title: Sex influenced association of directly measured insulin sensitivity and serum transaminase levels: Why alanine aminotransferase only predicts cardiovascular risk in men?
abstract: BACKGROUND
  Non alcoholic fatty liver disease (NAFLD) is an independent cardiovascular (CV) risk factor which is closely associated with insulin resistance measured by both direct or indirect methods. Gender specific findings in the relationship between alanine aminotransferase (ALT) and CV disease, the prevalence of NAFLD and type 2 diabetes (T2DM) have been published recently. The aim of the present study was to explore the gender aspects of the association between insulin sensitivity, liver markers and other metabolic biomarkers in order to elucidate the background behind the sex influenced difference in both NAFLD, T2DM and their association with CV risk.
  
  
  METHODS
  158 female (47 normal and 111 impaired glucose intolerant) and 148 male (74 normal and 74 impaired glucose tolerant) subjects were included (mean age: 46.5 ± 8.31 vs. 41.6 ± 11.3, average Hba1c < 6.1 %, i.e. prediabetic population, drug naive at the time of the study). Subjects underwent a hyperinsulinemic normoglycemic clamp to determine muscle glucose uptake (M3), besides liver function tests and other fasting metabolic and anthropometric parameters were determined.
  
  
  RESULTS
  Significant bivariate correlations were found between clamp measured M3 and all three liver enzymes (ALT, aspartate aminotransferase and gamma-glutamyl transferase) in both sexes. When data were adjusted for possible metabolic confounding factors correlations ceased in the male population but stayed significant in the female group. Feature selection analysis showed that ALT is an important attribute for M3 in the female but not in male group (mean Z: 3.85 vs. 0.107). Multiple regression analysis confirmed that BMI (p < 0.0001) and ALT (p = 0.00991) significantly and independently predicted clamp measured muscle glucose uptake in women (R(2) = 0.5259), while in men serum fasting insulin (p = 0.0210) and leptin levels (p = 0.0294) but none of the liver enzymes were confirmed as significant independent predictors of M3 (R(2) = 0.4989).
  
  
  CONCLUSIONS
  There is a gender specific association between insulin sensitivity, metabolic risk factors and liver transaminase levels. This might explain the sex difference in the predictive role of ALT elevation for CV disease. Moreover, ALT may be used as a simple diagnostic tool to identify insulin resistant subjects only in the female population according to our results.
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. budaybarb@hotmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Buday
authors.affiliation: Tritoo Informatics Ltd., Balatonfűzfő, Hungary. drpachpeter@gmail.com.
authors.forename: Peter Ferenc
authors.initials: PF
authors.lastname: Pach
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. botond.literati@drc.hu.
authors.forename: Botond
authors.initials: B
authors.lastname: Literati-Nagy
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. marta.vitai@drc.hu.
authors.forename: Marta
authors.initials: M
authors.lastname: Vitai
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. gyoree@hotmail.vom.
authors.forename: Gyorgyi
authors.initials: G
authors.lastname: Kovacs
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. vecsei@drc.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Vecsei
authors.affiliation: Drug Research Center, Department of Metabolism, Balatonfüred, Hungary. laszlo.koranyi@drc.hu.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Koranyi
authors.affiliation: Faculty of Medicine, First Department of Internal Medicine, University of Szeged, Szeged, Hungary. lecs.in1st@gmail.com.
authors.forename: Csaba
authors.initials: C
authors.lastname: Lengyel
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism*; D001219:Aspartate Aminotransferases / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D011236:Prediabetic State / Q000378:metabolism*; D012737:Sex Factors; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005947:Glucose