Isocaloric Fructose Restriction Reduces Serum d-Lactate Concentration in Children With Obesity and Metabolic Syndrome - PubMed (original) (raw)

Isocaloric Fructose Restriction Reduces Serum d-Lactate Concentration in Children With Obesity and Metabolic Syndrome

Ayca Erkin-Cakmak et al. J Clin Endocrinol Metab. 2019.

Abstract

Objective: To investigate the link between dietary sugar consumption and two separate pathogenetic mechanisms associated with metabolic syndrome: de novo lipogenesis (DNL) and nonenzymatic glycation.

Design and participants: We assessed changes in serum d-lactate (the detoxification end-product of methylglyoxal) concentration in response to 9 days of isocaloric fructose restriction in 20 children with obesity and metabolic syndrome, and examined correlations with changes in DNL, liver fat, insulin sensitivity, and other metrics of hepatic metabolism.

Interventions: Nine days of dietary sugar restriction, with substitution of equal amounts of refined starch.

Main outcome measures: On days 0 and 10, children had laboratory evaluation of d-lactate levels and other analytes, and underwent oral glucose tolerance testing, magnetic resonance spectroscopy to quantify fat depots, and 13C-acetate incorporation into triglyceride (TG) to measure DNL.

Results: d-Lactate was associated with baseline liver fat fraction (P < 0.001) and visceral adipose tissue (P < 0.001) but not with subcutaneous adipose tissue. At baseline, d-lactate was positively correlated with DNL-area under the curve (AUC) (P = 0.003), liver fat fraction (P = 0.02), TG (P = 0.004), and TG/high-density lipoprotein ratio (P = 0.002). After 9 days of isocaloric fructose restriction, serum d-lactate levels reduced by 50% (P < 0.0001), and changes in d-lactate correlated with both changes in DNL-AUC and measures of insulin sensitivity.

Conclusion: Baseline correlation of d-lactate with DNL and measures of insulin sensitivity and reduction in d-lactate after 9 days of isocaloric fructose restriction suggest that DNL and nonenzymatic glycation are functionally linked via intermediary glycolysis in the pathogenesis of metabolic syndrome and point to fructose as a key dietary substrate that drives both pathways.

Copyright © 2019 Endocrine Society.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Changes in individual serum

d

-lactate levels in children with obesity before and after nine days of isocaloric fructose restriction with average changes (mean ± SEM) (n = 20). *P < 0.0001.

Figure 2.

Figure 2.

Correlations between serum

d

-lactate level and (a) DNL-AUC, (b) liver fat fraction, (c) TG, and (d) TG/high-density lipoprotein ratio at baseline on day 0 and (e) percent change in serum

d

-lactate level and change in DNL-AUC and (f) change in serum TG from day 0 to day 10 (n = 20).

Figure 3.

Figure 3.

Hepatic fructose metabolism and its effects on DNL (red) and MG production (blue). Trioses are a metabolic crossroad that link both pathways (green). After absorption from the gut and transport to the liver via the portal vein, fructose is quickly phosphorylated by fructokinase-C (1), bypassing regulatory steps in glycolysis and increasing the flux of both trioses (2) and fatty acids (FA) (3). These are turned into fat through DNL (4). The process impairs FA oxidation by the mitochondria, as malonyl-CoA inhibits carnitine palmitoyl transferase-1 (CPT-1) and FA transport into mitochondria for _β_-oxidation. Some of the trioses decompose into the toxic metabolite MG (5), which can damage either proteins or DNA (6), or be detoxified to

d

-lactate (7, 8), by the enzyme Glo1, which is critical for this process and dependent on hepatic supplies of glutathione (GSH) (9). VLDL, very low-density lipoprotein.

Similar articles

Cited by

References

    1. Moraru A, Wiederstein J, Pfaff D, Fleming T, Miller AK, Nawroth P, Teleman AA. Elevated levels of the reactive metabolite methylglyoxal recapitulate progression of type 2 diabetes. Cell Metab. 2018;27:926–934.e8. - PubMed
    1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. American Gastroenterological AssociationAmerican Association for the Study of Liver DiseasesAmerican College of Gastroenterologyh. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142(7):1592–1609. - PubMed
    1. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018;68(1):349–360. - PMC - PubMed
    1. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357. - PubMed
    1. Kumar R, Mohan S. Non-alcoholic fatty liver disease in lean subjects: characteristics and implications. J Clin Transl Hepatol. 2017;5(3):216–223. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources