Tumor Necrosis Factor Alpha: Role in the Development of Obesity and Diabetes Mellitus

Main Article Content

Zulaykho M. Shamansurova
Talat S. Saatov
Lola Sh. Takhirov


Obesity and Diabetes Mellitus (DM) are defined as worldwide pandemics by the World health organization due to their economic burden and widespread. Although a huge amount of research is being done in the field of obesity and DM today, many questions remain unsolved. Tissue inflammation is the main factor in the development of both obesity and DM, leading towards irreversible changes in the tissue and formation of specific complications. One of the widespread cytokines, tumor necrosis factor alpha (TNF-α), was shown to be involved with inflammation in the development of metabolic disorders and neurodegenerative diseases. Even though the role of TNF-α in the pathogenesis of these two diseases remains unclear, new ways of treating and preventing diseases based on TNF-α antagonism attracted the attention of scientists. In this review, TNF-α and its receptors’ structures and properties are explored, and their role in disease development, including obesity and type 2 DM (DM2) will be discussed by viewing data from literature.

Tumor necrosis factor alpha, TNF receptors, TNF-α inhibitors, obesity, diabetes

Article Details

How to Cite
Shamansurova, Z. M., Saatov, T. S., & Takhirov, L. S. (2020). Tumor Necrosis Factor Alpha: Role in the Development of Obesity and Diabetes Mellitus. Asian Journal of Biochemistry, Genetics and Molecular Biology, 4(3), 29-42. https://doi.org/10.9734/ajbgmb/2020/v4i330108
Review Article


Borges AP, Guidoni CM, Freitas O, Pereira LR. Economic evaluation of outpatients with type 2 diabetes mellitus assisted by a pharmaceutical care service. Arq Bras Endocrinol Metabol. 2011;55(9):686-91.

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98-107.

Harris Nwanyanwu K, Talwar N, Gardner TW, Wrobel JS, Herman WH, Stein JD. Predicting development of proliferative diabetic retinopathy. Diabetes Care. 2013; 36(6):1562-8.

Li C, Siragy HM. High glucose induces podocyte injury via enhanced (pro)renin receptor-Wnt-beta-catenin-snail signaling pathway. PloS one. 2014;9(2):e89233.

Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. The Journal of Clinical Investigation. 2005;115(5):1111-9.

Gwozdziewiczova S, Lichnovska R, Ben Yahia R, Chlup R, Hrebicek J. TNF-alpha in the development of insulin resistance and other disorders in metabolic syndrome. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2005;149(1):109-17.

Balarini CM, Braga VA. Editorial: New Translational Insights on Metabolic Syndrome: Obesity, Hypertension, Diabetes and Beyond. Frontiers in Physiology. 2016;7:229.

Chen AI, Advani RH. Beyond the guidelines in the treatment of peripheral T-cell lymphoma: New drug development. Journal of the National Comprehensive Cancer Network : JNCCN. 2008;6(4):428-35.

Duarte CW, Willey CD, Zhi D, Cui X, Harris JJ, Vaughan LK, et al. Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PloS One. 2012;7(1): e29653.

Fischer R, Wajant H, Kontermann R, Pfizenmaier K, Maier O. Astrocyte-specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor. Glia. 2014;62(2): 272-83.

Alzamil H. Elevated Serum TNF-alpha Is Related to Obesity in Type 2 Diabetes Mellitus and Is Associated with Glycemic Control and Insulin Resistance. J Obes. 2020;2020:5076858.

Cheng X, Yang L, He P, Li R, Shen Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients. Journal of Alzheimer's Disease: JAD. 2010;19(2):621-30.

Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: A key component of the obesity-diabetes link. Diabetes. 1994; 43(11):1271-8.

Romanatto T, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, et al. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. The Journal of Biological Chemistry. 2009;284(52):36213-22.

Shin SH, Kim EK, Lee KY, Kim HS. TNF-alpha antagonist attenuates systemic lipopolysaccharide-induced brain white matter injury in neonatal rats. BMC Neurosci. 2019;20(1):45.

