Can Weight Loss andor Exercise Reverse Muscle Insulin Resistance

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It is unquestionable that cardiorespiratory fitness reduces the risk of CVD and that low rates of physical activity are associated with a greater risk of developing insulin resistance, obesity, MS, and T2DM (51, 231-233). In the midst of an epidemic of obesity and diabetes, renewed interest has developed in understanding the molecular pathways by which exercise appears to reverse defects associated with insulin resistance [reviewed in-depth under .234-236)]. While the role of exercise will be reviewed in other chapters, a few points deserve attention. First, as discussed in the previous section, it is important to recognize that lipid accumulation in skeletal muscle and insulin resistance are not just the result of excessive fatty acid supply, but likely the combination of increased supply and a reduced capacity of muscle to use it as a fuel for energy needs. Because disruption in lipid metabolism/FFA flux appears to be causal in the development of insulin resistance, it follows that it should be possible to reverse FFA-induced insulin resistance with interventions that improve lipid homeostasis, such as aerobic endurance training. An increase in lipid oxidation plays an important role in the improvement observed in insulin sensitivity in skeletal muscle from high-fat-fed rodents (237) and in obese subjects following training (238). Moderate-intensity physical activity (—four to five times per week for 30-40 min for 16 weeks), combined with weight loss, induces mitochondrial biogenesis, improved function, and morphologic changes (i.e., an increase in mitochondrial size) in previously sedentary obese subjects (227, 239). These changes have also been reported in older sedentary individuals (>65 years of age) with rather modest amounts of training (240). Exercise also enhances in a time- and intensity-dependent manner insulin signaling pathways at multiple levels in lean healthy subjects, including insulin receptor, IRS-1 and the PI 3-kinase association with IRS-1 phosphorylation (241), HKII mRNA/activity (242), GLUT-4 protein expression and glycogen synthase activity (243). and AMPK activity and AS160 phosphorylation, although in skeletal muscle from obese and T2DM subjects the potential of exercise to stimulate the above steps is blunted (188, 241, 242, 244). One mechanism by which regular exercise improves muscle insulin sensitivity involves inhibition of the inflammatory pathways discussed earlier, such as NF-kP that interfere with insulin signaling in T2DM (188).

While there is no doubt that aerobic exercise training is a potent and effective intervention strategy for individuals with insulin resistance, debate remains whether regular physical activity may improve insulin sensitivity independent of weight loss in T2DM, what is the minimum amount of exercise needed for health benefits and which exercise prescriptions may more successfully impact glycemic control and prevent CVD in patients with T2DM. The CV protection conferred by exercise includes antiinflammatory, hormonal, lipid, blood pressure, and multiple direct vascular effects beyond those related to improvements in muscle insulin sensitivity ( 232, 233). To highlight an example of the adverse CV impact that disrupted fatty acid metabolism may have in humans, we have observed that just a mild increase in plasma FFA (to levels observed in T2DM) by means of a lipid infusion increases blood pressure (245) and induces endothelial dysfunction and systemic inflammation in lean healthy nondiabetic volunteers (246). Exercise promotes an improvement in endothelial function and capillary recruitment in muscle, although this response is also reduced in patients with T2DM (247). However, in a finding of value toward understanding the CV protective effects of exercise in diabetics, we demonstrated that just 8 weeks of moderate-intensity aerobic exercise training can improve endothelial dysfunction together with increased muscle insulin sensitivity in patients with T2DM (248).

While regular exercise and weight loss combined appear to have the greatest impact on insulin resistance, reversal of lipotoxicity and CV risk (51, 231-233), it is sometimes discouraging to patients that weight loss is minimal or none at all. However, it should be noted that training even without weight loss has been reported to improve insulin sensitivity (22, 233, 249, 250), although not by all (185). Whether aerobic training, resistance training, or both combined are best for subjects with diabetes is a matter of debate. A recent Canadian study performed across eight community-based facilities in 251 adults (age 39-70, mean = 54) addressed this issue. Subjects were asked to exercise with moderation three times a week for 22 weeks. The authors reported improved glycemic control with all three modalities (0.5%), although greater for combined aerobic and resistance training (an additional 0.5% reduction). These results are consistent with a large body of evidence about the metabolic benefits of moderate intensity exercise in terms of better glycemic control for patients with T2DM (233). Regular physical activity is also important for the reduction of the risk of developing T2DM (22, 152, 250). Recently, Sui et al. (251) confirmed this in an observational cohort of 6,249 women aged 20-79 years that were free of diabetes at baseline. During a 17-year follow-up, 143 cases of T2DM occurred. In multivariate analysis (including BMI), comparing the least fit third with the upper third of cardiorespiratory fitness there was a highly significant 39% reduction in the development of diabetes. From a practical perspective, a large body of evidence has led to recent "minimum recommendations" by the American College of Sports Medicine and the American Heart Association (252, 253) for physical activity. These recommend 30 min of moderate intensity (or 20 min of vigorous intensity) exercise 5 days per week for individuals between 18 and 65 years of age and to be adapted as possible to individual 65 and older or with chronic medical conditions as functional capacity allows. Fitness is a significant mortality predictor in older adults, independent of overall or abdominal adiposity and even after adjustment for smoking, baseline health, and either BMI, waist circumference, or percent body fat (51). Clinicians should be aware of the importance of preserving functional capacity by recommending regular physical activity for overweight and obese insulin-resistant subjects, particularly in a high-risk category for developing T2DM (i.e., positive FH in a first-degree relative, ethnic minority, and history of gestational diabetes).

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