Fructose-Induced Insulin Resistance: Prospective Biochemical Mechanisms

Lina Nasser  Tamimi; Mousa Numan  Ahmad; Nidal Adel  Qinna

doi:10.35516/jjas.v17i4.96

Authors

Lina Nasser Tamimi University of Jordan, Amman, Jordan
Mousa Numan Ahmad University of Jordan, Amman, Jordan https://orcid.org/0000-0003-2863-3363
Nidal Adel Qinna Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan

DOI:

https://doi.org/10.35516/jjas.v17i4.96

Keywords:

Cytokines, Fructose, Inflammation, Insulin resistance, Leptin, Oxidative stress, ype 2 diabetes mellitus, T, Uric acid

Abstract

Increased intake of dietary fructose is markedly associated with multiple negative health outcomes and burdens. Insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are the most common complications that present with conjugated cellular-biochemical abnormalities. This article explains the involvement of increased dietary fructose intake in the occurrence of IR and T2DM and addresses basic metabolic mechanisms. PubMed, Medline, Science Direct, ADI, and WHO databases were searched through June 2021. Current research predicts that over 350 million people may have diabetes by 2030. IR acts as an influencer promoter of T2DM development. IR can occur as a result of high fructose intake. Fructose metabolism results in de novo lipogenesis, while its decreasing effect of peroxisome proliferator-activated receptor (PPAR) activity elevates the levels of inflammatory cytokines, resulting in down-regulation of insulin receptor substrate-1 phosphorylation. Fructose stimulates oxidative stress by activating nicotinamide adenine dinucleotide phosphate oxidase and synthesis of advanced glycation end-products. Fructose also stimulates purine-induced uric acid synthesis and leptin resistance, which contributes to abnormal insulin action. It is crucial to understand the mechanisms of fructose-induced IR via induction of oxidative stress, inflammation, leptin resistance, and uric acid production. This helps prevent and control variable diseases, T2DM being the most.

Downloads

Download data is not yet available.

Author Biographies

Lina Nasser Tamimi, University of Jordan, Amman, Jordan

Department of Nutrition and Food Technology, Human Nutrition and Dietetics, University of Jordan, Amman, Jordan

Mousa Numan Ahmad, University of Jordan, Amman, Jordan

Department of Nutrition and Food Technology, Human Nutrition and Dietetics, University of Jordan, Amman, Jordan

Nidal Adel Qinna, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan

Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan

References

Abolghasemi J., Sharifi M.H., Nasiri K., Akbari A. (2020). Thyme oxymel by improving inflammation, oxidative stress, dyslipidemia, and homeostasis of some trace elements ameliorates obesity induced by a high fructose/fat diet in male rats. Biomedicine and Pharmacotherapy, 126:110079. DOI: 10.1016/j.biopha.2020.110079.

Ahmad M.N., Farah A.I., Al-qirim T.M. (2020a). The cardiovascular complications of diabetes: a striking link through protein glycation. Romanian Journal of Internal Medicine, 58(4):188-198. DOI: 10.2478/rjim-2020-0021.

Ahmad M.N., Farah A.I., Al-qirim T.M. (2020b). Examining the role of alpha-lipoic acid and epigallocatechin-c-gallate in inhibiting sugar-induced myoglobin glycation: Scientific gaps in current knowledge? Nature and Science,18(6):17-25. DOI:10.7537/marsnsj 180620.04.

Aguilar Diaz De Leon J., Borges C.R. (2020). Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. Journal of Visualized Experiments, 2020(159): e61122. DOI: 10.3791/61122.

Ahn C.H., Choi E.H., Oh T.J., Cho Y.M. (2020). Ileal transposition increases pancreatic β cell mass and decreases β cell senescence in diet-induced obese rats. Obesity Surgery, 30(5):1849-1858. DOI: 10.1007/s11695-020-04406-6.

Ali M.Y., Zaib S., Rahman M.M., Jannat S., Iqbal J., Park S.K., C., et al. (2020). Poncirin, an orally active flavonoid exerts antidiabetic complications and improves glucose uptake activating PI3K/Akt signaling pathway in insulin-resistant C2C12 cells with anti-glycation capacities. Bioorganic Chemistry, 102:104061. DOI: 10.1016/j.bioorg.2020.104061.

