Abstract
Non-alcoholic fatty liver disease (NAFLD) is likely to be associated with elevated plasma branched-chain amino acids (BCAAs) and may precede the development of type 2 diabetes (T2D). We hypothesized that BCAAs may be involved in the pathogenesis of T2D attributable to NAFLD and determined the extent to which plasma BCAAs influence T2D development in NAFLD. We evaluated cross-sectional associations of NAFLD with fasting plasma BCAAs (nuclear magnetic resonance spectroscopy), and prospectively determined the extent to which the influence of NAFLD on incident T2D is attributable to BCAA elevations. In the current study, 5791 Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort participants without T2D at baseline were included. Elevated fatty liver index (FLI) ≥60, an algorithm based on triglycerides, gamma-glutamyltransferase, body mass index (BMI) and waist circumference, was used as proxy of NAFLD. Elevated FLI ≥ 60 was present in 1671 (28.9%) participants. Cross-sectionally, BCAAs were positively associated with FLI ≥ 60 (β = 0.208, p < 0.001). During a median follow-up of 7.3 years, 276 participants developed T2D, of which 194 (70.2%) had an FLI ≥ 60 (log-rank test, p < 0.001). Cox regression analyses revealed that both FLI ≥60 (hazard ratio (HR) 3.46, 95% CI 2.45–4.87, p < 0.001) and higher BCAA levels (HR 1.19, 95% CI 1.03–1.37, p = 0.01) were positively associated with incident T2D. Mediation analysis showed that the association of FLI with incident T2D was in part attributable to elevated BCAAs (proportion mediated 19.6%). In conclusion, both elevated FLI and elevated plasma BCAA levels are associated with risk of incident T2D. The association of NAFLD with T2D development seems partly mediated by elevated BCAAs.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common cause of chronic liver disease in the Western world [1]
The study population consisted of 5791 participants free of type 2 diabetes (T2D) at baseline
Subjects with an fatty liver index (FLI) ≥60 were older, more likely to be men (67.8% vs. 32.2%) and more likely to be classified with metabolic syndrome (MetS), history of cardiovascular disease and parental history of T2D
Summary
Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common cause of chronic liver disease in the Western world [1]. An elevated fatty liver index (FLI), as proxy of NAFLD and assessed by an algorithm based on obesity measures, plasma triglycerides and gamma-glutamyltransferase (GGT), has been shown to predict T2D in two independent European populations [6,7]. Fasting plasma BCAAs may be elevated in (obesity-associated) NAFLD [13,23,24,25,26], and may coincide with abnormalities in BCAA catabolic enzymes in liver and adipose tissue [27] Such abnormalities in (hepatic) BCAA metabolism conceivably affect carbon substrate oxidation that, together with impairment of antioxidant defence, may contribute to the generation of reactive oxygen species [13,19]. ENd-stage Disease (PREVEND) cohort, comprising a large and well-characterized population from the North of the Netherlands
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