Shu W, Pang Z, Xu C, Lin J, Li G, Wu W, et al. Anti-TNF-alpha monoclonal antibody therapy improves anemia through downregulating hepatocyte hepcidin expression in inflammatory bowel disease. Mediators Inflamm. 2019;2019:4038619.

Rath PC, Aggarwal BB. TNF-induced signaling in apoptosis. Journal of Clinical Immunology. 1999;19(6):350-64.

Rubin BY, Anderson SL, Sullivan SA, Williamson BD, Carswell EA, Old LJ. Purification and characterization of a human tumor necrosis factor from the LuKII cell line. Proceedings of the National Academy of Sciences of the United States of America. 1985;82(19):6637-41.

Old LJ. Tumor necrosis factor (TNF). Science. 1985;230(4726):630-2.

Van Lint J, Agostinis P, Vandevoorde V, Haegeman G, Fiers W, Merlevede W, et al. Tumor necrosis factor stimulates multiple serine/threonine protein kinases in Swiss 3T3 and L929 cells. Implication of casein kinase-2 and extracellular signal-regulated kinases in the tumor necrosis factor signal transduction pathway. The Journal of Biological Chemistry. 1992;267(36):25916-21.

Huang SM, Wu CS, Chiu MH, Wu CH, Chang YT, Chen GS, et al. High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-alpha: An important mechanism to delay the diabetic wound healing. J Dermatol Sci. 2019;96(3):159-67.

Gahring LC, Carlson NG, Kulmar RA, Rogers SW. Neuronal expression of tumor necrosis factor alpha in the murine brain. Neuroimmunomodulation. 1996;3(5):289-303.

Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: Players, rules and the games. Immunology. 2005;115(1):1-20.

Dong Y, Fischer R, Naude PJ, Maier O, Nyakas C, Duffey M, et al. Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(43):12304-9.

Fricker M, Vilalta A, Tolkovsky AM, Brown GC. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. The Journal of Biological Chemistry. 2013;288(13):9145-52.

Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000;288(5475):2351-4.

Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death and Differentiation. 2003;10(1):45-65.

Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell. 2001; 104(4):487-501.

Romanatto T, Cesquini M, Amaral ME, Roman EA, Moraes JC, Torsoni MA, et al. TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient--effects on leptin and insulin signaling pathways. Peptides. 2007; 28(5):1050-8.

Etemadi N, Holien JK, Chau D, Dewson G, Murphy JM, Alexander WS, et al. Lymphotoxin alpha induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor. The FEBS Journal. 2013;280(21): 5283-97.

Yang L, Hotamisligil GS. Stressing the brain, fattening the body. Cell. 2008;135(1): 20-2.

Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81(4):495-504.

Kang HJ, Kim JM, Kim SW, Shin IS, Park SW, Kim YH, et al. Associations of cytokine genes with Alzheimer's disease and depression in an elderly Korean population. Journal of Neurology, Neurosurgery, and Psychiatry. 2015;86(9): 1002-7.

Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, et al. Activation of necroptosis in multiple sclerosis. Cell Reports. 2015;10(11):1836-49.

Ramaswamy P, Goswami K, Dalavaikodihalli Nanjaiah N, Srinivas D, Prasad C. TNF-alpha mediated MEK-ERK signaling in invasion with putative network involving NF-kappaB and STAT-6: A new perspective in glioma. Cell Biol Int. 2019; 43(11):1257-66.

Flores L, Naf S, Hernaez R, Conget I, Gomis R, Esmatjes E. Transforming growth factor beta at clinical onset of Type 1 diabetes mellitus. A pilot study. Diabetic medicine : A Journal of the British Diabetic Association. 2004;21(8):818-22.

Yang S, Wang Y, Mei K, Zhang S, Sun X, Ren F, et al. Tumor necrosis factor receptor 2 (TNFR2).interleukin-17 receptor D (IL-17RD) heteromerization reveals a novel mechanism for NF-kappaB activation. The Journal of Biological Chemistry. 2015; 290(2):861-71.