Alipourfard I., Datukishvili N., Mikeladze D. (2019). TNF-α downregulation modifies insulin receptor substrate 1 (IRS-1) in metabolic signaling of diabetic insulin-resistant hepatocytes. Mediators of Inflammation, 2019:3560819. DOI: 10.1155/2019/3560819.

Al-Jawadi A., Patel C.R., Shiarella R.J., Romelus E., Auvinen M., Guardia J., et al. (2020). Cell-type-specific, ketohexokinase-dependent induction by fructose of lipogenic gene expression in mouse small intestine. Journal of Nutrition, 150(7):1722-30. DOI: 10.1093/ jn/nxaa113.

Baena M., Sangüesa G., Dávalos A., Latasa M.J., Sala-Vila A., Sánchez R.M., et al. (2016). Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Scientific Reports, 6(1):1-5. DOI: 10.1038/srep26149.

Bartley C., Brun T., Oberhauser L., Grimaldi M., Molica F., Kwak B. R., et al. (2019). Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling. American Journal of Physiology-Endocrinology and Metabolism, 25-41.;317(1): E25-E41. DOI: 10.1152/ajpendo.00456. 2018.

Bernardes N., Ayyappan P., De Angelis K., Bagchi A., Akolkar G., da Silva Dias D., et al. (2017). Excessive consumption of fructose causes cardiometabolic dysfunctions through oxidative stress and inflammation. Canadian Journal of Physiology and Pharmacology, 95(10):1078-1090. DOI: 10.1139/cjpp-2016-0663.

Beysen C., Ruddy M., Stoch A., Mixson L., Rosko K., Riiff T., et al. (2018). Dose-dependent quantitative effects of acute fructose administration on hepatic de novo lipogenesis in healthy humans. American Journal of Physiology-Endocrinology and Metabolism, 315 (1): E126-E132. DOI: 10.1152/ajpendo.00470.2017.

Buziau A.M., Schalkwijk C.G., Stehouwer C.D., Tolan D.R., Brouwers M.C. (2020). Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of the fructose-induced non-alcoholic fatty liver disease. Cellular & Molecular Life Sciences,77(9): 1709-1719.DOI:10.1007/s00018-019-03348-2.

Caputo T., Gilardi F., Desvergne B. (2017). From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions. Metabolism and Immunity Reviews, 591(19):3061-3088. DOI: 10.1002/1873-3468.12742.

Cigliano L., Spagnuolo M. S., Crescenzo R., Cancelliere R., Iannotta L., Mazzoli A., et al. (2018). Short-term fructose feeding induces inflammation and oxidative stress in the hippocampus of young and adult rats. Molecular Neurobiology, 55(4):2869-2883. DOI: 10.1007/s12035-017-0518-2.

Deo P., McCullough C. L., Almond T., Jaunay E. L., Donnellan L., Dhillon V. S., et al. (2020). Dietary sugars and related endogenous advanced glycation end-products increase chromosomal DNA damage in WIL2-NS cells, measured using cytokinesis-block micronucleus cytometry assay. Mutagenesis,35(2):169-177. DOI: 10.1093/mutage/geaa002.

Do Koo Y., Lee J. S., Lee S. A., Quaresma P. G., Bhat R., Haynes W. G., et al. (2019). SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle. Metabolism,95:27-35. DOI: 10.1016/j.metabol.2019.03.004.

Eberhart T., Schönenberger M. J., Walter K. M., Charles K. N., Faust P. L., Kovacs W. J. (2020). Peroxisome-Deficiency and HIF-2α Signaling Are Negative Regulators of Ketohexokinase Expression. Frontiers in Cell and Developmental Biology,8:566. DOI: 10.3389/fcell.2020.00566.

Egea G., Jiménez-Altayó F., Campuzano V. (2020). Reactive oxygen species and oxidative stress in the pathogenesis and progression of genetic diseases of the connective tissue. Antioxidants, 9(10). DOI: 10.3390/antiox9101013.

Farah AI, Ahmad MN, Al-qirim TM. (2020). The antioxidant and prooxidant impacts of varying levels of α-lipoic acid on biomarkers of myoglobin oxidation in vitro. Jordan Journal of Agricultural Sciences, 16(4): 83-93.

