Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Role of Macrophage in Type 2 Diabetes Mellitus: Macrophage Polarization a New Paradigm for Treatment of Type 2 Diabetes Mellitus

Author(s): Sarmin Banu and Debjeet Sur*

Volume 23, Issue 1, 2023

Published on: 03 October, 2022

Page: [2 - 11] Pages: 10

DOI: 10.2174/1871530322666220630093359

Price: $65

Abstract

Metabolic diseases such as type 2 diabetes mellitus are usually associated with meta-inflammation. β-cell failure is a marked feature observed in the pathogenesis of type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is a heterogeneous situation that is accompanied by not only defective insulin secretion but also peripheral insulin resistance. β-cells are the primary organ for insulin secretion; hence, it is crucial to maintain a significant β-cell mass in response to a variety of changes. Insulin resistance is a chief cause of T2DM, leading to increased free fatty acid (FFA) levels, which in turn elevates β-cell mass and insulin secretion as compensation for insulin insensitivity. It has recently been established that amplified numbers of innate immune cells, cytokines, and chemokines result in detrimental effects on islets in chronic conditions. Macrophage migration inhibitory factor (MIF) is the lymphokine that prevents arbitrary migration of macrophages and assembles macrophages at inflammatory loci. Inflammation is known to trigger monocytes to differentiate into macrophages. Progress of complications associated with type 2 diabetes mellitus, as indicated through recent findings, is also dependent on the buildup of macrophages in tissues vulnerable to diabetic injury. The present article scientifically evaluates the present knowledge concerning the mechanisms of monocyte and macrophage-mediated injury recruitment in complications associated with type 2 diabetes mellitus. It also describes some of the established and experimental therapies that might bring about a reduction in these inflammatory complications. Recent discoveries in the field of drug delivery have facilitated phenotype-specific targeting of macrophages. This review highlights the pathophysiology of type 2 diabetes mellitus, how macrophage induces type 2 diabetes mellitus and potential therapeutics for type 2 diabetes mellitus via macrophage-specific delivery.

Keywords: Type 2 diabetes mellitus (T2DM), macrophages, macrophage polarization, pathophysiology, macrophage targeted therapeutics.