Hawari FI, Rouhani FN, Cui X, Yu ZX, Buckley C, Kaler M, et al. Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: A mechanism for generation of soluble cytokine receptors. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(5): 1297-302.

Diez-Ruiz A, Tilz GP, Zangerle R, Baier-Bitterlich G, Wachter H, Fuchs D. Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. European Journal of Haematology. 1995;54(1):1-8.

Bai L, Song N, Yu J, Tan L, Shen Y, Xie J, et al. Elevated plasma levels of soluble TNFRs and TACE activity in Alzheimer's disease patients of Northern Han Chinese descent. Current Alzheimer Research. 2013;10(1):57-62.

Waetzig GH, Rosenstiel P, Arlt A, Till A, Brautigam K, Schafer H, et al. Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2005;19(1):91-3.

Jansen J, van der Poll T, Levi M, ten Cate H, Gallati H, ten Cate JW, et al. Inhibition of the release of soluble tumor necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-alpha antibody. Journal of Clinical Immunology. 1995;15(1):45-50.

Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonca VA, Gattaz WF, et al. Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer's disease. Journal of Alzheimer's Disease: JAD. 2010;22(4): 1305-11.

Scalzo P, Kummer A, Cardoso F, Teixeira AL. Increased serum levels of soluble tumor necrosis factor-alpha receptor-1 in patients with Parkinson's disease. Journal of Neuroimmunology. 2009;216(1-2):122-5.

Gregory AP, Dendrou CA, Attfield KE, Haghikia A, Xifara DK, Butter F, et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature. 2012;488(7412):508-11.

Kirchner S, Holler E, Haffner S, Andreesen R, Eissner G. Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine. 2004;28(2): 67-74.

Elessa D, Thietart S, Corpechot C, Fain O, Mekinian A. TNF-alpha antagonist infliximab for aseptic abscess syndrome. Presse Med. 2019;48(12):1579-80.

Godfrey MS, Friedman LN. Tuberculosis and Biologic Therapies: Anti-Tumor Necrosis Factor-alpha and Beyond. Clin Chest Med. 2019;40(4):721-39.

Zhang S, Tang S, Li S, Pan Y, Ding Y. Biologic TNF-alpha inhibitors in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: A systemic review. J Dermatolog Treat. 2020;31(1): 66-73.

Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annual review of medicine. 2000;51:207-29.

Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology. 2005;64(8):1468-70.

Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Current Alzheimer research. 2007;4(4):378-85.

Martinez TN, Chen X, Bandyopadhyay S, Merrill AH, Tansey MG. Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons. Molecular neurodegeneration. 2012;7:45.

Alessenko AV, Bachurin SO, Gurianova SV, Karatasso YO, Shevtsova EF, Shingarova LN. [Tumor necrosis fasmall es, Cyrillictor-alpha - potential target for neuroprotector dimebon]. Biomeditsinskaia khimiia. 2016;62(4):418-25.

Williams SK, Maier O, Fischer R, Fairless R, Hochmeister S, Stojic A, et al. Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis. PloS one. 2014;9(2):e90117.

Liu Y, Yang G, Zhang J, Xing K, Dai L, Cheng L, et al. Anti-TNF-alpha monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis. International immunopharmacology. 2015;28(1):731-43.

McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiology of disease. 2009;34(1):163-77.

Brambilla R, Ashbaugh JJ, Magliozzi R, Dellarole A, Karmally S, Szymkowski DE, et al. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain: A Journal of Neurology. 2011;134(Pt 9):2736-54.

Eugster HP, Frei K, Bachmann R, Bluethmann H, Lassmann H, Fontana A. Severity of symptoms and demyelination in MOG-induced EAE depends on TNFR1. European Journal of Immunology. 1999; 29(2):626-32.

Spinelli FR, Di Franco M, Metere A, Conti F, Iannuccelli C, Agati L, et al. Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis. Drug Development Research. 2014;75 Suppl 1:S67-9.

Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: Lessons learned, unresolved issues and future directions. Current Directions in Autoimmunity. 2010;11:180-210.

