Bile Modulates Secretion of Incretins and Insulin: A Study of Human Extrahepatic Cholestasis
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Bile Modulates Secretion of Incretins and Insulin: A Study of Human Extrahepatic Cholestasis. / Mezza, Teresa; Moffa, Simona; Ferraro, Pietro Manuel; Quero, Giuseppe; Capece, Umberto; Carfi, Andrea; Cefalo, Chiara M. A.; Cinti, Francesca; Sorice, Gian Pio; Impronta, Flavia; Mari, Andrea; Pontecorvi, Alfredo; Alfieri, Sergio; Holst, Jens J.; Giaccari, Andrea.
In: Journal of Clinical Endocrinology & Metabolism, Vol. 104, No. 7, 2019, p. 2685-2694.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Bile Modulates Secretion of Incretins and Insulin: A Study of Human Extrahepatic Cholestasis
AU - Mezza, Teresa
AU - Moffa, Simona
AU - Ferraro, Pietro Manuel
AU - Quero, Giuseppe
AU - Capece, Umberto
AU - Carfi, Andrea
AU - Cefalo, Chiara M. A.
AU - Cinti, Francesca
AU - Sorice, Gian Pio
AU - Impronta, Flavia
AU - Mari, Andrea
AU - Pontecorvi, Alfredo
AU - Alfieri, Sergio
AU - Holst, Jens J.
AU - Giaccari, Andrea
PY - 2019
Y1 - 2019
N2 - 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 gutpancreatic 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 beta-cell function, perhaps mediated by the impairment of incretin hormone function.
AB - 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 gutpancreatic 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 beta-cell function, perhaps mediated by the impairment of incretin hormone function.
U2 - 10.1210/jc.2018-02804
DO - 10.1210/jc.2018-02804
M3 - Journal article
C2 - 30874733
VL - 104
SP - 2685
EP - 2694
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 7
ER -
ID: 225670557