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The interactions between inflammation and insulin resistance: prospects of immunoregulation as a potential approach for the type 2 diabetes mellitus treatment

https://doi.org/10.14341/DM12982

Abstract

In the modern world the prevalence of obesity and type 2 diabetes mellitus (T2DM) significantly increases. In this light the risks of obesity-associated complications also grow up. The crucial linkage between obesity and its complications is inflammation, which is a convenient target for potential anti-diabetic therapy. There are some anti-inflammatory therapy strategies: action on secreted cytokines, circulating lipids or intracellular signaling cascades. Canakinumab (antibody to IL-1b receptor) and colchicine (IL-6 secretion blocker) have the most balanced anti-diabetic and cardioprotective action among cytokine anti-inflammatory therapy. Lipid-lowering therapy is very diverse, but bempedoic acid nowadays has the best combination of anti-inflammatory and cardioprotective effects. Salicylate is an inhibitor of IKK-dependent inflammatory signaling cascade and significantly lowers glycated hemoglobin and C-reactive protein levels among obese patients. The future of anti-inflammatory T2DM therapy can be related with anti-inflammatory cytokines (IL-4, IL-37), chimeric engineered cytokines (IC7Fc), novel inhibitors of inflammatory and cytokines signaling cascades (imatinib, CC90001) and cell-based therapy (mesenchymal stem cells). In summary, despite on the limitations of current clinical trials, anti-inflammatory drugs have a potential to become a part of modern combined T2DM therapy with anti-diabetic and cardioprotective properties. Novel findings in potential anti-inflammatory T2DM therapy have great perspectives in protection against T2DM and related complication prevention.

About the Authors

I. S. Stafeev
National Medical Research Centre for Cardiology named after academician E.I. Chazov
Russian Federation

Iurii S. Stafeev - PhD in Biology; Researcher ID: O-2949-2015; Scopus Author ID: 57204688438

15A 3rd Cherepkovskaya street, 121552, Moscow


Competing Interests:

none



A. D. Yudaeva
National Medical Research Centre for Cardiology named after academician E.I. Chazov; Pirogov Russian National Research Medical University
Russian Federation

Alexandra D. Yudaeva; Researcher ID: GWN-0814-2022

Moscow


Competing Interests:

none



S. S. Michurina
National Medical Research Centre for Cardiology named after academician E.I. Chazov; Lomonosov Moscow State University
Russian Federation

Svetlana S. Michurina Scopus Author ID: 57202136814

Moscow


Competing Interests:

none



M. Yu. Menshikov
National Medical Research Centre for Cardiology named after academician E.I. Chazov
Russian Federation

Mikhail Yu. Menshikov - PhD in Biology; Researcher ID: O-2949-2015; Scopus Author ID: 6701418250.

Moscow


Competing Interests:

none



M. V. Shestakova
Endocrinology Research Centre
Russian Federation

Marina V. Shestakova - MD, PhD, Professor; Researcher ID: D-9123-2012; Scopus Author ID: 7004195530

Moscow


Competing Interests:

none



Y. V. Parfyonova
National Medical Research Centre for Cardiology named after academician E.I. Chazov; Lomonosov Moscow State University
Russian Federation

Yelena V. Parfyonova - MD, PhD, Professor; Researcher ID: B-9307-2014; Scopus Author ID: 57190312316

Moscow


Competing Interests:

none



References

1. 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. doi:10.1126/science.7678183

2. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13(6):465-476. doi:10.1038/nrd4275

3. Donath MY, Dinarello CA, Mandrup-Poulsen T. Targeting innate immune mediators in type 1 and type 2 diabetes. Nat Rev Immunol. 2019;19(12):734-746. doi:10.1038/s41577-019-0213-9

4. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517-1526. doi:10.1056/NEJMoa065213.

