Treatment with orlistat was associated with a clinically beneficial weight loss, irrespective of the prescribed dietary energy restriction (-500 or -1000 kcal/day). Patients who achieved >or=5% weight loss at 3 months achieved long-term, clinically beneficial weight loss with orlistat plus either diet. Therefore, identifying patients who lose at least 5% weight after 3 months and who maintain this weight loss up to 6 months is a valuable treatment algorithm to select patients who will benefit most from orlistat treatment in combination with diet.

In massively obese patients hyperinsulinemia and insulin insensitivity usually improve with weight loss. To clarify the mechanism of these reversible abnormalities eight nondiabetic massively obese patients were studied before and at intervals (3 months and 1 yr) after weight loss following gastroplasty. Insulin dynamics were studied during the hyperglycemic clamp (change in glucose, 7 mmol L-1 for 2 h) by measuring the area under the insulin and C-peptide response curves, representing, respectively, systemic insulin response and insulin production. Compared to lean age-matched normal subjects the massively obese patients had the expected fasting hyperinsulinemia and an exaggerated insulin response (P less than 0.05). Within 3 months and after an approximately 20% weight loss, they had a marked reduction in the systemic insulin response but no change in the C-peptide response. Therefore, the reduction in insulin response was due to enhanced hepatic insulin clearance rather than reduced insulin production. Thus, the liver serves a gate-keeping role in regulating the systemic insulin response to a glucose challenge. With additional weight loss of 14% and then weight maintenance, insulin clearance was further increased, and a reduction in insulin production became evident, since the C-peptide response was reduced. Exogenous insulin clearance was measured using the euglycemic clamp technique before and after weight loss. Insulin clearance was initially lower in the massively obese patients compared to that in the normal subjects (P less than 0.05) and increased toward normal with weight loss (P less than 0.05). Similarly, insulin sensitivity, as measured by the ratio of glucose metabolised per U endogenous insulin, normalized with weight loss and weight maintenance. Thus, after significant weight loss followed by weight maintenance at a reduced, but not ideal, level, insulin clearance, production, and sensitivity all reverted to normal. These findings suggest that adipose mass per se may not be exclusively responsible for altered insulin and glucose dynamics in obesity and that additional factors associated with obesity, such as nutrient load, adipose distribution, fat cell size, or fatty acid flux, play a contributing role.

To determine the long-term effect of exercise training on glucose control, 13 subjects with type I diabetes and 7 control subjects performed 45 min of cycle exercise three times per wk for 12 wk. The acute blood glucose response, the long-term effect on glucose control (glycosylated hemoglobin and fasting plasma glucose), and changes in nutrient intake were assessed. Fitness as measured by VO2 MAX increased in both control (33.8 +/- 1.7 to 43.2 +/- 3.5 ml/min/kg) and diabetic (38.7 +/- 3.3 to 46.5 +/- 3.6 ml/min/kg) (P less than 0.05) subjects although body weight remained unchanged. In the diabetic subjects, an acute glucose-lowering effect occurred with each exercise session throughout the 12-wk training period (225.8 +/- 16.1 to 148.5 +/- 16.8 mg/dl, P less than 0.001). However, fasting plasma glucose and glycosylated hemoglobin remained essentially unchanged (pretraining, 193.7 +/- 27.5 mg/dl and 10.7 +/- 0.3%; 6-wk training, 192.5 +/- 27.1 mg/dl and 10.7 +/- 0.03%; 12-wk training, 202 +/- 30.1 mg/dl and 10.3 +/- 0.8%). Total caloric intake as assessed by diet history increased significantly on exercising days (2569-2849 kcal, P less than 0.05). Although plasma glucose decreases acutely with exercise, increased caloric intake on exercising days obviates a long-term effect of training on glucose control. More precise guidelines and recommendations as to exercise timing and nutrient intake, likely based on self-monitoring of blood glucose, are required to achieve a beneficial effect of exercise training on metabolic control in type I diabetes.