Atzeni F, Gianturco L, Talotta R, Varisco V, Ditto MC, Turiel M, et al. Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern? Immunotherapy. 2015;7(4):353-61.

Beigel F, Steinborn A, Schnitzler F, Tillack C, Breiteneicher S, John JM, et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. Pharmacoepidemiology and drug safety. 2014;23(7):735-44.

Guiddir T, Fremond ML, Triki TB, Candon S, Croisille L, Leblanc T, et al. Anti-TNF-alpha therapy may cause neonatal neutropenia. Pediatrics. 2014;134(4): e1189-93.

Dziewulska D, Mossakowski MJ. Cellular expression of tumor necrosis factor a and its receptors in human ischemic stroke. Clinical neuropathology. 2003;22(1):35-40.

Tuttolomondo A, Pinto A, Corrao S, Di Raimondo D, Fernandez P, Di Sciacca R, et al. Immuno-inflammatory and thrombotic/fibrinolytic variables associated with acute ischemic stroke diagnosis. Atherosclerosis. 2009;203(2):503-8.

Pan W, Kastin AJ. Tumor necrosis factor and stroke: role of the blood-brain barrier. Progress in neurobiology. 2007;83(6):363-74.

Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein. Journal of cerebral blood flow and metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2012;32(10):1933-8.

Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Medicine. 1996;2(7):788-94.

Dolga AM, Terpolilli N, Kepura F, Nijholt IM, Knaus HG, D'Orsi B, et al. KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. Cell Death & Disease. 2011;2:e147.

Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP. Ischemic and excitotoxic brain injury is enhanced in mice lacking the p55 tumor necrosis factor receptor. Journal of cerebral blood flow and metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 1998;18(12):1283-7.

Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Fenger C, Nielsen HH, et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. The Journal of neuroscience: The Official Journal of the Society for Neuroscience. 2009;29(5):1319-30.

Pradillo JM, Romera C, Hurtado O, Cardenas A, Moro MA, Leza JC, et al. TNFR1 upregulation mediates tolerance after brain ischemic preconditioning. Journal of cerebral blood flow and metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2005;25(2):193-203.

Taoufik E, Petit E, Divoux D, Tseveleki V, Mengozzi M, Roberts ML, et al. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(16): 6185-90.

Akassoglou K, Douni E, Bauer J, Lassmann H, Kollias G, Probert L. Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(2): 709-14.

Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U. Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: Opposite roles of TNF receptor 1 and TNF receptor 2. The Journal of neuroscience: The Official Journal of the Society for Neuroscience. 2002;22(7):RC216.

Shen Y, Li R, Shiosaki K. Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and beta-amyloid toxicity in human neuronal cell line. The Journal of Biological Chemistry. 1997;272(6):3550-3.

Wang LW, Chang YC, Chen SJ, Tseng CH, Tu YF, Liao NS, et al. TNFR1-JNK signaling is the shared pathway of neuroinflammation and neurovascular damage after LPS-sensitized hypoxic-ischemic injury in the immature brain. Journal of Neuroinflammation. 2014;11: 215.

Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. The Journal of Biological Chemistry. 2004; 279(31):32869-81.

Dolga AM, Nijholt IM, Ostroveanu A, Ten Bosch Q, Luiten PG, Eisel UL. Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. Journal of Alzheimer's Disease: JAD. 2008;13(2):111-22.

Allen D, Bond CT, Lujan R, Ballesteros-Merino C, Lin MT, Wang K, et al. The SK2-long isoform directs synaptic localization and function of SK2-containing channels. Nature Neuroscience. 2011;14(6):744-9.

Moidunny S, Vinet J, Wesseling E, Bijzet J, Shieh CH, van Ijzendoorn SC, et al. Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity. Journal of Neuroinflammation. 2012;9:198.

Gresle MM, Alexandrou E, Wu Q, Egan G, Jokubaitis V, Ayers M, et al. Leukemia inhibitory factor protects axons in experimental autoimmune encephalomyelitis via an oligodendrocyte-independent mechanism. PloS One. 2012; 7(10):e47379.

Parachikova A, Cotman CW. Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease. Neurobiology of Disease. 2007;28(2):143-53.