5. van Poppel PCM, van Asseldonk EJP, Holst JJ, et al. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes Metab. 2014;16(12):1269-1273. doi:10.1111/dom.12357

6. Hensen J, Howard CP, Walter V, Thuren T. Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial. Diabetes Metab. 2013;39(6):524-531. doi:10.1016/j.diabet.2013.07.003

7. Sloan-Lancaster J, Abu-Raddad E, Polzer J, et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes. Diabetes Care. 2013;36(8):2239-2246. doi:10.2337/dc12-1835

8. Kataria Y, Ellervik C, Mandrup-Poulsen T. Treatment of type 2 diabetes by targeting interleukin-1: a meta-analysis of 2921 patients. Semin Immunopathol. 2019;41(4):413-425. doi:10.1007/s00281-019-00743-6

9. Abbate A, Kontos MC, Grizzard JD, et al. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010;105(10):1371-1377.e1. doi:10.1016/j.amjcard.2009.12.059

10. Everett BM, Cornel JH, Lainscak M, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139(10):1289-1299. doi:10.1161/CIRCULATIONAHA.118.038010

11. Rehman K, Akash MSH, Liaqat A, et al. Role of interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr. 2017;27(3):229-236. doi:10.1615/CritRevEukaryotGeneExpr.2017019712

12. Carey AL, Steinberg GR, Macaulay SL, et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes. 2006;55(10):2688-2697. doi:10.2337/db05-1404

13. Boyce EG, Rogan EL, Vyas D, et al. Sarilumab: Review of a second IL-6 receptor antagonist indicated for the treatment of rheumatoid arthritis. Ann Pharmacother. 2018;52(8):780-791. doi:10.1177/1060028018761599

14. Aggarwal A, Misra R. Methotrexate inhibits interleukin-6 production in patients with juvenile rheumatoid arthritis. Rheumatol Int. 2003;23(3):134-137. doi:10.1007/s00296-002-0267-y

15. Martínez GJ, Robertson S, Barraclough J, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc. 2015;4(8):e002128. doi:10.1161/JAHA.115.002128

16. Pirkmajer S, Kulkarni SS, Tom RZ, et al. Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation. Diabetes. 2015;64(2):360-369. doi:10.2337/db14-0508

17. Baghdadi LR. Effect of methotrexate use on the development of type 2 diabetes in rheumatoid arthritis patients: A systematic review and meta-analysis. PLoS One. 2020;15(7):e0235637. doi:10.1371/journal.pone.0235637

18. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497-2505. doi:10.1056/NEJMoa1912388

19. Chu CC, Chen YC, Lin MH, et al. Association between clinical use of colchicine and risk of type 2 diabetes mellitus among gouty patients: A nationwide cohort study. Int J Environ Res Public Health. 2022;19(6):3395. doi:10.3390/ijerph19063395

20. Hwang DH, Kim JA, Lee JY. Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid. Eur J Pharmacol. 2016;785:24-35. doi:10.1016/j.ejphar.2016.04.024

21. Lestre S, Diamantino F, Veloso L, et al. Effects of etanercept treatment on lipid profile in patients with moderate-to-severe chronic plaque psoriasis: a retrospective cohort study. Eur J Dermatol. 2011;21(6):916-920. doi:10.1684/ejd.2011.1548

22. van Sijl AM, Peters MJL, Knol DL, et al. The effect of TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. Semin Arthritis Rheum. 2011;41(3):393-400. doi:10.1016/j.semarthrit.2011.04.003

23. De Sanctis S, Marcovecchio ML, Gaspari S, et al. Etanercept improves lipid profile and oxidative stress measures in patients with juvenile idiopathic arthritis. J Rheumatol. 2013;40(6):943-948. doi:10.3899/jrheum.121281

24. Ridker PM. Canakinumab for residual inflammatory risk. Eur Heart J. 2017;38(48):3545-3548. doi:10.1093/eurheartj/ehx723

25. Zhang FS, He QZ, Qin CH, Little PJ, Weng JP, Xu SW. Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review. Acta Pharmacol Sin. 2022;43(9):2173-2190. doi:10.1038/s41401-021-00835-w

