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Non-Alcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: Role of Circulating Branched-Chain Amino Acids.

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 (? = 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.

SUBMITTER: van den Berg EH

PROVIDER: S-EPMC6471562 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Non-Alcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: Role of Circulating Branched-Chain Amino Acids.

van den Berg Eline H EH Flores-Guerrero Jose L JL Gruppen Eke G EG de Borst Martin H MH Wolak-Dinsmore Justyna J Connelly Margery A MA Bakker Stephan J L SJL Dullaart Robin P F RPF

Nutrients 20190326 3

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 det ...[more]

PMID: 30917546

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Project description:IntroductionHypoglycemia is a major limiting factor in achieving recommended glycemic targets for people with type 1 diabetes. Exposure to recurrent hypoglycemia results in blunted hormonal counter-regulatory and symptomatic responses to hypoglycemia. Limited data on metabolic adaptation to recurrent hypoglycemia are available. This study examined the acute metabolic responses to hypoglycemia and the effect of antecedent hypoglycemia on these responses in type 1 diabetes.Research design and methodsTwenty-one outpatients with type 1 diabetes with normal or impaired awareness of hypoglycemia participated in a study assessing the response to hypoglycemia on 2 consecutive days by a hyperinsulinemic glucose clamp. Participants underwent a period of normoglycemia and a period of hypoglycemia during the hyperinsulinemic glucose clamp. Plasma samples were taken during normoglycemia and at the beginning and the end of the hypoglycemic period. Metabolomic analysis of the plasma samples was conducted using comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry.ResultsIn total, 68 metabolites were studied. On day 1, concentrations of the branched-chain amino acids, leucine (p=3.8×10-3) and isoleucine (p=2.2×10-3), decreased during hypoglycemia. On day 2, during hypoglycemia, five amino acids (including leucine and isoleucine) significantly decreased, and two fatty acids (tetradecanoic and oleic acids) significantly increased (p<0.05). Although more metabolites responded to hypoglycemia on day 2, the responses of the single metabolites were not statistically significant between the 2 days.ConclusionsIn individuals with type 1 diabetes, one episode of hypoglycemia decreases leucine and isoleucine concentrations. Antecedent hypoglycemia results in the decrement of five amino acids and increases the concentrations of two fatty acids, suggesting an alteration between the two hypoglycemic episodes, which could indicate a possible adaptation. However, more studies are needed to gain a comprehensive understanding of the consequences of these alterations.Trial registration numberNCT01337362.

Dataset Information

Non-Alcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: Role of Circulating Branched-Chain Amino Acids.

Publications

Non-Alcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: Role of Circulating Branched-Chain Amino Acids.

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