Sex influenced association of directly measured insulin sensitivity and serum transaminase levels: Why alanine aminotransferase only predicts cardiovascular risk in men?

Abstract

BackgroundNon 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.Patients and methods158 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.ResultsSignificant 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 (R2 = 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 (R2 = 0.4989).ConclusionThere 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.

Alanine Aminotransferase and Body Composition in Obese Men and Women

“…Thus, ALT predicted coronary heart disease in men but not in women in a European-American population-based study [48]. Further, a link between ALT and muscular glucose uptake was found in women only, which may hypothetically explain why ALT appears to play a different role as a CVD risk marker in men and women [49]. In parallel, ALT correlated with metabolic variables (glucose, HbA 1C , and cholesterol) in women but not in men in the present study.…”

Gender differences in hospital admissions for major cardiovascular events and procedures in people with and without diabetes in England: a nationwide study 2004–2014

“…These risk factors encompass inflammation, impaired fibrinolysis, coagulation, dyslipidemia, hypertension and endothelial dysfunction, amongst other metabolic and hormonal factors [ 11 , 36 – 38 ]. Gender differences in the association between diabetes and CVD risk factors have been partly attributed to differences in central adiposity and insulin resistance [ 11 , 12 , 35 , 37 ]. Women tend to have peripheral fat distribution by contrast to central obesity with visceral fat accumulation in men, resulting in improved insulin sensitivity even at greater levels of weight gain [ 11 ].…”

Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus

“…In a historical cohort of the Brisighella Heart Study, the fatty liver index, including liver enzymes, triglycerides, WCR, and BMI, was even a better predictor of the MetS in women than in men ( 58 ). Furthermore, a sex-specific association between liver transaminase levels and insulin sensitivity was described ( 59 ). Alanine aminotransferase independently predicted muscle glucose uptake measured by hyperinsulinemic euglycemic clamp in females only, whereas in males, fasting insulin and leptin were stronger predictors of insulin resistance.…”