Bile Modulates Secretion of Incretins and Insulin: A Study of Human Extrahepatic Cholestasis

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 7; pp. 2685 - 2694
• Main Authors: Mezza, Teresa, Moffa, Simona, Ferraro, Pietro Manuel, Quero, Giuseppe, Capece, Umberto, Carfì, Andrea, Cefalo, Chiara M A, Cinti, Francesca, Sorice, Gian Pio, Impronta, Flavia, Mari, Andrea, Pontecorvi, Alfredo, Alfieri, Sergio, Holst, Jens J, Giaccari, Andrea
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.07.2019; Copyright Oxford University Press; Oxford University Press
• Subjects: Analysis; Beta cells; Bile; Bilirubin; Cholestasis; Dextrose; Diabetes mellitus; Ethylenediaminetetraacetic acid; Fasting; Gallbladder diseases; Gastrointestinal surgery; GIP protein; Glucagon; Glucagon-like peptide 1; Glucose; Glucose tolerance; Glucose tolerance tests; Insulin; Insulin secretion; Jaundice, Obstructive; Laboratory testing; Obesity; Pancreas; Physiological aspects; Remission; Secretion; Surgery; Tumors; Type 2 diabetes
• DOI: 10.1210/jc.2018-02804
• ISSN: 0021-972X; 1945-7197

Abstract 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 is still unclear. Here, we propose an alternative method to investigate the relationship between alterations in physiological bile flow and insulin and incretin secretion by studying changes in gut-pancreatic function in extrahepatic cholestasis in nondiabetic humans. Methods To pursue this aim, 58 nondiabetic patients with recent diagnosis of periampullary tumors underwent an oral glucose tolerance test (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 a strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as a marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during the OGTT. Altered bile flow elicited a markedly greater increase in glucagon and glucagon-like peptide 1 (GLP-1) secretion at fasting state, and following the meal, both glucagon and GLP-1 levels remained increased over time. Conversely, Glucose-dependent insulinotropic polypeptide (GIP) levels were comparable at the fasting state, whereas the increase following meal ingestion was significantly blunted with high bilirubin levels. We reveal strong correlations between total bilirubin and glucagon and GLP-1 levels. Conclusions Our findings suggest that acute extrahepatic cholestasis determines major impairment in enteroendocrine gut-pancreatic secretory function. The altered bile flow may determine a direct deleterious effect on β-cell function, perhaps mediated by the impairment of incretin hormone function. Acute alteration in bile flow in nondiabetic humans is associated with hyperglycemia, impaired insulin secretion capacity, increased glucagon and GLP-1 secretion, and a reduction in GIP secretion.