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

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.

The Correlation between Extracellular Heat Shock Protein 70 and Lipid Metabolism in a Ruminant Model

“…In humans and laboratory mice with insulin resistance and T2DM, there is a lower concentration of iHsp70 and a higher concentration of eHsp70, both changes lead to an increase in TNF-α, and the higher the ratio in favor of eHsp70 the more pronounced the insulin resistance [20]. TNF-α shows a significant effect on the variability of the insulin resistance index even in healthy euglycemic subjects [68]. These results support our finding that both mediators are of great importance in the development of insulin resistance, with eHsp70 showing a significant correlation with the RQUICKI-BHB index only when controlled by TNF-α, while it correlates independently with NEFA/insulin ratio.…”

Nutritional management in diabetic dogs: review

“…A extensa adiposidade aumenta de forma significativa a sinalização pró-inflamatória, sendo considerada um fator predisponente ao desenvolvimento da resistência à insulina. Esta condição ocorre quando os tecidos periféricos perdem sua sensibilidade a tal hormônio hipoglicemiante e, assim, os cães diabéticos, por sua vez, acabam aumentando de forma exacerbada a secreção insulínica como um mecanismo compensatório para manter o nível de glicemia próximo ao valor de referência para a espécie (Park & Ahima, 2015;Fragua et al, 2015;Streeter et al, 2015;Lakić et al, 2020).…”

“…O TNF-α é uma citocina que prejudica a sinalização do receptor de insulina, interferindo negativamente na captação de glicose pelas células dos mais diversos tecidos. Logo, a capacidade das células β pancreáticas de secretar insulina vai sendo diminuída com o aumento do TNF-α, além deste fator também reduzir a atuação de importantes transportadores de glicose como o GLUT-4 (Bajpai & Tilley, 2018;Fragua et al, 2015;Lakić et al, 2020;Streeter et al, 2015).…”