (7). According to this model, peripheral insulin resistance represents the earliest event, but this is initially compensated by enhanced insulin secretion. Later, the β cell no longer keeps pace with the increased needs, and a relative lack of insulin is followed by an absolute deficiency of the hormone. At about the same time, the liver develops insulin resistance, thus leading to accelerated production of glucose. Whatever the precise sequence of the events by which impaired glucose tolerance matures to diabetes, there is little doubt that insulin resistance represents an important component of the fulminant disease. Insulin signaling then and now To appreciate studies of the pathophysiology of insulin resistance, one must be familiar with the state of knowledge of insulin signal transduction and how these pathways link to biological outputs. Twenty years ago, when it became clear that the insulin receptor not only conferred specificity in terms of hormone binding, but also possessed intrinsic protein tyrosine kinase activity, the predominant hypothesis was that insulin signaled by initiating a cascade of enzyme reactions. This concept was largely influenced by the biochemistry of glycogen metabolism, in which one kinase phosphorylates another, producing a linear path of amplifying reactions. Thus, it was expected that the insulin receptor would act by transferring a phosphate group to a tyrosine residue on another enzyme, thereby influencing the latter’s activity. A radical change in thinking was inspired by the discovery that the major sites phosphorylated by the PDGF receptor were not on a downstream signaling molecule but were instead specific tyrosine residues in the cytoplasmic domain of the PDGF receptor itself. Moreover, these covalent modifications did not alter the catalytic activity of the receptor but rather provided docking sites for the recruitment of a number of proteins, each capable of initiating a distinct signaling pathway. Thus, by the time a cDNA encoding the first major substrate of the insulin receptor, insulin receptor substrate 1 (IRS-1), was cloned and the primary structure of the protein deduced, it came as no surprise that it acted as a scaffolding protein (8). The predicted sequence contains numerous tyrosine residues in contexts that made them likely candidates for phosphorylation by the insulin receptor. Moreover, these sites, when phosphorylated, recruit several Turning down insulin signaling