Type 2 diabetes is characterized by insulin resistance (at the level of skeletal muscle, adipose tissue, and liver) and by impaired P-cell function (68,129-134). Both genetic and acquired defects have been shown to play a role in affecting insulin action and insulin secretion. Among the acquired defects, obesity and glucotoxicity (135-137) have received special attention as both are believed to worsen insulin resistance and possibly contribute to the decline in P-cell function. Dissecting the role of genetic factors from those attributed to obesity and/or hyperglycemia itself has been particularly challenging. Equally difficult has been to define the sequence of events that results in the development of insulin resistance, and ultimately T2DM, in genetically predisposed subjects. For instance, it can be argued that adipose tissue insulin resistance may be the initiating event as it is present in nonobese normal glucose-tolerant subjects with a FH of type 2 diabetes long before the development of hyper-glycemia. In such individuals, adipose tissue resistance to the action of insulin is characterized by increased rates of lipolysis with elevated plasma FFA levels despite chronic hyperinsulinemia and impaired suppression of plasma FFA by insulin, or just the latter with "normal" plasma FFA levels (although inadequately "normal" for the elevated plasma insulin concentration) (138-142) . This is also typical of obese nondiabetic (143-145) and in T2DM individuals (68, 129-134, 146).
The term "lipotoxicity" was coined by Unger et al. (147, 148) to describe the deleterious effects of high fatty acid supply on P-cell function. Since then much work in the field has given the term lipo-toxicity a broader sense and is currently applied more generally to the deleterious effects of fatty acids on tissues that would not normally be destined to store large amounts of fat. This places an extraordinary metabolic stress to these tissues. So when fat supply surpasses the metabolic needs of skeletal muscle, liver, and/or pancreatic P-cells, the offer of fatty acids in excess of their normal storage and oxidative capacity redirects lipid flux into harmful pathways of nonoxidative metabolism and intracellular accumulation of toxic metabolites renders tissues resistant to the action of insulin. Many studies have shown that hepatic and skeletal muscle insulin resistance can be readily induced in healthy individuals after short periods of lipid infusion that acutely raise plasma FFA levels (68, 129-134, 146).
Liver and muscle insulin resistance are both central to the pathogenesis of T2DM. Hepatic insulin resistance per se may drive a chronic increase in insulin secretion aimed at refraining excessive rates of hepatic glucose production and prevent subsequent hyperglycemia. Hepatic insulin resistance is frequently associated with a fatty liver, diminished insulin clearance, and perpheral hyperinsulinemia. In such a scenario, hepatic insulin resistance could cause/contribute to muscle insulin resistance as mild chronic hyperinsulinemia per se (i.e., an approximately two- to threefold increase in plasma insulin concentration above normal, as seen in insulin-resistant states such as obesity or T2DM) may cause peripheral (muscle) insulin resistance just after 72 h in otherwise insulin-sensitive individuals (149). Steatosis and hepatic insulin resistance are also characterized by an excessive secretion of proinflam-matory cytokines [transforming growth factor-P (TGF-P), TNF-a, hsCRP, etc.] that also are known to promote peripheral insulin resistance and could "close the loop" of a self-perpetuating state of insulin resistance and systemic inflammation as described above for adipose tissue insulin resistance.
Finally, it is well established that there is an intrinsic defect in insulin action in skeletal muscle of patients with T2DM. Skeletal muscle insulin resistance has been well documented in muscle biopsy studies from lean normal glucose-tolerant and, otherwise, healthy subjects genetically predisposed to T2DM (without the confounding factor of obesity and elevated plasma FFA levels), long before the development of frank lipo- and/or gluco-toxicity observed in T2DM (141, 142, 150). If skeletal muscle insulin resistance would be the initiating event in the cascade of events toward T2DM, one could put forward the hypothesis that skeletal muscle insulin resistance would lead to chronic hyper-insulinemia and place a sustained P-cell demand that could lead to T2DM in genetically susceptible individuals. Sustained systemic hyperinsulinemia is also known to promote hepatic steatosis, insulin resistance, and diminished hepatic insulin clearance, which combined would feed and perpetuate chronic hyperinsulinemia. It would also stimulate hepatic triglyceride secretion with potential to cause more lipotoxicity by delivering more lipid to insulin-sensitive tissues, such as muscle (130), while potentially causing P-cell lipotoxicity (147, 148) . as well as promoting a MS phenotype by stimulating HDL-C turnover with increased clearance and lower plasma HDL-C levels (86). Taken together, the above scenarios indicate that defects causing chronic hyperinsulinemia (either secondary to liver or muscle insulin resistance) can easily downregulate the insulin receptor and its downstream signaling steps and cause insulin resistance at the level of muscle, liver, and/or adipose tissue, again closing the loop for a state of self-sustaining insulin resistance and chronic inflammation as seen in obesity and T2DM.
In summary, genetic and acquired factors establish a tangled web of metabolic disturbances. Individual defects in each target tissue (muscle, liver, or adipose tissue) appear to be sufficient to trigger a self-perpetuating and down-spiraling cascade of events difficult to reverse. It is important to recognize that insulin resistance can be entirely acquired by fatty acid excess, as demonstrated in healthy lean insulin-sensitive individuals that develop muscle and hepatic insulin resistance within hours of a low-dose lipid infusion (141, 142, 151). Therefore, we cannot miss the opportunity to apply this knowledge to the care of our patients; lifestyle interventions can reverse the acquired defects associated with sedentary behaviors that grip modern society (i.e., lipotoxicity from obesity), and delay the development of diabetes in subjects genetically predisposed to the disease as shown in clinical trials (22, 23, 152), even as their intrinsic genetic abnormalities (i.e., insulin resistance, mitochondrial dysfunction, and aerobic capacity) appear to be more "fixed" and difficult to overcome compared to those without such a genetic background.
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