« Previous Next »
Graphical Abstract

[1]
Himanshu, D.; Ali, W.; Wamique, M. Type 2 diabetes mellitus: Pathogenesis and genetic diagnosis. J. Diabetes Metab. Disord., 2020, 19(2), 1959-1966.
[http://dx.doi.org/10.1007/s40200-020-00641-x]
[2]
Kharroubi, A.T.; Darwish, H.M. Diabetes mellitus: The epidemic of the century. World J. Diabetes, 2015, 6(6), 850-867.
[http://dx.doi.org/10.4239/wjd.v6.i6.850] [PMID: 26131326]
[3]
Eguchi, K.; Nagai, R. Islet inflammation in type 2 diabetes and physiology. J. Clin. Invest., 2017, 127(1), 14-23.
[http://dx.doi.org/10.1172/JCI88877]
[4]
Frydrych, L.M.; Bian, G.; O’Lone, D.E.; Ward, P.A.; Delano, M.J. Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality. J. Leukoc. Biol., 2018, 104(3), 525-534.
[http://dx.doi.org/10.1002/JLB.5VMR0118-021RR] [PMID: 30066958]
[5]
Hotamisligil, G.S. Inflammation and metabolic disorders. Nature, 2006, 444(7121), 860-867.
[http://dx.doi.org/10.1038/nature05485] [PMID: 17167474]
[6]
Unnikrishnan, R.; Anjana, R.M.; Mohan, V. Diabetes mellitus and its complications in India. Nat. Rev. Endocrinol., 2016, 357-370.
[http://dx.doi.org/10.1038/nrendo.2016.53]
[7]
Xiang, G.; Huang, X.; Wang, T.; Wang, J.; Zhao, G.; Wang, H.; Feng, Y.; Lei, W.; Hu, X. The impact of sitagliptin on macrophage polarity and angiogenesis in the osteointegration of titanium implants in type 2 diabetes. Biomed. Pharmacother., 2020, 126, 110078.
[http://dx.doi.org/10.1016/j.biopha.2020.110078] [PMID: 32172067]
[8]
Kaplan, M.; Aviram, M.; Hayek, T. Oxidative stress and macrophage foam cell formation during diabetes mellitus-induced atherogenesis: Role of insulin therapy. Pharmacol. Ther., 2012, 136(2), 175-185.
[http://dx.doi.org/10.1016/j.pharmthera.2012.08.002] [PMID: 22890211]
[9]
Ying, W.; Fu, W.; Lee, Y.S.; Olefsky, J.M. The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities. Nat. Rev. Endocrinol., 2020, 16(2), 81-90.
[http://dx.doi.org/10.1038/s41574-019-0286-3]
[10]
Cucak, H.; Grunnet, L.G.; Rosendahl, A. Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization. J. Leukoc. Biol., 2014, 95(1), 149-160.
[http://dx.doi.org/10.1189/jlb.0213075] [PMID: 24009176]
[11]
Klessens, C.Q.F.; Zandbergen, M.; Wolterbeek, R.; Bruijn, J.A.; Rabelink, T.J.; Bajema, I.M.; IJpelaar, D.H.T. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol. Dial. Transplant., 2017, 32(8), 1322-1329.
[http://dx.doi.org/10.1093/ndt/gfw260] [PMID: 27416772]
[12]
Lecube, A.; Pachón, G.; Petriz, J.; Hernández, C.; Simó, R. Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement. PLoS One, 2011, 6(8), e23366.
[http://dx.doi.org/10.1371/journal.pone.0023366] [PMID: 21876749]
[13]
Morris, D.L. Minireview: Emerging concepts in islet macrophage biology in type 2 diabetes. Mol. Endocrinol., 2015, 29(7), 946-962.
[http://dx.doi.org/10.1210/me.2014-1393]
[14]
Kimball, A.; Schaller, M.; Joshi, A.; Davis, F.M.; denDekker, A.; Boniakowski, A.; Bermick, J.; Obi, A.; Moore, B.; Henke, P.K.; Kunkel, S.L.; Gallagher, K.A. Ly6CHi blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus. Arterioscler. Thromb. Vasc. Biol., 2018, 38(5), 1102-1114.
[http://dx.doi.org/10.1161/ATVBAHA.118.310703] [PMID: 29496661]
[15]
Olefsky, J.M.; Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol., 2010, 72, 219-246.
[http://dx.doi.org/10.1146/annurev-physiol-021909-135846] [PMID: 20148674]
[16]
Olokoba, A.B.; Obateru, O.A.; Olokoba, L.B. Type 2 diabetes mellitus: a review of current trends. Oman Med. J., 2012, 27(4), 269-273.
[http://dx.doi.org/10.5001/omj.2012.68]
[17]
Javeed, N.; Matveyenko, A.V. Circadian etiology of type 2 diabetes mellitus. Physiology, 2018, 33(2), 138-150.
[http://dx.doi.org/10.1152/physiol.00003.2018]
[18]
Ozougwu, O. The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. J. Physiol. Pathophysiol., 2013, 4(4), 46-57.
[http://dx.doi.org/10.5897/JPAP2013.0001]
[19]
Kahn, S.E. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia, 2003, 46, 3-19.
[http://dx.doi.org/10.1007/s00125-002-1009-0]
[20]
Broniowska, K.A.; Corbett, J.A. Amyloid and the macrophage: It’s all about local production of IL-1β. Diabetes, 2014, 63(5), 1448-1450.
[http://dx.doi.org/10.2337/db14-0003]
[21]
Böni-Schnetzler, M.; Meier, D.T. Islet inflammation in type 2 diabetes. Semin. Immunopathol., 2019, 41, 501-513.
[http://dx.doi.org/10.1007/s00281-019-00745-4]
[22]
Kloc, M.; Ghobrial, R.M.; Lewicki, S.; Kubiak, J.Z. Macrophages in diabetes mellitus (DM) and COVID-19: Do they trigger DM? J. Diabetes Metab. Disord., 2020, 19, 2045-2048.
[http://dx.doi.org/10.1007/s40200-020-00665-3]
[23]
Rizza, R.A. Pathogenesis of fasting and postprandial hyperglycemia in type 2 diabetes: Implications for therapy. Diabetes, 2010, 59(11), 2697-2707.
[http://dx.doi.org/10.2337/db10-1032] [PMID: 20705776]
[24]
Valaiyapathi, B.; Gower, B.; Ashraf, A.P. Pathophysiology of type 2 diabetes in children and adolescents. Curr. Diabetes Rev., 2020, 16(3), 220-229.
[http://dx.doi.org/10.2174/1573399814666180608074510] [PMID: 29879890]
[25]
Jourdan, T.; Godlewski, G.; Cinar, R.; Bertola, A.; Szanda, G.; Liu, J.; Tam, J.; Han, T.; Mukhopadhyay, B.; Skarulis, M.C.; Ju, C.; Aouadi, M.; Czech, M.P.; Kunos, G. Activation of the NLRP3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat. Med., 2013, 19(9), 1132-1140.
[http://dx.doi.org/10.1038/nm.3265] [PMID: 23955712]
[26]
Cnop, M. Fatty acids and glucolipotoxicity in the pathogenesis of type 2 diabetes. Biochem. Soc. Trans., 2008, 36(Pt 3), 348-352.
[http://dx.doi.org/10.1042/BST0360348] [PMID: 18481955]
[27]
Epelman, S.; Lavine, K.J.; Randolph, G.J. Origin and functions of tissue macrophages. Immunity, 2014, 41(1), 21-35.
[http://dx.doi.org/10.1016/j.immuni.2014.06.013]
[28]
Hu, F.; Lou, N.; Jiao, J.; Guo, F.; Xiang, H.; Shang, D. Macrophages in pancreatitis: Mechanisms and therapeutic potential. Biomed. Pharmacother., 2020, 131, 110693.
[http://dx.doi.org/10.1016/j.biopha.2020.110693]
[29]
Murray, P.J.; Wynn, T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol., 2011, 11(11), 723-737.
[http://dx.doi.org/10.1038/nri3073] [PMID: 21997792]
[30]
Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol., 2008, 8(12), 958-969.
[http://dx.doi.org/10.1038/nri2448] [PMID: 19029990]
[31]
Liu, G.; Yang, H. Modulation of macrophage activation and programming in immunity. J. Cell. Physiol., 2013, 228(3), 502-512.
[http://dx.doi.org/10.1002/jcp.24157] [PMID: 22777800]
[32]
Cucak, H.; Mayer, C.; Tonnesen, M.; Thomsen, L.H.; Grunnet, L.G.; Rosendahl, A. Macrophage contact dependent and independent TLR4 mechanisms induce β-cell dysfunction and apoptosis in a mouse model of type 2 diabetes. PLoS One, 2014, 9(3), e90685.
[http://dx.doi.org/10.1371/journal.pone.0090685] [PMID: 24594974]
[33]
Ehses, J.A.; Böni-Schnetzler, M.; Faulenbach, M.; Donath, M.Y. Macrophages, cytokines and β-cell death in type 2 diabetes. Biochem. Soc. Trans., 2008, 36(Pt 3), 340-342.
[http://dx.doi.org/10.1042/BST0360340] [PMID: 18481953]
[34]
Fletcher, B.; Gulanick, M.; Lamendola, C. Risk factors for type 2 diabetes mellitus. J. Cardiovasc. Nurs., 2002, 16(2), 17-23.
[http://dx.doi.org/10.1097/00005082-200201000-00003] [PMID: 11800065]
[35]
Davanso, M.R.; Crisma, A.R.; Braga, T.T.; Masi, L.N.; do Amaral, C.L.; Leal, V.N.C.; de Lima, D.S.; Patente, T.A.; Barbuto, J.A.; Corrêa-Giannella, M.L.; Lauterbach, M.; Kolbe, C.C.; Latz, E.; Camara, N.O.S.; Pontillo, A.; Curi, R. Macrophage inflammatory state in Type 1 diabetes: Triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid. Clin. Sci. (Lond.), 2021, 135(1), 19-34.
[http://dx.doi.org/10.1042/CS20201348] [PMID: 33399849]
[36]
Chan, J.Y.; Lee, K.; Maxwell, E.L.; Liang, C.; Laybutt, D.R. Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes. Diabetologia, 2019, 62(6), 993-999.
[http://dx.doi.org/10.1007/s00125-019-4844-y] [PMID: 30830262]
[37]
Chan, J.Y.; Luzuriaga, J.; Bensellam, M.; Biden, T.J.; Laybutt, D.R. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes. Diabetes, 2013, 62(5), 1557-1568.
[http://dx.doi.org/10.2337/db12-0701] [PMID: 23274897]
[38]
Drareni, K.; Gautier, J.F.; Venteclef, N.; Alzaid, F. Transcriptional control of macrophage polarisation in type 2 diabetes. Semin. Immunopathol., 2019, 41(4), 515-529.
[http://dx.doi.org/10.1007/s00281-019-00748-1]
[39]
Lee, Y.S.; Wollam, J.; Olefsky, J.M. An integrated view of immunometabolism. Cell, 2018, 172(1-2), 22-40.
[http://dx.doi.org/10.1016/j.cell.2017.12.025]