26. Ariel D, Kim SH, Liu A, et al. Salsalate-induced changes in lipid, lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals. J Clin Lipidol. 2015;9(5):658-663. doi:10.1016/j.jacl.2015.06.009

27. Hauser TH, Salastekar N, Schaefer EJ, et al. Effect of targeting inflammation with salsalate: The TINSAL-CVD randomized clinical trial on progression of coronary plaque in overweight and obese patients using statins. JAMA Cardiol. 2016;1(4):413. doi:10.1001/jamacardio.2016.0605

28. Kandelouei T, Abbasifard M, Imani D, et al. Effect of statins on serum level of hs-CRP and CRP in patients with cardiovascular diseases: A systematic review and meta-analysis of randomized controlled trials. Mediators Inflamm. 2022;2022:8732360. doi:10.1155/2022/8732360

29. Cao YX, Li S, Liu HH, Li JJ. Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2018;8(9):e022348. doi:10.1136/bmjopen-2018-022348

30. Ruscica M, Tokgözoğlu L, Corsini A, Sirtori CR. PCSK9 inhibition and inflammation: A narrative review. Atherosclerosis. 2019;288:146-155. doi:10.1016/j.atherosclerosis.2019.07.015

31. Masson W, Lobo M, Lavalle-Cobo A, Molinero G. Effect of Bempedoic Acid on atherogenic lipids and inflammation: A meta-analysis. Clin Investig Arterioscler. 2021;33(3):117-126. doi:10.1016/j.arteri.2020.09.002

32. Kim J, Lee HS, Lee KY. Effect of statins on fasting glucose in non-diabetic individuals: nationwide population-based health examination in Korea. Cardiovasc Diabetol. 2018;17(1):155. doi:10.1186/s12933-018-0799-4

33. Abbasi F, Lamendola C, Harris CS, et al. Statins are associated with increased insulin resistance and secretion. Arterioscler Thromb Vasc Biol. 2021;41(11):2786-2797. doi:10.1161/ATVBAHA.121.316159

34. Goldman A, Raschi E, Cukierman-Yaffe T, et al. Hyperglycaemic disorders associated with PCSK9 inhibitors: a real-world, pharmacovigilance study. Eur J Prev Cardiol. 2022;29(9):1334-1342. doi:10.1093/eurjpc/zwab209

35. Leiter LA, Banach M, Catapano AL, et al. Bempedoic acid in patients with type 2 diabetes mellitus, prediabetes, and normoglycaemia: A post hoc analysis of efficacy and glycaemic control using pooled data from phase 3 clinical trials. Diabetes Obes Metab. 2022;24(5):868-880. doi:10.1111/dom.14645

36. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008;31(2):289-294. doi:10.2337/dc07-1338

37. Goldfine AB, Fonseca V, Jablonski KA, et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial: A Randomized Trial. Ann Intern Med. 2013;159(1):1-12. doi:10.7326/0003-4819-159-1-201307020-00003

38. Lou G, Chen J, Xia Y. Effects of low-dose aspirin in subjects with dyslipidemia. Lipids Health Dis. 2016;15(1):106. doi:10.1186/s12944-016-0274-8

39. Popmihajlov Z, Sutherland DJ, Horan GS, et al. CC-90001, a c-Jun N-terminal kinase (JNK) inhibitor, in patients with pulmonary fibrosis: design of a phase 2, randomised, placebo-controlled trial. BMJ Open Respir Res. 2022;9(1). doi:10.1136/bmjresp-2021-001060

40. Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002; 420(6913): 333-336. doi: 10.1038/nature01137

41. Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140(6): 900-917. doi: 10.1016/j.cell.2010.02.034

42. Marchetti C, Swartzwelter B, Gamboni F, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A. 2018;115(7):E1530-E1539. doi:10.1073/pnas.1716095115