Patel JR, Williams JL, Muccigrosso MM, Liu L, Sun T, Rubin JB, et al. Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS. Acta Neuropathologica. 2012; 124(6):847-60.

Veroni C, Gabriele L, Canini I, Castiello L, Coccia E, Remoli ME, et al. Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways. Molecular and Cellular Neurosciences. 2010;45(3):234-44.

Schwartz MW. Central nervous system regulation of food intake. Obesity. 2006;14 Suppl 1:1S-8S.

Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annual Review of Physiology. 2008;70:537-56.

Araujo EP, De Souza CT, Ueno M, Cintra DE, Bertolo MB, Carvalheira JB, et al. Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes. Endocrinology. 2007;148(12): 5991-7.

Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997; 389(6651):610-4.

Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: Implications for the pathogenesis of obesity. The Journal of neuroscience: The official Journal of the Society for Neuroscience. 2009;29(2):359-70.

Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of Clinical Investigation. 2006; 116(11):3015-25.

Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56(8):1986-98.

Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology. 1998;139(12): 4832-8.

Schreyer SA, Chua SC, Jr, LeBoeuf RC. Obesity and diabetes in TNF-alpha receptor- deficient mice. The Journal of Clinical Investigation. 1998;102(2):402-11.

Crawford M, Curtis JR. Tumor necrosis factor inhibitors and infection complications. Current Rheumatology Reports. 2008; 10(5):383-9.

Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, et al. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World journal of Diabetes. 2014;5(5):586-600.

Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993;73(3): 457-67.

Yu R, Tian L, Ding Y, Gao Y, Li D, Tang Y. Correlation between inflammatory markers and impaired circadian clock gene expression in type 2 diabetes mellitus. Diabetes Res Clin Pract. 2019;156:107831.

Karavanaki K, Kakleas K, Georga S, Bartzeliotou A, Mavropoulos G, Tsouvalas M, et al. Plasma high sensitivity C-reactive protein and its relationship with cytokine levels in children with newly diagnosed type 1 diabetes and ketoacidosis. Clinical Biochemistry. 2012; 45(16-17):1383-8.

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259(5091):87-91.

Akash MSH, Rehman K, Liaqat A. Tumor Necrosis Factor-Alpha: Role in Development of Insulin Resistance and Pathogenesis of Type 2 Diabetes Mellitus. Journal of Cellular Biochemistry. 2018; 119(1):105-10.

Cheung AT, Ree D, Kolls JK, Fuselier J, Coy DH, Bryer-Ash M. An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: Evidence for differential regulation of insulin signaling by TNF-alpha. Endocrinology. 1998;139(12):4928-35.

Qiao YC, Chen YL, Pan YH, Tian F, Xu Y, Zhang XX, et al. The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. PloS One. 2017; 12(4):e0176157.

Lampropoulou IT, Stangou M, Papagianni A, Didangelos T, Iliadis F, Efstratiadis G. TNF-alpha and microalbuminuria in patients with type 2 diabetes mellitus. Journal of Diabetes Research. 2014;2014: 394206.

Qian TW, Zhao MY, Li XX, Xu X. Efficiency and safety of laser photocoagulation with or without intravitreal ranibizumab for treatment of diabetic macular edema: A systematic review and Meta-analysis. International Journal of Ophthalmology. 2017;10(7):1134-43.

Sfikakis PP, Grigoropoulos V, Emfietzoglou I, Theodossiadis G, Tentolouris N, Delicha E, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: A randomized, double-blind, placebo-controlled, crossover, 32-week study. Diabetes Care. 2010;33(7): 1523-8.

Elmarakby AA, Quigley JE, Pollock DM, Imig JD. Tumor necrosis factor alpha blockade increases renal Cyp2c23 expression and slows the progression of renal damage in salt-sensitive hypertension. Hypertension. 2006;47(3): 557-62.

Justin Rucker A, Crowley SD. The role of macrophages in hypertension and its complications. Pflugers Archiv: European Journal of Physiology. 2017;469(3-4):419-30.