Down-regulation of Insulin Sensitivity After Oral Glucose Administration: Evidence for the "Anti-Incretin Effect"

Intestinal nutrients stimulate insulin-secretion more potently than intravenous glucose administration under similar plasma glucose levels ("incretin effect"). According to the "anti-incretin theory", intestinal nutrients should also cause 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 while reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery.Eight healthy volunteers and eight severely obese subjects with insulin-resistance were studied. Insulin secretion, insulin sensitivity, rate of glucose appearance, and disposition index were measured after oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass (biliopancreatic diversion- BPD). D-xylose test and lactulose/rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Montecarlo 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 I.V. glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. There was no evidence of glucose malabsorption. 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 down-regulates 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.