Regulation of tissue insulin sensitivity as a mechanism of functional priority: Implications for adaptation, survival, and rehabilitation
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Keywords

endocrinology
insulin resistance
immunometabolism
hyperglycemia
allostasis
stress

How to Cite

Biletska, O., GaryachiуY., & Shevchenko, A. (2026). Regulation of tissue insulin sensitivity as a mechanism of functional priority: Implications for adaptation, survival, and rehabilitation. Experimental and Clinical Medicine, 95(1). https://doi.org/10.35339/ekm.2026.95.1.bgs

Abstract

In press

Background. Insulin Resistance (IR) is traditionally regarded as one of the key mechanisms underlying metabolic syndrome, type 2 diabetes mellitus, and associated cardiovascular complications. However, alterations in insulin sensitivity also occur during fasting, physical exercise, pregnancy, acute stress, trauma, and inflammation, suggesting their potential adaptive role in the regulation of energy metabolism.

Aim. To summarize current evidence on the role of tissue insulin sensitivity in systemic immunometabolic adaptation and to substantiate the concept of its regulation as a mechanism of functional priority.

Materials and Methods. A literature search for the narrative review was conducted in PubMed, Scopus, Web of Science, and Google Scholar. Data synthesis was performed using conceptual and integrative approaches. The study was carried out as a private initiative of the authors, without grant support and state registration of the topic.

Research Ethics. Only sources that complied with current bioethical standards were selected for the analysis.

Results. Available evidence indicates that alterations in insulin sensitivity are tissue-specific and may serve adaptive functions. During acute inflammation, activation of the cytokine network, the hypothalamic-pituitary-adrenal axis, the sympathoadrenal system, and other counter-regulatory mechanisms is accompanied by stress hyperglycemia, mobilization of energy substrates, and selective reduction of insulin sensitivity in skeletal muscle and adipose tissue. These changes increase the availability of energy resources for innate immune cells, the central nervous system, and other vital structures. Regulation of tissue insulin sensitivity is proposed as a mechanism of functional priority that ensures redistribution of resources according to the organism's adaptive needs. The concept of immunometabolic allostasis is substantiated, according to which insulin resistance may represent not only a manifestation of metabolic pathology but also a component of a coordinated adaptive response. Acute post-traumatic and low-grade sterile inflammation associated with metabolic syndrome appear to share common mechanisms of neuroendocrine regulation.

Conclusions. Tissue insulin sensitivity may be regarded as an important component of systemic immunometabolic adaptation. The proposed concept of functional priority provides a basis for considering the regulation of insulin sensitivity as one of the mechanisms involved in the redistribution of energy resources among functional systems according to their importance for adaptation, survival, and recovery.

Keywords: endocrinology, insulin resistance, immunometabolism, hyperglycemia, allostasis, stress.

https://doi.org/10.35339/ekm.2026.95.1.bgs
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References

Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133-223. DOI:10.1152/physrev.00063.2017. PMID: 30067154.

Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12-22. DOI: 10.1172/JCI77812. PMID: 26727229.

Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-1801. DOI: 10.1172/JCI29069. PMID: 16823477.

Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542(7640):177-85. DOI: 10.1038/nature21363. PMID: 28179656.

Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017;127(1):1-4. DOI: 10.1172/JCI92035. PMID: 28045402.

Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2012;32(9):2052-9. DOI: 10.1161/ATVBAHA.111.241919. PMID: 22895666.

Wang A, Huen SC, Luan HH, Yu S, Zhang C, Gallezot JD, et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell. 2016;166(6):1512-25.e12. DOI: 10.1016/j.cell.2016.07.026. PMID: 27610573.

Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93(3):993-1017. DOI: 10.1152/physrev.00038.2012. PMID: 23899560.

Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30(Suppl_2):S112-9. DOI: 10.2337/dc07-s202. PMID: 17596458.

Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5(7):374-81. DOI: 10.1038/nrendo.2009.106. PMID: 19488073.

Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428-35. DOI: 10.1038/nature07201. PMID: 18650913.

James DE, Stöckli J, Birnbaum MJ. The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol. 2021;22(11):751-771. DOI: 10.1038/s41580-021-00390-6. PMID: 34285405.

