OBJECTIVE: The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery. RESEARCH DESIGN AND METHODS: Peripheral insulin sensitivity and beta-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured. RESULTS: The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 +/- 816 to 577 +/- 155 pmol x l(-1) x min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 +/- 24.4 to 424.4 +/- 64.3 pmol x l(-1) . min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration. CONCLUSIONS: Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.