Downregulation of Insulin Sensitivity After Oral Glucose Administration: Evidence for the Anti-Incretin Effect.

Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti-incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery.

Glycemic control after metabolic surgery: a Granger causality and graph analysis.

The purpose of this study was to examine the contribution of nonesterified fatty acids (NEFA) and incretin to insulin resistance and diabetes amelioration after malabsorptive metabolic surgery that induces steatorrhea. In fact, NEFA infusion reduces glucose-stimulated insulin secretion, and high-fat diets predict diabetes development. Six healthy controls, 11 obese subjects, and 10 type 2 diabetic (T2D) subjects were studied before and 1 mo after biliopancreatic diversion (BPD). Twenty-four-hour plasma glucose, NEFA, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) time courses were obtained and analyzed by Granger causality and graph analyses. Insulin sensitivity and secretion were computed by the oral glucose minimal model. Before metabolic surgery, NEFA levels had the strongest influence on the other variables in both obese and T2D subjects. After surgery, GLP-1 and C-peptide levels controlled the system in obese and T2D subjects. Twenty-four-hour GIP levels were markedly reduced after BPD. Finally, not only did GLP-1 levels play a central role, but also insulin and C-peptide levels had a comparable relevance in the network of healthy controls. After BPD, insulin sensitivity was completely normalized in both obese and T2D individuals. Increased 24-h GLP-1 circulating levels positively influenced glucose homeostasis in both obese and T2D subjects who underwent a malabsorptive bariatric operation. In the latter, the reduction of plasma GIP levels also contributed to the improvement of glucose metabolism. It is possible that the combination of a pharmaceutical treatment reducing GIP and increasing GLP-1 plasma levels will contribute to better glycemic control in T2D. The application of Granger causality and graph analyses sheds new light on the pathophysiology of metabolic surgery.

Insulin sensitivity and secretion changes after gastric bypass in normotolerant and diabetic obese subjects.

OBJECTIVE: To elucidate the mechanisms of improvement/reversal of type 2 diabetes after Roux-en-Y gastric bypass (RYGB). METHODS: Fourteen morbidly obese subjects, 7 with normal glucose tolerance and 7 with type 2 diabetes, were studied before and 1 month after RYGB by euglycemic hyperinsulinemic clamp (EHC), by intravenous glucose tolerance test (IVGTT) and by oral glucose tolerance test (OGTT) in 3 different sessions. Intravenous glucose tolerance test IVGTT and OGTT insulin secretion rate (ISR) and sensitivity were obtained by the minimal model. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Six healthy volunteers were used as controls. RESULTS: Total ISR largely increased in diabetic subjects only when glucose was administered orally (37.8 ± 14.9 vs 68.3 ± 22.8 nmol; P < 0.05, preoperatively vs postoperatively). The first-phase insulin secretion was restored in type 2 diabetic after the IVGTT (Φ1 × 10: 104 ± 54 vs 228 ± 88; P < 0.05, preoperatively vs postoperatively; 242 ± 99 in controls). Insulin sensitivity by EHC (M × 10) was slightly but significantly improved in both normotolerant and diabetic subjects (1.46 ± 0.22 vs 1.37 ± 0.55 mmol·min·kg; P < 0.05 and 1.53 ± 0.23 vs 1.28 ± 0.62 mmol·min·kg; P < 0.05, respectively). Quantitative insulin sensitivity check index was improved in all normotolerant (0.32 ± 0.02 vs 0.30 ± 0.02; P < 0.05) and diabetic subjects (0.33 ± 0.03 vs 0.31 ± 0.02; P < 0.05). GIP and GLP-1 levels increased both at fast and after OGTT mainly in type 2 diabetic subjects. CONCLUSIONS: The large increase of ISR response to the OGTT together with the restoration of the first-phase insulin secretion in diabetic subjects might explain the reversal of type 2 diabetes after RYGB. The large incretin secretion after the oral glucose load might contribute to the increased ISR.