43. Qiu Y, Nguyen KD, Odegaard JI, et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell. 2014;157(6):1292-1308. doi:10.1016/j.cell.2014.03.066

44. Michurina S, Stafeev I, Beloglazova I, et al. Regulation of glucose transport in adipocytes by interleukin-4. J Interferon Cytokine Res. 2022;42(3):127-136. doi:10.1089/jir.2021.0213

45. Lee SE, Kang SG, Choi MJ, et al. Growth differentiation factor 15 mediates systemic glucose regulatory action of T-helper type 2 cytokines. Diabetes. 2017;66(11):2774-2788. doi:10.2337/db17-0333

46. Youngblood R, Flesher CG, Delproposto J, et al. Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin-4. Biotechnol Bioeng. 2020;117(12):3891-3901. doi:10.1002/bit.27523

47. Ballak DB, van Diepen JA, Moschen AR, et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun. 2014;5(1):4711. doi:10.1038/ncomms5711

48. Ballak DB, Li S, Cavalli G, et al. Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue. J Biol Chem. 2018;293(37):14224-14236. doi:10.1074/jbc.ra118.003698

49. Li H, Wu G, Fang Q, et al. Fibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat. Nat Commun. 2018;9(1):272. doi:10.1038/s41467-017-02677-9

50. Liu Q, Wang S, Wei M, et al. Improved FGF21 sensitivity and restored FGF21 signaling pathway in high-fat diet/streptozotocin-induced diabetic rats after duodenal-jejunal bypass and sleeve gastrectomy. Front Endocrinol (Lausanne). 2019;10:566. doi:10.3389/fendo.2019.00566

51. Wang Q, Yuan J, Yu Z, et al. FGF21 attenuates high-fat diet-induced cognitive impairment via metabolic regulation and anti-inflammation of obese mice. Mol Neurobiol. 2018;55(6):4702-4717. doi:10.1007/s12035-017-0663-7

52. Findeisen M, Allen TL, Henstridge DC, et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature. 2019;574(7776):63-68. doi:10.1038/s41586-019-1601-9

53. Donath MY. Designer cytokine for the treatment of diabetes. Nat Metab. 2019;1(10):933-934. doi:10.1038/s42255-019-0130-z

54. Xiao X, Gaffar I, Guo P, et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc Natl Acad Sci U S A. 2014;111(13):E1211-20. doi:10.1073/pnas.1321347111

55. Okawa T, Nagai M, Hase K. Dietary intervention impacts immune cell functions and dynamics by inducing metabolic rewiring. Front Immunol. 2020;11:623989. doi:10.3389/fimmu.2020.623989

56. AlAsfoor S, Rohm TV, Bosch AJT, et al. Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver. Sci Rep. 2018;8(1):15331. doi:10.1038/s41598-018-32853-w

57. Shang Q, Bai Y, Wang G, et al. Delivery of adipose-derived stem cells attenuates adipose tissue inflammation and insulin resistance in obese mice through remodeling macrophage phenotypes. Stem Cells Dev. 2015;24(17):2052-2064. doi:10.1089/scd.2014.0557


Supplementary files

1. Figure 1. Main pharmacological approaches to the disruption of the central inflammatory mechanism in the development of insulin resistance and type 2 diabetes mellitus in obesity. Among them: blocking lipid activation of Toll-like receptors, blocking intracellular inflammatory signaling cascades, blocking the action of pro-inflammatory cytokines. Drugs introduced into clinical practice are highlighted in blue, promising drugs are highlighted in green.
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Stafeev I.S., Yudaeva A.D., Michurina S.S., Menshikov M.Yu., Shestakova M.V., Parfyonova Y.V. The interactions between inflammation and insulin resistance: prospects of immunoregulation as a potential approach for the type 2 diabetes mellitus treatment. Diabetes mellitus. 2023;26(2):192-202. (In Russ.) https://doi.org/10.14341/DM12982

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ISSN 2072-0351 (Print)
ISSN 2072-0378 (Online)