Bile modulates secretion of incretins and insulin: a study on human extrahepatic cholestasis

OBJECTIVE: changes in bile flow after bariatric surgery may beneficially modulate secretion of insulin and incretins leading to diabetes remission. However, the exact mechanism(s) involved are still unclear. We here propose an alternative method to investigate the relation between alterations in physiological bile flow and insulin and incretin secretion by studying the changes in gut-pancreatic function in extrahepatic cholestasis in non-diabetic humans. METHODS: to pursue this aim, 58 non-diabetic patients with recent diagnosis of periampullary tumors underwent an OGTT, and a subgroup of 16 patients also underwent 4-hour mixed meal tests and hyperinsulinemic euglycemic clamps. RESULTS: The analysis of the entire cohort revealed strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during OGTT. Altered bile flow elicited a markedly greater increase in glucagon and GLP-1 secretion at fasting state and following the meal both glucagon and GLP-1 levels remained increased over time. Conversely, GIP levels were comparable at the fasting state, while the increase following meal ingestion was significantly blunted in H-Bil. We revealed strong correlations between total bilirubin and glucagon and GLP-1 levels. CONCLUSIONS: Our findings suggest that acute extrahepatic cholestasis determines a significant impairment in the entero-endocrine gut-pancreatic secretory function. The altered bile flow might determine a direct deleterious effect on beta cell function perhaps mediated by the impairment of incretin hormone function.