title: Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease.
abstract: Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6-D2 -glucose and U-(13) C-glucose) in the basal state and during an oral glucose tolerance test. The best-performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test-derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61-0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63-0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45-0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003).
  
  
  
  OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD.
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rosso
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Mezzabotta
authors.affiliation: Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.|University of Pisa, Pisa, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Gaggini
authors.affiliation: Division of Gastroenterology, Azienda Sanitaria Provinciale di Catania, Catania, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Salomone
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marengo
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saba
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Vanni
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Ramy
authors.initials: R
authors.lastname: Younes
authors.affiliation: Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.|University of Siena, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Saponaro
authors.affiliation: Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Buzzigoli
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Caviglia
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Abate
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
authors.affiliation: Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.affiliation: Division of Gastroenterology and Hepatology and Laboratory of Diabetology, Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008107:Liver Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000378:metabolism*; D011379:Prognosis