Relationship of Circulating Tumor Necrosis Factor Alpha (TNF-α) and Insulin Secretion and Resistance in Euglycaemic Dogs

Ivana Lakić, Branislava Belić, Marko Cincović, Aleksandar Potkonjak, Dragiša Trailović, Zorana Kovačević

Abstract


Background: Insulin resistance is a state that is characterized with reduced sensitivity of peripheral tissues to insulin. It can be related with increased level of tumor necrosis factor alpha (TNF-α) in dogs. Insulin resistance can be evaluated by homeostasis model assessment (HOMA-IR, HOMA-β). The aim of this study was to determine correlation of circulating TNF-α level with insulin production and insulin resistance indexes in euglycaemic dogs. 

Materials, Methods & Results: Seventydogs of normal body score were included in this study. After blood sampling levels of glucose, insulin and TNF-α were determined and indexes HOMA-IR and HOMA-β were calculated. Three groups in accordance to TNF-α levels were formed: the first-TNF-α 0-2.0 pg/mL, the second-TNF-α below median (2.1-17.0 pg/mL) and the third-TNF-α above median (17.1-51.8 pg/mL). Differences in insulin and glucose levels, HOMA-IR and HOMA-β were determined in all three groups. ANOVA and posthock LSD analyses were used. Correlation between HOMA-IR and HOMA-β was determined. Linear regression between HOMA-β/HOMA-IR ratio and glucose concentration was calculated. SPSS statistical program was used (IBM). Highest insulin level was detected in the second group and the lowest was detected in the third group. The lowest glucose level was detected in the first group. The highest value of HOMA-β index was noted in the first group and it decreases with TNF-α increase. The highest HOMA-IR value was detected in the second group and the lowest was in the third group. Positive correlation was noted between HOMA-IR and HOMA-β. Significant linear correlation was noted between glucose levels in function of HOMA-β/HOMA-IR (R2= 0.51-0.78, P = 0.0007). The first group showed the minor change of glucose level (b= 0.29 mmol/L). In the third group the greatest change of glucose level in function of HOMA-β/HOMA-IR was noted (b= 0.52 mmol/L). In the third group the highest increase of glucose level followed by decrease in HOMA-β/HOMA-IR ratio was noted.  

Discussion: Increase of TNF-α followed by increase of insulin was noted in the second group. That indicates reduced insulin action and compensatory increase in his concentrations in order to achieve the same effect. TNF-α induces reduction in expression of glucose transporter 4 that is insulin-regulating hormone. Serine phosphorylation of insulin receptor substrate-1 that is induced by TNF-α causes inhibition of insulin receptors. These actions cause insulin resistance and compensatory increase in insulin secretion. Increased tissue resistance is reflected in increased HOMA-IR index which is directly associated with insulin and glucose level. Increase of insulin value and HOMA-IR index were noted in second group. This indicates the influence of TNF-α on insulin resistance. The lowest insulin level was noted in the third group of dogs. Decrease in production and secretion leads to reduction in circulating insulin and can be evaluated by HOMA-β index. The highest value of this index was noted in first group and decreases with TNF-α increase. This can be related with apoptotic effect that TNF-α has on beta- pancreatic cells. Increase of HOMA-β index causes increase of HOMA-IR. This is indication of increased peripheral resistance. Compensatory mechanism for that state is increased insulin secretion. Glucose level will increase more during increase of HOMA-IR and decrease of HOMA-β. This indicates that TNF-α regulates glucose level directly and explains differences in glucose concentrations in dogs with different concentrations of TNF-α showed. Values of insulin resistance indexes, glucose and insulin were affected by circulating concentration of TNF-α. The most unfavorable change in glucose concentration based on insulin production and tissue resistance was founded in dogs with the highest circulating TNF-α concentration in blood. 



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References


Ader M., Stefanovski D., Richey J.M., Kim S.P., Kolka C.M., Ionut V., Kabir M. & Bergman R.N. 2014. Failure of homeostatic model assessment of insulin resistance to detect marked diet-induced insulin resistance in dogs. Diabetes. 63(6): 1914-1919.

