title: Prolonged saturated fat-induced, glucose-dependent insulinotropic polypeptide elevation is associated with adipokine imbalance and liver injury in nonalcoholic steatohepatitis: dysregulated enteroadipocyte axis as a novel feature of fatty liver.
abstract: 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).
  
  
  METHODS
  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.
authors.affiliation: Gradenigo Hospital, Turin, Italy. giovanni_musso@yahoo.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacini
authors.forename: Franco
authors.initials: F
authors.lastname: De Michieli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
mesh_terms: D054392:Adipokines / Q000378:metabolism*; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D015930:Diet Records; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D053538:Keratin-18 / Q000097:blood; D050356:Lipid Metabolism; D008297:Male; D011110:Polymorphism, Genetic; D019518:Postprandial Period; D052243:Resistin / Q000097:blood; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein
chemical_list: D054392:Adipokines; D001786:Blood Glucose; D004041:Dietary Fats; D005232:Fatty Acids, Volatile; D007328:Insulin; D053538:Keratin-18; D052243:Resistin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005749:Gastric Inhibitory Polypeptide