BACKGROUND: Altered gut hormone secretion may bolster resolution of insulin resistance after gastric bypass (GB). The independent effects of weight loss and hormonal secretions on insulin resistance are unknown. We sought to: 1) delineate short-term changes in insulin-mediated peripheral glucose uptake (M-Value), gut and pancreatic hormone secretion, and body composition, while controlling for energy balance; and 2) delineate the same changes after massive weight loss at 6 months after GB. METHODS: Non-diabetic morbidly obese patients were randomized to GB followed by standardized calorie restriction (GB, n=10) or to caloric restriction only (Diet, n=10). Metabolic evaluations were done at baseline and at 15 days. Patients randomized to the Diet group underwent GB after completing the initial evaluation. The 10 GB patients were evaluated again at 6 months post-operatively.RESULTS: Baseline body composition, fasting insulin, and HOMA-IR did not differ between groups. During baseline euglycemic hyperinsulinemic clamp, insulin resistance was profound in all subjects; average M-Value was about one-third of that for lean controls (2.3±0.5 vs. 7.3±0.3 mg/kg/min, p<0.01). At 15 days, body composition and weight loss did not differ between groups (% Excess Weight Loss, EWL; Diet, 8.1+0.9 vs. GB, 10.1+0.9, P=0.19). During a 5-hour meal test, only the GB group had altered patterns of glucose kinetics, GIP, GLP-1 and insulin secretions. At 15 days, fasting insulin and HOMA-IR decreased similarly in both groups. M-Values did not change in either group (Diet, 2.3±0.4 vs. GB, 2.5±0.5, P=0.78), but average serum insulin concentrations during clamp decreased in the GB group (-22±5 vs. -2±6, P=0.032). At 6 months, GB patients had significant weight loss (%EWL 52+4.1), the altered pattern of glucose kinetics and gut and pancreatic hormones secretions persisted, fasting insulin and HOMA-IR decreased further, and only then did M-values improve significantly (4.3±0.4, p<0.01 vs. GB Group at baseline and 15 days). Average serum insulin concentrations during clamp remained low.CONCLUSIONS: The decrease in fasting insulin and HOMA-IR at 15 days in both groups reflects primarily an improvement in hepatic insulin sensitivity. The same M-Value achieved with lower serum insulin levels in the GB group at 15 days suggests better hepatic insulin clearance with GB. This is likely a reflection of improved reduction in liver fat and altered hormonal secretions with GB. The altered pattern of glucose kinetics, gut and pancreatic hormone secretions around a meal is present early after GB and persists at 6 months, but M-Values only improved significantly after significant weight loss.