In type 2 diabetes patients treated with steady-state plasma concentrations of insulin, muscle glycogen synthesis was ~50% lower than in normal individuals and accounted for almost the entire insulin-stimulated glucose uptake in both normal and diabetic subjects . These studies demonstrate that under hyperglycemic, hyperinsulinemic conditions, muscle glycogen synthesis is the major pathway for glucose utilization in both normal and diabetic subjects and that impairment in muscle glycogen synthesis may have a key role in causing insulin resistance in patients with type 2 diabetes. Intracellular glucose-6-phosphate is an intermediary metabolite between glucose transport/phosphorylation and glycogen synthesis, hence the intracellular concentration of glucose-6-phosphate will be determined by the relative activities of these two steps. In patients with type 2 diabetes, the decreased activity of glycogen synthase should lead to increased glucoses-phosphate concentrations compared with those of normal individuals . In type 2 diabetic patients, increases in glucose-6-phosphate in response to insulin stimulation were significantly blunted, suggesting that either decreased glucose transport or decreased glucose phosphorylation activity could be involved in the development of muscle insulin resistance. In order to determine whether failing the boost glucose-6-phosphate levels is a primary or an acquired defect, lean normoglycemic insulin-resistant offspring of parents with type 2 diabetes were also studied . These individuals have a ~40% likelihood of developing diabetes later in life. In these subjects a ~50% reduction was shown in the rate of insulin-stimulated whole body glucose metabolism, which has been attributed to a decrease in the rate of muscle glycogen synthesis . Collectively, these data suggest that defects in insulin-stimulated muscle glucose transport/phosphorylation activity are very early events in the pathogenesis of type 2 diabetes. To examine the role of the glucose phosphorylation step in determining muscle glu-cose-6-phosphate concentrations, the hexokinase activity in type 2 diabetic individuals was evaluated. Intracellular glucose is an intermediary metabolite between glucose transport and glucose phosphorylation, and its concentration reflects the relative activities of these two steps in muscle glucose metabolism. In patients with type 2 diabetes, the intracellular glucose concentrations have been found to be lower than the concentrations expected if hexokinase II was the primary rate-controlling enzyme for glycogen synthesis . These data strongly suggest that, in type 2 diabetic patients, defective insulin-stimulated glucose transport activity is the primary factor responsible for the development of insulin resistance.
In a cross-sectional study of young, normal weight offspring of type 2
diabetic patients, an inverse relationship between fasting plasma fatty acid concentrations and insulin sensitivity was found, which is in agreement with the hypothesis that impaired fatty acid metabolism contributes to insulin resistance in patients with type 2 diabetes [20,21]. Competition between fatty acids and glucose for substrate oxidation was observed in rat heart more than 40 years ago. Randle et al.  speculated, for the first time, that increased fat oxidation led to insulin resistance associated with obesity and hypothesized that intracellular fatty acid accumulation would lead to an increase in the intramitochondrial acetyl coenzyme A/coenzyme A and NADH/NAD+ ratios, leading to inhibition of pyruvate dehydrogenase and increasing concentrations of intracellular citrate. The citrate is a negative modulator of phosphofructokinase, the most important rate-controlling enzyme in glycolysis. Thus, citrate accumulation would lead to increasing intracellular glucose-6-phosphate concentrations through the inhibition of hexokinase II activity. The inhibition of hexokinase II activity would result in an increase in intracellular glucose concentrations and decreased muscle glucose uptake. Recently, Schulman and colleagues  have recently shown that maintaining high levels of plasma fatty acid concentrations for 5 h resulted in a ~50% reduction in insulin-stimulated rates of muscle glycogen synthesis and whole body glucose oxidation compared with the control subjects. Contrary to the prediction of Randle's model, where fat-induced insulin resistance would result in an increase in intramuscular glucose-6-phosphate concentrations, these new data suggest that increases in plasma fatty acid concentrations first induce insulin resistance by inhibiting glucose transport and/or phosphorylation activity and that this event causes the reduction in muscle glycogen synthesis and glucose oxidation. Obese individuals , patients with type 2 diabetes , and lean, normoglycemic insulin-resistant offspring of type 2 diabetic individuals  show a reduction in insulin-activated glucose transport/phosphorylation activity, similar to normal subjects maintained at high plasma fatty acid levels. Hence, this evidence suggests that accumulation of intramuscular fatty acid metabolites may play a key role in the pathogenesis of insulin resistance in obese patients and patients with type 2 diabetes. Furthermore, elevated plasma fatty acid concentrations significantly reduced intracellular glucose concentrations , implying that the rate-controlling step for fatty acid-induced insulin resistance in humans is glucose transport. These data are in disagreement with the mechanism proposed by Randle, which postulates an increase in both intracellular glucose-6-phosphate and glucose concentrations. The reduced glucose transport activity found in these subjects could be the result of fatty acid effects on the glucose transporter-4 (GLUT-4). In skeletal muscle GLUT-4 mRNA were found normal in multiple insulin-resistant disease state, including obesity and type 2 diabetes [27,28] such as in lean and non-diabetic subjects. This has given rise to the inference that defects in GLUT-4 translocation cause insulin resistance in muscle, and supportive data are available [29,30].An important study of Garvey et al.  demonstrated that in diabetic subjects a greater proportion of GLUT-4 was abnormally localized in denser membrane vesicles and it is not normally transferred in the cellular membrane limiting the uptake of the glucose from the cell. The decreased GLUT-4 translocation to the plasma membrane may be the result of a direct mechanism involving alterations in the trafficking, budding, fusion, or activity of GLUT-4 or it may be due to fatty acid-induced alterations in upstream insulin signaling events. The latter possibility has been analyzed in muscle biopsy samples, in which an accumulation of intracellular lipid metabolites such as diacylglycerol was found. This condition was shown to activate a serine kinase cascade that leads to defects in insulin signaling and action [26,32].
An attractive hypothesis that explains the cause of several forms of insulin resistance in humans holds that a serine/threonine kinase cascade may be activated by increasing intracellular fatty acid metabolites like diacylglyc-erol [32-37]. The serine kinase activation may lead to phosphorylation of critical serine sites (Ser 307, Ser 612) on IRS-1 [38-40]. Serine phosphorylated forms of IRS-1 fail to associate with and activate PI3K cascade, resulting in decreased activation of glucose transport and other down-stream events. If this hypothesis is correct, any alteration that leads to an increase in intra-cellular fatty acid metabolites in muscle, through increased delivery from excess caloric intake, sedentary life style, or alterations in adipocyte fatty acid metabolism and/or through decreased mitochondrial oxidation, might be expected to induce insulin resistance in muscle .
The capacity of chronic exercise training to reverse this defect in glucose transport/phosphorylation activity was then examined .After exercise training, insulin sensitivity and insulin-simulated muscle glycogen synthesis normalized in the insulin-resistant offspring, and this could be attributed to the correction of their defects in muscle glucose transport/phos-phorylation activity. These data strongly suggest that aerobic exercise might be useful in reversing insulin-resistance in these pre-diabetic individuals and that it may prevent the development of type 2 diabetes.
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