Akash M.S.H., Rehman K. & Liaqat A. 2017. Tumor necrosis factor alpha: Role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. Journal of Cellular Biochemistry. 119(1): 105-110.

Borst S.E. 2004. The role of TNF-α in insulin resistance. Endocrine. 23(2-3): 177-185.

Cefalu W.T. 2001. Insulin resistance: cellular and clinical concepts. Experimental Biology and Medicine. 226(1): 13-26.

Chen L., Chen R., Wang H. & Liang F. 2015. Mechanisms linking inflammation to insulin resistance. International Journal of Endocrinology. 2015. .

Cieslak M., Wojtczak A. & Cieslak M. 2015. Role of pro-inflamatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment. Acta Biochemica Polonica. 62(1): 15-21.

Cincović M., Đoković R., Belić B., Lakić I., Stojanac N., Stevančević O. & Staničkov N. 2018. Insulin resistance in cows during the periparturient period. Acta Agriculturae Serbica. 23(46): 233-245.

Dong Y., Dekens D.W., De Deyn P.P., Naudé P.J. & Eisel U.L. 2015. Targeting of tumor necrosis factor alpha receptors as a therapeutic strategy for neurodegenerative disorders. Antibodies. 4(4): 369-408.

Ehses J.A., Lacraz G., Giroix M.H., Schmidlin F., Coulaud J., Kassis N., Irminger J.C., Kergoat M., Portha B., Homo-Delarche F. & Donath M.Y. 2009. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proceedings of the National Academy of Sciences of the United States of America. 106(33): 13998-14003.

Elochukwu A.C., Opara U.C., Chinyere N.A., Jeremiah O.S. & Chukwuma O.O. 2017. Evaluation of tumor necrosis factor alpha, insulin and homeostasis model assessment of insulin resistance among obese participants living in Calabar, Nigeria. Tropical Journal of Medical Research. 20(1): 45-52.

Gayet C., Bailhache E., Dumon H., Martin L., Siliart B. & Nguyen P. 2004. Insulin resistance and changes in plasma concentration of TNFα, IGF1, and NEFA in dogs during weight gain and obesity. Journal of Animal Physiology and Animal Nutrition. 88(3-4): 157-165.

German A.J., Hervera M., Hunter L., Holden S.L., Morris P.J., Biourge V. & Trayhurn P. 2009. Improvement in insulin resistance and reduction in plasma inflammatory adipokines after weight loss in obese dogs. Domestic Animal Endocrinology. 37(4): 214-226.

Gutch M., Kumar S., Razi S.M., Gupta K.K. & Gupta A. 2015. Assessment of insulin sensitivity/resistance. Indian journal of endocrinology and metabolism. 19(1): 160-164.

Gwozdziewiczova S., Lichnovska R., Yahia R.B., Chlup R. & Hrebicek J. 2005. TNF-α in the development of insulin resistance and other disorders in metabolic syndrome. Biomedical Papers. 149(1): 109-117.

Haffner S.M., Mykkanen L., Festa A., Burke J.P. & Stern M.P. 2000. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive subjects: Implications for preventive coronary heart disease during the prediabetic state. Circulation. 101(9): 975-980.

Hamada D., Maynard R., Schott E., Drinkwater C.J., Ketz J.P., Kates S.L., Jonason J.H., Hilton M.J., Zuscik M.J. & Mooney R.A. 2016. Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated with Obesity and Type 2 Diabetes Mellitus. Arthritis & Rheumatology. 68(8): 1392-1402.

Hosker J.P., Matthews D.R., Rudenski A.S., Burnett M.A., Darling P., Bown E.G. & Turner R.C. 1985. Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man. Diabetologia. 28(7): 401-411.

