BACKGROUND: Genetic and acquired mechanisms underlying the association of nonalcoholic fatty liver disease (NAFLD) with diabetes are unknown. Glucose-dependent insulinotropic polypeptide (GIP) was recently linked to adipocyte metabolism and obesity-related metabolic disorders, including NAFLD, induced by an excess of saturated fatty acids (SFAs), but its role in vivo, as well as underlying mechanisms, is unknown. We hypothesized that altered GIP secretion may contribute to the pathogenesis of NAFLD. OBJECTIVE: We assessed GIP response to SFA ingestion and its effect on glucose and lipid metabolism and on liver injury in patients with nonalcoholic steatohepatitis (NASH). DESIGN: Thirty-two nonobese, nondiabetic patients with NASH and 32 healthy controls matched for age, body mass index, and sex underwent a 7-d dietary record, an oral-glucose-tolerance test (OGTT), and a high-fat-load test. OGTT-derived indexes of glucose homeostasis were calculated; circulating lipoproteins, total antioxidant status, GIP, adiponectin, resistin, and cytokeratin-18 fragments (markers of hepatocyte apoptosis) after a high-fat meal were assessed. All subjects were genotyped for transcription factor 7-like 2 (TCF7L2) polymorphism. RESULTS: Patients with NASH exhibited a prolonged GIP elevation after fat ingestion. GIP response correlated directly with hepatic steatosis, postprandial resistin, and free fatty acid (FFA) increase and inversely with beta cell function and incretin effect. Dietary polyunsaturated:saturated fatty acid ratio and TCF7L2 polymorphism independently predicted postprandial GIP response. Cytokeratin-18 fragments increased significantly postprandially in both groups but more consistently in patients with NASH; their increase was predicted by postprandial adiponectin and FFA responses. CONCLUSIONS: GIP response to SFA ingestion is prolonged in nondiabetic patients with NASH and is correlated with liver disease, an unfavorable dynamic adipokine profile, and beta cell dysfunction, which provides a rationale for GIP antagonism in these subjects.
BACKGROUND: Genetic and acquired mechanisms underlying the association of nonalcoholic fatty liver disease (NAFLD) with diabetes are unknown. Glucose-dependent insulinotropic polypeptide (GIP) was recently linked to adipocyte metabolism and obesity-related metabolic disorders, including NAFLD, induced by an excess of saturated fatty acids (SFAs), but its role in vivo, as well as underlying mechanisms, is unknown. We hypothesized that altered GIP secretion may contribute to the pathogenesis of NAFLD. OBJECTIVE: We assessed GIP response to SFA ingestion and its effect on glucose and lipid metabolism and on liver injury in patients with nonalcoholic steatohepatitis (NASH). DESIGN: Thirty-two nonobese, nondiabeticpatients with NASH and 32 healthy controls matched for age, body mass index, and sex underwent a 7-d dietary record, an oral-glucose-tolerance test (OGTT), and a high-fat-load test. OGTT-derived indexes of glucose homeostasis were calculated; circulating lipoproteins, total antioxidant status, GIP, adiponectin, resistin, and cytokeratin-18 fragments (markers of hepatocyte apoptosis) after a high-fat meal were assessed. All subjects were genotyped for transcription factor 7-like 2 (TCF7L2) polymorphism. RESULTS:Patients with NASH exhibited a prolonged GIP elevation after fat ingestion. GIP response correlated directly with hepatic steatosis, postprandial resistin, and free fatty acid (FFA) increase and inversely with beta cell function and incretin effect. Dietary polyunsaturated:saturated fatty acid ratio and TCF7L2 polymorphism independently predicted postprandial GIP response. Cytokeratin-18 fragments increased significantly postprandially in both groups but more consistently in patients with NASH; their increase was predicted by postprandial adiponectin and FFA responses. CONCLUSIONS:GIP response to SFA ingestion is prolonged in nondiabeticpatients with NASH and is correlated with liver disease, an unfavorable dynamic adipokine profile, and beta cell dysfunction, which provides a rationale for GIP antagonism in these subjects.
Authors: Mohammad S Siddiqui; Kai L Cheang; Velimir A Luketic; Sherry Boyett; Michael O Idowu; Kavish Patidar; Puneet Puri; Scott Matherly; Richard T Stravitz; Richard K Sterling; Arun J Sanyal Journal: Dig Dis Sci Date: 2015-03-18 Impact factor: 3.199
Authors: Farnaz Keyhani-Nejad; Martin Irmler; Frank Isken; Eva K Wirth; Johannes Beckers; Andreas L Birkenfeld; Andreas F H Pfeiffer Journal: Diabetologia Date: 2014-10-28 Impact factor: 10.122
Authors: Andrew A Pierce; Caroline C Duwaerts; Russell K Soon; Kevin Siao; James P Grenert; Mark Fitch; Marc K Hellerstein; Carine Beysen; Scott M Turner; Jacquelyn J Maher Journal: J Nutr Biochem Date: 2015-11-17 Impact factor: 6.048