Federico A., Rosato V., Masarone M., Torre P., Dallio M., Romeo M., et al. (2021). The role of fructose in non-Alcoholic steatohepatitis: old relationship and new insights. Nutrients,13(4). DOI: 10.3390/nu13041314.

Furuhashi M. (2020). New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. American Journal of Physiology-Endocrinology and Metabolism, 319(5): E827-E834. DOI: 10.1152/ajpendo.00378.2020.

Ganesan S., Summers C. M., Pearce S. C., Gabler N. K., Valentine R. J., Baumgard L. H., et al. (2018). Short-term heat stress altered metabolism and insulin signaling in skeletal muscle. Journal of Science, 96(1):154-167. DOI: 10.1093/jas/skx083.

García-Arroyo F. E., Monroy-Sánchez F., Muñoz-Jiménez I., Gonzaga G., Andrés-Hernando A., Zazueta C., et al. (2019). Allopurinol prevents the lipogenic response induced by an acute oral fructose challenge in short-term fructose fed rats. Biomolecules, 9(10) :601. DOI: 10.3390/biom9100601.

Gassaway B. M., Petersen M. C., Surovtseva Y. V., Barber K. W., Sheetz J. B., Aerni H. R., et al. (2018). PKCε contributes to lipid-induced insulin resistance through cross-talk with p70S6K and through previously unknown regulators of insulin signaling. Proceedings of National Academy of Sciences, 115(38): E8996-E9005. DOI: 10.1073/pnas.1804379115.

Geidl-Flueck B., Hochuli M., Németh Á., Eberl A., Derron N., Köfeler H. C., et al. (2021). Fructose-and sucrose-but, not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial. Journal of Hepatology, S0168-8278 (21): 00161-6. DOI: 10.1016/j.jhep.2021.02.027.

Gong Y., Geng N., Zhang H., Luo Y., Giesy J. P., Sun S., et al. (2021). Exposure to short-chain chlorinated paraffin inhibited PPARα-mediated fatty acid oxidation and stimulated aerobic glycolysis in vitro in human cells. Science of The Total Environment, 772:144957. DOI: 10.1016/j.scitotenv.2021.144957.

Gugliucci A. (2017). Formation of fructose-mediated advanced glycation end products and their roles in metabolic and inflammatory diseases. Advances in Nutrition (Bethesda, Md.).;8(1):54-62. DOI: 10.3945/an.116.013912.

Gugliucci A. (2016). Fructose surges damage hepatic adenosyl-monophosphate-dependent kinase and leads to increased lipogenesis and hepatic insulin resistance. Medical Hypotheses, 93:87-92. DOI: 10.1016/j.mehy.2016.05.026.

Gupta P., Taiya A., Hassan M. I. (2021). The emerging role of protein kinases in diabetes mellitus: from mechanism to therapy. Advances in Protein Chemistry and Structural Biology, 124:47-85. DOI: 10.1016/bs.apcsb.2020.11.001.

Higgins C. B., Zhang Y., Mayer A. L., Fujiwara H., Stothard A. I., Graham M. J., et al. (2018). Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ. Journal of Clinical Investigation Insight, 3(16). DOI: 10.1172/jci.insight.120794.

Hong J. N., Li W. W., Wang L. L., Guo H., Jiang Y., Gao Y. J., et al. (2017). Jiangtang decoction ameliorates diabetic nephropathy through the regulation of PI3K/Akt-mediated NF-κB pathways in KK-Ay mice. Chinese Medicine, 12:13. DOI: 10.1186/s13020-017-0134-0.

Hotta N., Kawamura T., Umemura T. (2020). Are the polyol pathway and hyperuricemia partners in the development of non‐alcoholic fatty liver disease in diabetes? Journal of Diabetes Investigation, 11(4):786-788. DOI: 10.1111/jdi.13190.

Hu Y., Hou Z., Yi R., Wang Z., Sun P., Li G., et al. (2017). Tartary buckwheat flavonoids ameliorate high fructose-induced insulin resistance and oxidative stress associated with the insulin signaling and Nrf2/HO-1 pathways in mice. Food and Function, 8(8):2803-2816. DOI: 10.1039/c7fo00359e.

Huang D. W., Chang W. C., Wu J. S. B., Shih R. W., Shen S. C. (2016). Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet. Nutrition Research, 36(2):150-160. DOI: 10.1016/j.nutres.2015.10.001.

Iskender H., Yenice G., Terim Kapakin K. A., Dokumacioglu E., Sevim C., Hayirli A. et al. (2021). Effects of high fructose diet on lipid metabolism and the hepatic NF-κB/SIRT-1 pathway. Biotechnics and Histochemistry, 45(3):1-9. DOI:10.1080/10520295.2021.1890 214.

Jeong B. Y., Lee H. Y., Park C. G., Kang J., Yu S. L., Choi D. R., et al. (2018). Oxidative stress caused by activation of NADPH oxidase 4 promotes contrast-induced acute kidney injury. PLoS One, 13(1): e0191034. DOI: 10.1371/journal.pone.0191034.

Jones G. M., Caccavello R., Palii S. P., Pullinger C. R., Kane J. P., Mulligan K., et al. (2020). Separation of postprandial lipoproteins: Improved purification of chylomicrons using an apob100 immunoaffinity method. Journal of Lipid Research, 61(3):455-463. DOI: 10.1194/jlr. d119000121.

Jung Y. H., Bu S. Y. (2020). Suppression of long-chain acyl-CoA synthetase blocks intracellular fatty acid flux and glucose uptake in skeletal myotubes. Biochimica et Biophysica Acta (BBA)- Molecular and Cell Biology of Lipids, 1865(7):158678. DOI: 10.1016/j.bbalip.2020.158678.

Kang B. B., Chiang B. H. (2020). Amelioration of insulin resistance using the additive effect of ferulic acid and resveratrol on vesicle trafficking for skeletal muscle glucose metabolism. Phytotherapy Research, 34(4):808-816. DOI: 10.1002/ptr.6561.

Katsuyama H., Czeczor J. K., Roden M. (2019). Role of Mitochondria in the Liver Metabolism in Obesity and Type 2 Diabetes. In Mitochondria in Obesity and Type 2 Diabetes. 1st ed. United States: Academic Press;2019.

Kim M., Do G. Y., Kim I. (2020). Activation of the renin-angiotensin system in high fructose-induced metabolic syndrome. Korean Journal of Physiology and Pharmacology, 126(11): 4372-4386. DOI: 10.1172/jci81993.

Koepsell H (2020). Glucose transporters in the small intestine in health and disease. European Journal of Physiology, 472(9):1207-1248. DOI: 10.1007/s00424-020-02439-5.

Kurajoh M., Fukumoto S., Yoshida S., Akari S., Murase T., Nakamura T., et al. (2021). Uric acid was shown to contribute to increased oxidative stress levels independent of xanthine oxidoreductase activity in the MedCity21 health examination registry. Scientific Reports, 11(1):7378. DOI: 10.1038/s41598-021-86962-0.

Lanaspa M. A., Kuwabara M., Andres-Hernando A., Li N., Cicerchi C., Jensen T., et al. (2018). High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism. Proceedings of National Academy of Sciences, 115 (12):3138-3143. DOI: 10.1073/pnas.1713837115.

Lawan A., Min K., Zhang L., Canfran-Duque A., Jurczak M. J., Camporez J. P. G., et al. (2018). Skeletal muscle-specific deletion of MKP-1 reveals a p38 MAPK/JNK/Akt signaling node that regulates obesity-induced insulin resistance. Diabetes, 67(4):624-635. DOI: 10.2337/db17-0826.

Lehti S., Nguyen S. D., Belevich I., Vihinen H., Heikkilä H. M., Soliymani R., et al. (2018). Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties. American Journal of Pathology, 188(2): 525-538. DOI: 10.1016/j.ajpath.2017.09.019.

Liu N., Xu H., Sun Q., Yu X., Chen W., Wei H., et al. (2021). The role of oxidative stress in hyperuricemia and xanthine oxidoreductase (XOR) inhibitors. Oxidative Medicine and Cellular Longevity, 2021(1):1470380. DOI: 10.1155/2021/1470380.

Lozano I., Van der Werf R., Bietiger W., Seyfritz E., Peronet C., Pinget M., et al. (2016). High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutrition and Metabolism, 13(1):15. DOI: 10.1186/s12986-016-0074-1.

Maguiña-Alfaro M., Suárez-Cunza S., Salcedo-Valdez L., Soberón-Lozano M., Carbonel-Villanueva K., Carrera-Palao R. (2020). Antioxidant role of L-carnitine in an experimental model of oxidative stress induced by increased fructose consumption. Revista Peruana de Medicina Experimental y Salud Pública, 37(4):662-671. DOI:10.17843/rpmesp.2020. 374.4733.

Mai B. H., Yan L. J. (2019). The negative and detrimental effects of high fructose on the liver, with special reference to metabolic disorders. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 121:821-826. DOI: 10.2147/dmso. s198968.

Mansyur M. A., Bakri S., Patellongi I. J., Rahman I. A. (2020). The association between metabolic syndrome components, low-grade systemic inflammation, and insulin resistance in non-diabetic Indonesian adolescent males. Clinical Nutrition, 35:69-74. DOI: 10.1016/ j. clnesp.2019.12.001.

Marunaka Y. (2018). The proposal of molecular mechanisms of weak organic acids intake-induced improvement of insulin resistance in diabetes mellitus via elevation of interstitial fluid pH. International Journal of Molecular Sciences, 19(10):3244. DOI: 10.3390/ijms 19103244.

Mehmood A., Zhao L., Ishaq M., Xin W., Zhao L., Wang C., et al. (2020). Anti-hyperuricemic potential of stevia (Stevia rebaudiana Bertoni) residue extract in hyperuricemic mice. Food and Function, 11(7):6387-6406. DOI: 10.1039/c9fo02246e.

Morigny P., Boucher J., Arner P., Langin D. (2021). Lipid and glucose metabolism in white adipocytes: pathways, dysfunction, and therapeutics. Nature Reviews Endocrinology, 17(5):276-295. DOI: 10.1038/s41574-021-00471-8.

Oyabambi A. O., Olaniyi K. S., Soladoye A. O., Olatunji L. A. (2020). Suppression of uric acid and lactate production by sodium acetate ameliorates hepatic triglyceride accumulation in fructose-insulin resistant pregnant rats. Environmental Toxicology and Pharmacology, 80, 103452. DOI: 10.1016/j.etap.2020.103452.

Qais F. A., Khan M. S., Althubiani A. S., Al-Ghamdi S. B., Ahmad I. (2019). Understanding the biochemical and molecular mechanism of complications of glycation and its management by herbal medicine. In New Look to Phytomedicine, 1st ed. The United States Academic Press;2019.

Qu W., Han C., Li M., Zhang J., Jiang Z. (2018). Anti-TNF-α antibody alleviates insulin resistance in rats with sepsis-induced stress hyperglycemia. Journal of Endocrinological Investigation, 41(4):455-463. DOI: 10.1007/s40618-017-0742-7.

Rai S. N., Dilnashin H., Birla H., Singh S. S., Zahra W., Rathore A. S., et al. (2019). The role of PI3K/Akt and ERK in neurodegenerative disorders. Neurotoxicity Research, 35(3):775-795. DOI: 10.1007/s12640-019-0003-y.

Rehman K., Haider K., Jabeen K., Akash M. S. H. (2020). Current perspectives of oleic acid: regulation of molecular pathways in mitochondrial and endothelial functioning against insulin resistance and diabetes. Reviews in Endocrine and Metabolic Disorders, 21(4):631-643. DOI: 10.1007/s11154-020-09549-6.

Rodrigues B. D. A., Muñoz V. R., Kuga G. K., Gaspar R. C., Nakandakari S. C., Crisol B. M., et al. (2017). Obesity increases mitogen-activated protein kinase phosphatase-3 levels in the hypothalamus of mice. Frontiers in Cellular Neuroscience, 11(1):313. DOI: 10.3389/ fncel.2017.00313.

Saeedi P., Petersohn I., Salpea P., Malanda B., Karuranga S., Unwin N., et al. (2019). Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas. Diabetes Research and Clinical Practice,157(9):107843. DOI: 10.1016/j.diabres.2019.107843.

Sanchez-Lozada L. G., Andres-Hernand A., Garcia-Arroyo F. E., Cicerchi C., Li N., Kuwabara M., et al. (2019). Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing the development of fatty liver in rats. Journal of Biological Chemistry, 294(11):4272-4281. DOI: 10.1074/jbc.ra118.006158.

Sangüesa G., Roglans N., Montañés J. C., Baena M., Velázquez A. M., Sánchez R. M., et al. (2018). Chronic liquid fructose, but not glucose, supplementation selectively induces visceral adipose tissue leptin resistance and hypertrophy in female sprague‐dawley rats. Molecular Nutrition and Food Research, 62(22): e1800777. DOI:10.1002/mnfr.201800 777.

Sanvee G. M., Panajatovic M. V., Bouitbir J., Krähenbühl S. (2019). Mechanisms of insulin resistance by simvastatin in C2C12 myotubes and in mouse skeletal muscle. Biochemical Pharmacology, 164(1):23-33. DOI: 10.1016/j.bcp.2019.02.025.

Selen E. S., Choi J., Wolfgang M. J. (2021). Discordant hepatic fatty acid oxidation and triglyceride hydrolysis lead to liver disease. Journal of Clinical Investigation Insight, 6(2): e135626. DOI: 10.1172/jci.insight.135626.

Sharma N., Sircar A., Anders H. J., Gaikwad A. B. (2020). Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Archives of Physiology and Biochemistry,1-5. DOI:10.1080/13813455.2020.1745851.

Sigala D. M., Widaman A. M., Hieronimus B., Nunez M. V., Lee V., Benyam Y., et al. (2020). Effects of consuming sugar-sweetened beverages for 2 weeks on 24-h circulating leptin profiles, ad libitum food intake, and body weight in young adults. Nutrients, 12(12) :3893. DOI: 10.3390/nu12123893.

Simons N., Debray F. G., Schaper N. C., Feskens E. J., Hollak C. E., Bons J. A., et al. (2020). Kidney and vascular function in adult patients with hereditary fructose intolerance. Molecular Genetics and Metabolism Reports, 23(1): e0247683.

DOI: 10.1016/j.ymgmr.2020.100600.

Todoric J., Di Caro G., Reibe S., Henstridge D. C., Green C. R., Vrbanac A., et al. (2020). Fructose stimulated de novo lipogenesis is promoted by inflammation. Nature Metabolism, 2(10): 1034-1045. DOI: 10.1038/s42255-020-0261-2.

Unsal V., Deveci K., Ozmen Z. C., Tumer M. K. (2020). Research on the effects of L-carnitine and trans-chalcone on endoplasmic reticulum stress and oxidative stress in high-fructose corn syrup-fed rats. Nutrition and Food Science, 51(2): 345-361. DOI: 10.1108/NFS-05-2020-0162.

Veedfald S., Albrechtsen N.J., Holst J.J. (2019). Glucose homeostasis and the gastrointestinal tract. In Molecular Nutrition: Carbohydrates. 1st ed. The United States Academic Press; 2019.

Xie H., Heier C., Kien B., Vesely P. W., Tang Z., Sexl V., et al. (2020). Adipose triglyceride lipase activity regulates cancer cell proliferation via AMP-kinase and mTOR signaling. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, (9): 158737. DOI: 10.1016/j.bbalip.2020.158737.

Xu D., Li X., Shao F., Lv G., Lv H., Lee J. H., et al. (2019). The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62. Science Advances, 5(4), e4570. DOI: 10.1126/sciadv. aav4570.

Zatterale F., Longo M., Naderi J., Raciti G. A., Desiderio A., Miele C., et al. (2020). Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Frontiers in Physiology, 5(4): eaav4570. DOI: 10.1126/sciadv. aav4570.

Zhang D., Tong X., VanDommelen K., Gupta N., Stamper K., Brady G. F., et al. (2017). Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity. Journal of Clinical Investigation, 127(7):2855-2867. DOI: 10. 1172/JCI89934.

Zwarts I., Van Zutphen T., Kruit J. K., Liu W., Oosterveer M. H., Verkade H. J., et al. (2019). Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR. Scientific Reports, 9(1): 9299. DOI: 10.1038/s41598-019-45803-x.