Insulin Resistance In Type Diabetes

Insulin resistance is literally a lowered sensitivity/responsiveness of a tissue or multiple tissues to insulin. However, in the context of type 2 diabetes, it is defined as impaired insulin-mediated glucose clearance into skeletal muscle, usually (but not always) with dysregulation of hepatic glucose production by insulin. This is because early studies showed dual effects of the insulin response to a meal for control of postmeal glycemia: activation of glucose transport into skeletal muscle, which is the major site of insulin-mediated clearance of a glucose load, and deactivation of hepatic glucose production. Both of these effects are impaired in type 2 diabetes, which explains how the term was first applied. This does not imply that insulin signaling in other tissues is intact. In the last decade, the intracellular signaling cascade that is downstream from the insulin receptor has, to a large degree, been mapped. Unexpectedly, this cascade is present in tissues other than the classic insulin-regulated end-organs, such as islet B-cells, endothelial cells, neurons, etc. In addition, tissue specific knockout mouse studies have confirmed the presence of important physiologic effects of insulin in these tissues, with speculation that hyperglycemia causes dysregulation. However, the term "insulin resistance" still typically focuses only on muscle and liver, with endothelial dysfunction increasingly being added because of the presumed link between insulin resistance and cardiovascular disease in type 2 diabetes.

Simplistically, in the fasting state, the degree of hyperglycemia is directly determined by the rate of glucose overproduction by the liver. With eating, failure of adequate insulin-mediated nutrient-clearance into skeletal muscle combined with an attenuated deactivation of hepatic glucose production causes postprandial hyperglycemia (122).

Recent investigation has focused on defining the cellular defects, aided by powerful new technologies, including glucose clamping with muscle biopsies, NMR analysis of cellular metabolic pathways, genetic mapping of target and novel mutations, and knockout mouse models (often tissue specific) for most of the key enzymes and transcription factors in the intracellular insulin action cascade. The major defect in muscle is impaired glucose transport into the cell combined with defective storage as glycogen (123). Initially, it was assumed that genetic defects would be discovered in the glucose transport machinery, the insulin receptor, or its downstream signaling cascade. This has not been the case. Instead, current hypotheses mainly focus on disruption of the cellular insulin signaling cascade by external factors. Several mechanisms are under investigation:

1. Serine phosphorylation ofIRS-1. IRS-1 (Insulin Receptor Substrate-1, a component of the insulin signaling cascade that is immediately downstream from the insulin receptor) plays a key role in insulin signaling in skeletal muscle. The insulin signal propagates from the insulin receptor through IRS-1 to the distal signaling peptides, mainly through phosphorylation of tyrosines. Normoglycemic relatives of persons with type 2 diabetes have decreased insulin-stimulated IRS-1 tyrosine phosphorylation (124). A potential explanation relates to the recent finding that serine phosphorylation of IRS-1 attenuates insulin signaling, perhaps normally to turn off the insulin response, and that states of insulin resistance are characterized by enhanced serine phosphorylation of IRS-1 (125-128). Another idea is that degradation of IRS-1 is accelerated (129).

2. Excess glucosamine: Glucose is mainly metabolized through glycolysis, but a small percentage forms UDP-acetylglucosamine. Increased flux through this pathway has been shown to impair insulin-mediated glucose transport in adipocytes (130). Subsequent studies in mice whose livers overexpress the hexosamine biosynthesis enzyme, fructose-6-phosphate amidotransferase, showed enhanced glycogen storage and the metabolic syndrome (obesity, hyperlipidemia, and, glucose intolerance) (131), and rats fed glucosamine developed skeletal muscle insulin resistance (132). It is currently thought that this system normally acts as a cellular nutrient sensor, but goes awry when flux is excessive (133). At present, it remains unclear what role this pathway plays in human type 2 diabetes (134).

3. Defective mitochondria: There is great interest in mitochondrial dysfunction as a cause of skeletal muscle insulin resistance. This was highlighted in an important study that used state of the art NMR technology to examine normal weight, normoglycemic, insulin resistant offspring of parents with type 2 diabetes, finding defective skeletal muscle mitochondrial function (135). Increased storage of triglyceride in muscle and liver has recently been proposed to be a marker of insulin resistance (136,137). Petersen et al have speculated that mitochondrial dysfunction explains both the excess triglyceride accumulation and the defective glucose uptake that characterize muscle-related insulin resistance in type 2 diabetes because of decreased fatty acid oxidation and ATP production (135). Additional findings that support mitochondrial dysfunction are more type IIb muscle fibers (nonoxidative type) in persons with type 2 diabetes (138), and a reduced function and number of skeletal muscle mitochondria (139) that improved in tandem with an increased insulin sensitivity after weight loss and dietary therapy (140).

4. Fatty acid-induced insulin resistance and a role for inflammation. As discussed earlier, another aspect of the diabetes phenotype is hyperlipidemia. There is now strong experimental support for insulin resistance-inducing effects of excess fatty acids from both lipid infusion studies in healthy man and in vitro studies (141-144). It was initially assumed that the mechanism was a competition between fatty acids and glucose oxidation (the Randle cycle), but a much more complex effect of fatty acids on insulin signaling has evolved. Considerable evidence now supports fatty acids interfering with insulin signaling through a cascade of effects that includes protein kinase C (PKC)-induced serine phosphorylation of IRS-1 (PKC-theta knockout mice are resistant to fat-induced insulin resistance (145)), the proinflammatory mediators c-Jun N-terminal kinase (JNK) and IkappaB/NfkappaB (146), and suppressor of cytokine signaling 3(SOCS-3), which impairs insulin signaling at several sites (147). High dose aspirin ameliorates insulin resistance in animals by interfering with IkappaB kinase beta (IKKbeta) (148), and multicenter human trials to test that effect are underway.

5. Alternate fatty acid effects. Other aspects of lipotoxicity-induced insulin resistance are being investigated, including induction of oxidative stress (95) and malonyl-CoA-induced alterations in AMP kinase (149). The latter is proposed to be a site of action of the oral agent metformin (150).

6. Altered adipokine regulation. The last decade has seen the discovery that adipose tissue is far more complex than simply acting as a storage site for triglyceride. Adipocytes are now known to produce many proteins (cytokines and adipokines) that have effects on a number of tissues, including skeletal muscle and liver, and concurrently on insulin sensitivity (151). Of particular interest regarding the effect on skeletal muscle are TNFa (152) and adiponectin (153-155), as well as the recently described retinol binding protein 4 (156). Another adipocyte-related factor of current interest is resistin, which was initially linked to the insulin resistance of obesity and diabetes (157). Subsequently its pathological role has been questioned (158). However, interest in resistin has returned, as resistin null mice have been shown to become hypoglycemic during fasting, and are protected against glucose intolerance and insulin resistance during fat feeding, confirming a physiologic effect (159). This study localized the action of resistin to the liver, showing that it de-activates AMP-kinase, impairing transcriptional regulation of gluconeogenic enzymes. Subsequent studies using knockout mice, transgenic resistin overexpressing mice, adenoviral overexpression systems, interfering RNA, etc. confirmed and expanded this hypothesis (160-162). The results unequivocally show that resistin has an important regulatory role over hepatic glucose production in health and disease, at least in rodents. However, the role of resistin has not yet been elucidated in humans.

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