O'Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553-65. DOI: 10.1038/nri.2016.70. PMID: 27396447.

Hotamisligil GS. Foundations of immunometabolism and implications for metabolic health and disease. Immunity. 2017;47(3):406-20. DOI: 10.1016/j.immuni.2017.08.009. PMID: 28930657.

Biletska OM, Gаryachiу YeV, Markovska OV, Latohuz SI, Shevchenko AS. Integration of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–thyroid axes in immunometabolic allostasis of the acute phase of inflammation: A unified cytokine-mediated regulatory complex. Medicine Today and Tomorrow. 2025;94(4):18p. In press. DOI: 10.35339/msz.2025.94.4.bgm. [In Ukrainian].

Chawla A, Nguyen KD, Goh YPS. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11(11):738-49. DOI: 10.1038/nri3071. PMID: 21984069.

Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633-43. DOI: 10.1016/j.immuni.2013.04.005. PMID: 23601682.

Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014; 32:609-34. DOI: 10.1146/annurev-immunol-032713-120236. PMID: 24655299.

Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804-14. DOI: 10.1038/nm.4350. PMID: 28697184.

Chrousos GP, Gold PW. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351-62. DOI: 10.1056/NEJM199505183322008. PMID: 7715646.

Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473-81. DOI: 10.1172/JCI10842. PMID: 10953022.

Medzhitov R. Disease tolerance as a defense strategy. Science. 2012;335(6071):936-941. DOI: 10.1126/science.1214935. PMID: 22363001.

Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487-95. DOI: 10.2337/diacare.27.6.1487. PMID: 15161807.

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3): E214-23. DOI: 10.1152/ajpendo.1979.237.3. E214. PMID: 382871.

Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing's syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611-29. DOI: 10.1016/S2213-8587(16)00086-3. PMID: 27177728.

Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205(1):1-13. DOI: 10.1677/JOE-09-0412. PMID: 20016054.

Fliers E, Bianco AC, Langouche L, Boelen A. Thyroid function in critically ill patients. Lancet Diabetes Endocrinol. 2015;3(10):816-25. DOI: 10.1016/S2213-8587(15)00225-9. PMID: 26071885.

Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. 2014;24(10):1456-65. DOI: 10.1089/thy.2014.0201. PMID: 24845024.

Biletska OM, Golka GG, Danylchenko SI, Arestova TV, Shevchenko AS. Low triiodothyronine in metabolic and inflammatory stress: A context-dependent model of thyroid adaptation. Inter Collegas. 2026;13(1):9p. In press. DOI: 10.35339/ic.2026.13.1.bgd.

McEwen BS, Wingfield JC. What is in a name? Integrating homeostasis, allostasis and stress. Horm Behav. 2010;57(2):105-111. DOI: 10.1016/j.yhbeh.2009.09.011. PMID: 19786032.

Eming SA, Wynn TA, Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017;356(6342):1026-30. DOI: 10.1126/science.aam7928. PMID: 28596335.

Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450-62. DOI: 10.1016/j.immuni.2016.02.015. PMID: 26982353.

Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003;17(Suppl_1):S112-8. DOI: 10.1016/S0889-1591(02)00027-6. PMID: 12615196.

Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101. DOI: 10.1038/nature13479. PMID: 24899309.

Bano G, Trevisan C, Carraro S, Solmi M, Luchini C, Stubbs B, et al. Inflammation and sarcopenia: a systematic review and meta-analysis. Maturitas. 2017;96:10-5. DOI: 10.1016/j.maturitas.2016.11.006. PMID: 28041587.

Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314-21. DOI: 10.1038/nature07039. PMID: 18480812.

Cruz-Pineda WD, Parra-Rojas I, Rodríguez-Ruíz HA, Illades-Aguiar B, Matia-García I, Garibay-Cerdenares OL. The regulatory role of insulin in energy metabolism and leukocyte functions. J Leukoc Biol. 2022;111(1):197-208. DOI: 10.1002/JLB.2RU1220-847R. PMID: 33724523.

Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015;15(10):599-614. DOI: 10.1038/nri3901. PMID: 26403194.

O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346-55. DOI: 10.1038/nature11862. PMID: 23325217.

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