Metabolic effects of weight loss The pathogenesis of type 2 diabetes involves peripheral insulin resistance (i.e. resistance of peripheral tissues and particularly skeletal muscle to the glucose uptake-promoting effect of insulin) and inadequate secretion of insulin from the pancreatic beta-cells upon glucose stimulation, leading to fasting and postprandial hyperglycemia. Weight loss, achieved as a result of chronic negative energy balance induced by a variety of ways (calorie restriction, exercise, pharmacotherapy, bariatric surgery), improves metabolic function and is considered the cornerstone of diabetes prevention and management. Part of the beneficial effect of weight loss could be due to the reduction in total body fat, intra-abdominal fat, and ectopic fat accumulation in metabolically active organs (e.g. muscle, pancreas, and liver), however acute perturbations in energy balance (whether positive or negative, for a period of 24-72 hours) can affect insulin action, beta-cell function, and glycemic control even before any changes in body weight or body fat distribution occur. For example, one day of overfeeding disrupts 24-hr glucose homeostasis, and two days of caloric restriction improves insulin action. Likewise, exercise can also lead to negative energy balance and is a very potent intervention that readily improves metabolic function and particularly insulin sensitivity, even after just a single session. Nevertheless, the degree of negative energy balance that needs to be achieved by calorie restriction or exercise in order to improve insulin action and beta-cell function is not known, and the dose-response relationship between negative energy balance and metabolic function remains elusive. Furthermore, the comparative efficacy of calorie restriction and exercise on improving the mechanisms regulating glucose homeostasis (i.e. insulin sensitivity and beta-cell function) has not been adequately studied. One study found that for the same amount weight loss (8-9 % of initial body weight) induced by a low-calorie diet or endurance exercise, exercise caused a greater reduction in fat mass, a smaller decrease in muscle mass, and led to a greater increase in insulin-mediated glucose disposal during a hyperinsulinemic-euglycemic clamp (by ~30 %), and a greater reduction in the total insulin response to an oral glucose tolerance test (by ~2.5-fold), compared with matched diet-induced weight loss; although these differences did not reach statistical significance. These observations raise the possibility that, for the same negative energy balance, exercise may be more effective than calorie restriction in improving metabolic function; however these findings are difficult to interpret in the face of the concomitant more favorable changes in body composition and fat distribution. No study has directly assessed the effects of the same acute negative energy balance induced by calorie restriction or aerobic exercise on metabolic function.