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.
Figures
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.
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.
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
- Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With Obesity.
Schwarz JM, Noworolski SM, Erkin-Cakmak A, Korn NJ, Wen MJ, Tai VW, Jones GM, Palii SP, Velasco-Alin M, Pan K, Patterson BW, Gugliucci A, Lustig RH, Mulligan K. Schwarz JM, et al. Gastroenterology. 2017 Sep;153(3):743-752. doi: 10.1053/j.gastro.2017.05.043. Epub 2017 Jun 1. Gastroenterology. 2017. PMID: 28579536 Free PMC article. - Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome.
Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, Gugliucci A, Schwarz JM. Lustig RH, et al. Obesity (Silver Spring). 2016 Feb;24(2):453-60. doi: 10.1002/oby.21371. Epub 2015 Oct 26. Obesity (Silver Spring). 2016. PMID: 26499447 Free PMC article. - Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease.
Cohen CC, Li KW, Alazraki AL, Beysen C, Carrier CA, Cleeton RL, Dandan M, Figueroa J, Knight-Scott J, Knott CJ, Newton KP, Nyangau EM, Sirlin CB, Ugalde-Nicalo PA, Welsh JA, Hellerstein MK, Schwimmer JB, Vos MB. Cohen CC, et al. J Clin Invest. 2021 Dec 15;131(24):e150996. doi: 10.1172/JCI150996. J Clin Invest. 2021. PMID: 34907907 Free PMC article. Clinical Trial. - Fructose as a key player in the development of fatty liver disease.
Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Basaranoglu M, et al. World J Gastroenterol. 2013 Feb 28;19(8):1166-72. doi: 10.3748/wjg.v19.i8.1166. World J Gastroenterol. 2013. PMID: 23482247 Free PMC article. Review. - Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease.
Ter Horst KW, Serlie MJ. Ter Horst KW, et al. Nutrients. 2017 Sep 6;9(9):981. doi: 10.3390/nu9090981. Nutrients. 2017. PMID: 28878197 Free PMC article. Review.
Cited by
- Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.
Rabbani N, Thornalley PJ. Rabbani N, et al. Front Endocrinol (Lausanne). 2024 Jan 16;14:1268308. doi: 10.3389/fendo.2023.1268308. eCollection 2023. Front Endocrinol (Lausanne). 2024. PMID: 38292764 Free PMC article. - Sugar and Dyslipidemia: A Double-Hit, Perfect Storm.
Gugliucci A. Gugliucci A. J Clin Med. 2023 Aug 31;12(17):5660. doi: 10.3390/jcm12175660. J Clin Med. 2023. PMID: 37685728 Free PMC article. Review. - Fructose impairs fat oxidation: Implications for the mechanism of western diet-induced NAFLD.
Inci MK, Park SH, Helsley RN, Attia SL, Softic S. Inci MK, et al. J Nutr Biochem. 2023 Apr;114:109224. doi: 10.1016/j.jnutbio.2022.109224. Epub 2022 Nov 18. J Nutr Biochem. 2023. PMID: 36403701 Free PMC article. Review. - Measurement of lipid flux to advance translational research: evolution of classic methods to the future of precision health.
Salvador AF, Shyu CR, Parks EJ. Salvador AF, et al. Exp Mol Med. 2022 Sep;54(9):1348-1353. doi: 10.1038/s12276-022-00838-5. Epub 2022 Sep 8. Exp Mol Med. 2022. PMID: 36075949 Free PMC article. Review.
References
- 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
- 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
- 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
- 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
Publication types
MeSH terms
Substances
Grants and funding
- P30 DK056341/DK/NIDDK NIH HHS/United States
- T32 DK007161/DK/NIDDK NIH HHS/United States
- P30 DK098722/DK/NIDDK NIH HHS/United States
- R01 DK089216/DK/NIDDK NIH HHS/United States
- UL1 TR000004/TR/NCATS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous