Antidiabetic Properties of Naringenin: A Citrus Fruit Polyphenol

Sweet, 2004, Regulation of ATP/ADP in Pancreatic Islets, Diabetes, 53, 401, 10.2337/diabetes.53.2.401

Tripathy, 2010, Defects in insulin secretion and action in the pathogenesis of type 2 diabetes mellitus, Curr. Diab. Rep., 10, 184, 10.1007/s11892-010-0115-5

Petersen, 2018, Mechanisms of Insulin Action and Insulin Resistance, Physiol. Rev., 98, 2133, 10.1152/physrev.00063.2017

Saltiel, 2001, New perspectives into the molecular pathogenesis and treatment of type 2 diabetes, Cell, 104, 517, 10.1016/S0092-8674(01)00239-2

Alam, 2014, Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action, Adv. Nutr., 5, 404, 10.3945/an.113.005603

DeFronzo, 2004, Dysfunctional fat cells, lipotoxicity and type 2 diabetes, Int. J. Clin. Pract. Suppl., 58, 9, 10.1111/j.1368-504X.2004.00389.x

Lee, 2006, PPAR regulates glucose metabolism and insulin sensitivity, Proc. Natl. Acad. Sci. USA, 103, 3444, 10.1073/pnas.0511253103

Defronzo, 2009, Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus, Diabetes, 58, 773, 10.2337/db09-9028

Frigolet, 2013, The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity, J. Nutr. Biochem., 24, 2003, 10.1016/j.jnutbio.2013.07.002

Hotamisligil, 1994, Tumor necrosis factor alpha: A key component of the obesity-diabetes link, Diabetes, 43, 1271, 10.2337/diab.43.11.1271

Cho, 2018, IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045, Diabetes Res. Clin. Pract., 138, 271, 10.1016/j.diabres.2018.02.023

Shrestha, 2019, Factors Contributing to Increases in Diabetes-Related Preventable Hospitalization Costs Among U.S. Adults During 2001–2014, Diabetes Care, 42, 77, 10.2337/dc18-1078

Baur, 2006, Therapeutic potential of resveratrol: The in vivo evidence, Nat. Rev. Drug. Discov., 5, 493, 10.1038/nrd2060

Park, 2015, The pharmacology of resveratrol in animals and humans, Biochim. Biophys. Acta, 1852, 1071, 10.1016/j.bbadis.2015.01.014

Anja, 2017, The cost of diabetes in Canada over 10 years: Applying attributable health care costs to a diabetes incidence prediction model, Health Promot. Chronic Dis. Prev. Can., 37, 49, 10.24095/hpcdp.37.2.03

Vieira, 2016, Fruits, vegetables and lung cancer risk: A systematic review and meta-analysis, Ann. Oncol., 27, 81, 10.1093/annonc/mdv381

Kuzma, 2017, Prevention of metabolic diseases: Fruits (including fruit sugars) vs. vegetables, Curr. Opin. Clin. Nutr. Metab. Care, 20, 286, 10.1097/MCO.0000000000000378

Stefan, 2018, Metabolically healthy obesity: The low-hanging fruit in obesity treatment?, Lancet Diabetes Endocrinol., 6, 249, 10.1016/S2213-8587(17)30292-9

Serino, A., and Salazar, G. (2018). Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease. Nutrients, 11.

Moore, J., Yousef, M., and Tsiani, E. (2016). Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols. Nutrients, 8.

Yousef, M., Vlachogiannis, I.A., and Tsiani, E. (2017). Effects of Resveratrol against Lung Cancer: In Vitro and In Vivo Studies. Nutrients, 9.

Naimi, M., Vlavcheski, F., Shamshoum, H., and Tsiani, E. (2017). Rosemary Extract as a Potential Anti-Hyperglycemic Agent: Current Evidence and Future Perspectives. Nutrients, 9.

Dreosti, 2000, Antioxidant polyphenols in tea, cocoa, and wine, Nutrition, 16, 692, 10.1016/S0899-9007(00)00304-X

Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha, Cell, 127, 1109, 10.1016/j.cell.2006.11.013

Amor, S., Châlons, P., Aires, V., and Delmas, D. (2018). Polyphenol Extracts from Red Wine and Grapevine: Potential Effects on Cancers. Diseases, 6.

Yahfoufi, N., Alsadi, N., Jambi, M., and Matar, C. (2018). The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients, 10.

Filesi, 2007, Polyphenols, dietary sources and bioavailability, Ann. Ist. Super. Sanita, 43, 348

Kumar, 2013, Chemistry and Biological Activities of Flavonoids: An Overview, Sci. World J., 2013, 162750, 10.1155/2013/162750

Erlund, 2004, Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology, Nutr. Res., 24, 851, 10.1016/j.nutres.2004.07.005

Gattuso, 2007, Flavonoid Composition of Citrus Juices, Molecules, 12, 1641, 10.3390/12081641

Aherne, 2002, Dietary flavonols: Chemistry, food content, and metabolism, Nutrition, 18, 75, 10.1016/S0899-9007(01)00695-5

Zaidun, 2018, Combating oxidative stress disorders with citrus flavonoid: Naringenin, Life Sci., 208, 111, 10.1016/j.lfs.2018.07.017

Sharma, 2015, Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications, Curr. Top. Med. Chem., 15, 187, 10.2174/1568026615666141209163013

Coelho, 2013, Anti-inflammatory properties of orange juice: Possible favorable molecular and metabolic effects, Plant. Foods Hum. Nutr., 68, 1, 10.1007/s11130-013-0343-3

Rani, 2016, Pharmacological Properties and Therapeutic Potential of Naringenin: A Citrus Flavonoid of Pharmaceutical Promise, Curr. Pharm. Des., 22, 4341, 10.2174/1381612822666160530150936

Zeng, 2018, Naringenin as a potential immunomodulator in therapeutics, Pharmacol. Res., 135, 122, 10.1016/j.phrs.2018.08.002

Muriel, 2018, Beneficial effects of naringenin in liver diseases: Molecular mechanisms, World J. Gastroenterol., 24, 1679, 10.3748/wjg.v24.i16.1679

Mulvihill, 2010, Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice, Arterioscler. Thromb. Vasc. Biol., 30, 742, 10.1161/ATVBAHA.109.201095

Orhan, 2015, Naringenin and atherosclerosis: A review of literature, Curr. Pharm. Biotechnol., 16, 245, 10.2174/1389201015666141202110216

Mulvihill, 2016, Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis, Annu. Rev. Nutr., 36, 275, 10.1146/annurev-nutr-071715-050718

Testai, L., and Calderone, V. (2017). Nutraceutical Value of Citrus Flavanones and Their Implications in Cardiovascular Disease. Nutrients, 9.

Assini, 2013, Citrus flavonoids and lipid metabolism, Curr. Opin. Lipidol., 24, 34, 10.1097/MOL.0b013e32835c07fd

Kannappan, 2010, Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome, Eur. J. Nutr., 49, 101, 10.1007/s00394-009-0054-6

Kanaze, 2007, Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects, Eur. J. Clin. Nutr., 61, 472, 10.1038/sj.ejcn.1602543

Marks, 2004, The differential tissue distribution of the citrus flavanone naringenin following gastric instillation, Free Radic. Res., 38, 1329, 10.1080/10715760400017293

Zygmunt, 2010, Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK, Biochem. Biophys. Res. Commun., 398, 178, 10.1016/j.bbrc.2010.06.048

Bhattacharya, 2013, Bioactive components from flowers of Sambucus nigra L. increase glucose uptake in primary porcine myotube cultures and reduce fat accumulation in Caenorhabditis elegans, J. Agric. Food Chem., 61, 11033, 10.1021/jf402838a

2017, Polyphenols activate energy sensing network in insulin resistant models, Chem. Biol. Interact., 275, 95, 10.1016/j.cbi.2017.07.016

Iossa, 2017, Skeletal muscle insulin resistance: Role of mitochondria and other ROS sources, J. Endocrinol., 233, R15, 10.1530/JOE-16-0598

Haber, 2003, N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: Possible role of oxidative stress, Am. J. Physiol. Endocrinol. Metab., 285, 744, 10.1152/ajpendo.00355.2002

Harmon, 2001, Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis, Am. J. Physiol. Cell Physiol., 280, C807, 10.1152/ajpcell.2001.280.4.C807

Yoshida, 2010, The citrus flavonoids hesperetin and naringenin block the lipolytic actions of TNF-alpha in mouse adipocytes, Biochem. Biophys. Res. Commun., 394, 728, 10.1016/j.bbrc.2010.03.060

Claussnitzer, 2011, Effect of flavonoids on basal and insulin-stimulated 2-deoxyglucose uptake in adipocytes, Mol. Nutr. Food Res., 55, S26, 10.1002/mnfr.201000372

Yoshida, 2013, Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes, J. Nutr. Biochem., 24, 1276, 10.1016/j.jnutbio.2012.10.003

Richard, 2013, Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes, Evid. Based Complement. Altern. Med., 2013, 549750, 10.1155/2013/549750

Rebello, 2019, Naringenin Promotes Thermogenic Gene Expression in Human White Adipose Tissue, Obesity, 27, 103, 10.1002/oby.22352

Kaisanlahti, 2018, Browning of white fat: Agents and implications for beige adipose tissue to type 2 diabetes, J. Physiol. Biochem., 75, 1, 10.1007/s13105-018-0658-5

Wilcox, 2001, Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP, J. Lipid Res., 42, 725, 10.1016/S0022-2275(20)31634-5

Borradaile, 2003, Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation, Diabetes, 52, 2554, 10.2337/diabetes.52.10.2554

Allister, 2008, Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor, J. Lipid Res., 49, 2218, 10.1194/jlr.M800297-JLR200

Purushotham, 2009, The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells, Mol. Nutr. Food Res., 53, 300, 10.1002/mnfr.200700514

Goldwasser, J., Cohen, P.Y., Yang, E., Balaguer, P., Yarmush, M.L., and Nahmias, Y. (2010). Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: Role of PPARalpha, PPARgamma and LXRalpha. PLoS ONE, 5.

Constantin, 2014, Molecular mechanisms of citrus flavanones on hepatic gluconeogenesis, Fitoterapia, 92, 148, 10.1016/j.fitote.2013.11.003

Bhattacharya, 2014, Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells, Diabetes Obes. Metab., 16, 602, 10.1111/dom.12236

Li, 2006, Inhibition of intestinal and renal Na+-glucose cotransporter by naringenin, Int. J. Biochem. Cell Biol., 38, 985, 10.1016/j.biocel.2005.10.002

Webster, 2008, Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation, Diabetes Obes. Metab., 10, 1097, 10.1111/j.1463-1326.2008.00869.x

Punithavathi, 2008, Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats, J. Appl. Toxicol., 28, 806, 10.1002/jat.1343

Tsai, 2012, Anti-inflammatory and antifibrotic effects of naringenin in diabetic mice, J. Agric. Food Chem., 60, 514, 10.1021/jf203259h

Sharma, 2011, Up-regulation of PPARγ, heat shock protein-27 and -72 by naringin attenuates insulin resistance, β-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes, Br. J. Nutr., 106, 1713, 10.1017/S000711451100225X

Annadurai, 2012, Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats, J. Physiol. Biochem., 68, 307, 10.1007/s13105-011-0142-y

Mahmoud, 2012, Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats, J. Diabetes Complicat., 26, 483, 10.1016/j.jdiacomp.2012.06.001

Priscilla, 2014, Naringenin inhibits α-glucosidase activity: A promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats, Chem. Biol. Interact., 210, 77, 10.1016/j.cbi.2013.12.014

Hasanein, 2014, Role of naringenin in protection against diabetic hyperalgesia and tactile allodynia in male Wistar rats, J. Physiol. Biochem., 70, 997, 10.1007/s13105-014-0369-5

Kapoor, 2014, Naringenin accords hepatoprotection from streptozotocin induced diabetes in vivo by modulating mitochondrial dysfunction and apoptotic signaling cascade, Toxicol. Rep., 1, 569, 10.1016/j.toxrep.2014.08.002

Aleisa, 2015, Naringenin neutralises oxidative stress and nerve growth factor discrepancy in experimental diabetic neuropathy, Neurol. Res., 37, 924, 10.1179/1743132815Y.0000000079

Ren, 2016, Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats, Eur. J. Pharmacol., 773, 13, 10.1016/j.ejphar.2016.01.002

Yan, 2016, Naringenin Ameliorated Kidney Injury through Let-7a/TGFBR1 Signaling in Diabetic Nephropathy, J. Diabetes Res., 2016, 8738760, 10.1155/2016/8738760

Roy, 2016, Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-β1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events, Pharm. Biol., 54, 1616, 10.3109/13880209.2015.1110599

Al-Dosari, D.I., Ahmed, M.M., Al-Rejaie, S.S., Alhomida, A.S., and Ola, M.S. (2017). Flavonoid Naringenin Attenuates Oxidative Stress, Apoptosis and Improves Neurotrophic Effects in the Diabetic Rat Retina. Nutrients, 9.

Ahmed, 2017, Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats, Biomed. Pharmacother., 94, 197, 10.1016/j.biopha.2017.07.094

Singh, 2018, Isolated mangiferin and naringenin exert antidiabetic effect via PPARγ/GLUT4 dual agonistic action with strong metabolic regulation, Chem. Biol. Interact., 280, 33, 10.1016/j.cbi.2017.12.007

Gajski, 2011, DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice, Eur. J. Pharmacol., 656, 110, 10.1016/j.ejphar.2011.01.021

Sirovina, 2016, Naringenin ameliorates pathological changes in liver and kidney of diabetic mice: A preliminary study, Arh. Hig. Rada Toksikol., 67, 19, 10.1515/aiht-2016-67-2708

Jung, 2006, Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice, Int. J. Biochem. Cell Biol., 38, 1134, 10.1016/j.biocel.2005.12.002

Burke, A.C., Telford, D.E., Edwards, J.Y., Sutherland, B.G., Sawyez, C.G., and Huff, M.W. (2018). Naringenin Supplementation to a Chow Diet Enhances Energy Expenditure and Fatty Acid Oxidation, and Reduces Adiposity in Lean, Pair-Fed Ldlr−/− Mice. Mol. Nutr. Food Res.

Jeon, 2004, Antihypercholesterolemic property of naringin alters plasma and tissue lipids, cholesterol-regulating enzymes, fecal sterol and tissue morphology in rabbits, Clin. Nutr., 23, 1025, 10.1016/j.clnu.2004.01.006

Mulvihill, 2009, Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance, Diabetes, 58, 2198, 10.2337/db09-0634

Cho, 2011, Dietary naringenin increases hepatic peroxisome proliferators-activated receptor α protein expression and decreases plasma triglyceride and adiposity in rats, Eur. J. Nutr., 50, 81, 10.1007/s00394-010-0117-8

Pu, 2012, Naringin ameliorates metabolic syndrome by activating AMP-activated protein kinase in mice fed a high-fat diet, Arch. Biochem. Biophys., 518, 61, 10.1016/j.abb.2011.11.026

Alam, 2013, Naringin improves diet-induced cardiovascular dysfunction and obesity in high carbohydrate, high fat diet-fed rats, Nutrients, 5, 637, 10.3390/nu5030637

Assini, 2013, Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr−/− mice, J. Lipid Res., 54, 711, 10.1194/jlr.M032631

Yoshida, 2014, Naringenin suppresses macrophage infiltration into adipose tissue in an early phase of high-fat diet-induced obesity, Biochem. Biophys. Res. Commun., 454, 95, 10.1016/j.bbrc.2014.10.038

Assini, 2015, Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21, Endocrinology, 156, 2087, 10.1210/en.2014-2003

Chtourou, 2016, Naringenin ameliorates renal and platelet purinergic signalling alterations in high-cholesterol fed rats through the suppression of ROS and NF-κB signaling pathways, Food Funct., 7, 183, 10.1039/C5FO00871A

Burke, 2018, Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr−/− mice, J. Lipid Res., 59, 1714, 10.1194/jlr.M087387

Knekt, 2002, Flavonoid intake and risk of chronic diseases, Am. J. Clin. Nutr., 76, 560, 10.1093/ajcn/76.3.560

Farook, 2015, Metabolites as Novel Biomarkers for Childhood Obesity-Related Traits in Mexican American Children, Pediatr. Obes., 10, 320, 10.1111/ijpo.270

Jung, 2003, Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects, Clin. Nutr., 22, 561, 10.1016/S0261-5614(03)00059-1

Dallas, 2014, Clinical Study to Assess the Efficacy and Safety of a Citrus Polyphenolic Extract of Red Orange, Grapefruit, and Orange (Sinetrol-XPur) on Weight Management and Metabolic Parameters in Healthy Overweight Individuals, Phytother. Res., 28, 212, 10.1002/ptr.4981