Hossain M., Faruque M.O., Kabir G., Hassan N., Sikdar D., Nahar Q. & Ali L. 2010. Association of TNF-α and IL-6 with insulin secretion and insulin resistance in IFG and IGT subjects in a Bangladeshi population. International Journal of Diabetes Mellitus. 2(3): 165-168.

Ibfelt T., Fischer C.P., Plomgaard P., van Hall G. & Pedersen B.K. 2014. The acute effects of low dose TNF-α on glucose metabolism and β-cell function in humans. Mediators of Inflammation. 2014. http://dx.doi.org/10.1155/2014/295478.

Lasram M.M., Bouzid K., Douib I.B., Annabi A., El Elj N., El Fazaa S., Abdelmoula J. & Gharbi N. 2015. Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat. Drug and chemical toxicology. 38(2): 227-234.

Rehman K. & Akash M.S. 2016. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? Journal of biomedical science. 23(1): 87.

Sharma R.B. & Alonso L.C. 2014. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Current Diabetes Reports. 14(6): 492.

Song Y., Manson J.E., Tinker L., Howard B., Kuller L.H., Nathan L. & Liu S. 2007. Insulin sensitivity and insulin secretion determined by homeostasis model assessment and risk of diabetes in a multiethnic cohort of women. Diabetes Care. 30(7): 1747-1752.

Stagakis I., Bertsias G., Karvounaris S., Kavousanaki M., Virla D., Raptopoulou A., Kardassis D., Boumpas D.T. & Sidiropoulos P.I. 2012. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Research and Therapy. 14(3): R141.

Stanley T.L., Zanni M.V., Johnsen S., Rasheed S., Makimura H., Lee H., Khor V.K., Ahima R.S. & Grinspoon S.K. 2011. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. The Journal of Clinical Endocrinology and Metabolism. 96(1): E146-150.

Vaccaro O., Masulli M., Cuomo V., Albarosa-Rivellese A., Uusitupa M., Vessby B., Hermansen K., Tapsell L. & Riccardi G. 2004. Comparative Evaluation of Simple Indices of Insulin Resistance. Metabolism. 53(12): 1522-1526.

Verkest K.R., Rand J.S., Fleeman L.M. & Morton J.M. 2012. Spontaneously obese dogs exhibit greater postprandial glucose, triglyceride, and insulin concentrations than lean dogs. Domestic Animal Endocrinology. 42(2): 103-112.

Wachlin G., Augstein P., Schoder D., Kuttler B., Kloting I., Heinke P. & Schmidt S. 2003. IL-1beta, IFN-Gamma and TNF-alpha increase vulnerability of pancreatic beta cells to autoimmune destruction. Journal of Autoimmunity. 20(4): 303-312.

Wallace T.M., Levy J.C. & Matthews D.R. 2004. Use and abuse of HOMA modeling. Diabetes Care. 27(6): 1487-1495.

Walsh J.M., McGowan C.A., Byrne J.A., Rath A. & McAuliffe F.M. 2013. The association between TNF-α and insulin resistance in euglycemic women. Cytokine. 64(1): 208-212.

Wang C., Guan Y. & Yang J. 2010. Cytokines in the Progression of Pancreatic β-Cell Dysfunction. International Journal of Endocrinology. 2010. .

Wilcox G. 2005. Insulin and Insulin Resistance. The Clinical Biochemist Review. 26(2): 19-39.

Yazdani-Biuki B., Stelzl H., Brezinschek H.P., Hermann J., Mueller T., Krippl P., Graninger V. & Wascher T.C. 2004. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. European Journal of Clinical Investigation. 34(9): 641-642.

Zhang S. & Kim K.H. 1995. TNF-α inhibits glucose-induced insulin secretion in a pancreatic β-cell line (INS-1). FEBS Letters. 377(2): 237-239.




DOI: https://doi.org/10.22456/1679-9216.100400

Copyright (c) 2020 Ivana Lakic, Branislava Belić, Marko Cincović, Aleksandar Potkonjak, Dragiša Trailović, Zorana Kovačević

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