[40]
McNelis, J.C.; Olefsky, J.M. Macrophages, immunity, and metabolic disease. Immunity, 2014, 41(1), 36-48.
[http://dx.doi.org/10.1016/j.immuni.2014.05.010]
[41]
Lauterbach, M.A.R.; Wunderlich, F.T. Macrophage function in obesity-induced inflammation and insulin resistance. Pflugers Arch., 2017, 469(3-4), 385-396.
[http://dx.doi.org/10.1007/s00424-017-1955-5]
[42]
Kolliniati, O.; Ieronymaki, E.; Vergadi, E.; Tsatsanis, C. Metabolic regulation of macrophage activation. J. Innate Immun., 2022, 14(1), 51-68.
[http://dx.doi.org/10.1159/000516780]
[43]
Appari, M.; Channon, K.M.; McNeill, E. Metabolic regulation of adipose tissue macrophage function in obesity and diabetes. Antioxid. Redox Signal., 2018, 29(3), 297-312.
[http://dx.doi.org/10.1089/ars.2017.7060]
[44]
Eizirik, D.L.; Mandrup-Poulsen, T. A choice of death ± the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia, 2001, 44, 2115-2133.
[45]
Donath, M.Y.; Ehses, J.A. Mechanisms of beta-cell death in diabetes.Pancreatic Beta Cell in Health and Disease; Seino, S.; Bell, G.I., Eds.; Springer: Tokyo, 2008, pp. 75-89.
[46]
Lee, H.M.; Kim, J.J.; Kim, H.J.; Shong, M.; Ku, B.J.; Jo, E.K. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes, 2013, 62(1), 194-204.
[http://dx.doi.org/10.2337/db12-0420] [PMID: 23086037]
[47]
Ding, S.; Xu, S.; Ma, Y.; Liu, G.; Jang, H.; Fang, J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules, 2019, 9(12), 850.
[http://dx.doi.org/10.3390/biom9120850]
[48]
Dixit, V.D. Nlrp3 inflammasome activation in type 2 diabetes: Is it clinically relevant? Diabetes, 2013, 62(1), 22-24.
[http://dx.doi.org/10.2337/db12-1115] [PMID: 23258906]
[49]
Tesch, G.H. Role of macrophages in complications of type 2 diabetes. Clin. Exp. Pharmacol. Physiol., 2007, 34(10), 1016-1019.
[http://dx.doi.org/10.1111/j.1440-1681.2007.04729.x] [PMID: 17714088]
[50]
Ehses, J.A.; Perren, A.; Eppler, E.; Ribaux, P.; Pospisilik, J.A.; Maor-Cahn, R.; Gueripel, X.; Ellingsgaard, H.; Schneider, M.K.J.; Biollaz, G.; Fontana, A.; Reinecke, M.; Homo-Delarche, F.; Donath, M.Y. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes, 2007, 56(9), 2356-2370.
[http://dx.doi.org/10.2337/db06-1650] [PMID: 17579207]
[51]
Ahmed, M.; de Winther, M.P.J.; van den Bossche, J. Epigenetic mechanisms of macrophage activation in type 2 diabetes. Immunobiology, 2017, 937-943.
[http://dx.doi.org/10.1016/j.imbio.2016.08.011]
[52]
Wolf, S.J.; Melvin, W.J.; Gallagher, K. Macrophage-mediated inflammation in diabetic wound repair. Semin. Cell Dev. Biol., 2021, 119, 111-118.
[http://dx.doi.org/10.1016/j.semcdb.2021.06.013] [PMID: 34183242]
[53]
Cai, Y.; Xu, T.T.; Lu, C.Q.; Ma, Y.Y.; Chang, D.; Zhang, Y.; Gu, X.C.; Ju, S. Endogenous regulatory T cells promote M2 macrophage phenotype in diabetic stroke as visualized by optical imaging. Transl. Stroke Res., 2021, 12(1), 136-146.
[http://dx.doi.org/10.1007/s12975-020-00808-x] [PMID: 32240524]
[54]
Oh, D.Y.; Morinaga, H.; Talukdar, S.; Bae, E.J.; Olefsky, J.M. Increased macrophage migration into adipose tissue in obese mice. Diabetes, 2012, 61(2), 346-354.
[http://dx.doi.org/10.2337/db11-0860] [PMID: 22190646]
[55]
Peterson, K.R.; Cottam, M.A.; Kennedy, A.J.; Hasty, A.H. Macrophage-targeted therapeutics for metabolic disease. Trends Pharmacol. Sci., 2018, 39(6), 536-546.
[http://dx.doi.org/10.1016/j.tips.2018.03.001]
[56]
Nguyen, D.; Ping, F.; Mu, W.; Hill, P.; Atkins, R.C.; Chadban, S.J. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton), 2006, 11(3), 226-231.
[http://dx.doi.org/10.1111/j.1440-1797.2006.00576.x] [PMID: 16756636]
[57]
Tashimo, A.; Mitamura, Y.; Nagai, S.; Nakamura, Y.; Ohtsuka, K.; Mizue, Y.; Nishihira, J. Aqueous levels of macrophage migration inhibitory factor and monocyte chemotactic protein-1 in patients with diabetic retinopathy. Diabet. Med., 2004, 21(12), 1292-1297.
[http://dx.doi.org/10.1111/j.1464-5491.2004.01334.x] [PMID: 15569131]
[58]
Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: The importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol., 2005, 25(11), 2255-2264.
[http://dx.doi.org/10.1161/01.ATV.0000184783.04864.9f] [PMID: 16141399]
[59]
Ren, W.; Xia, Y.; Chen, S.; Wu, G.; Bazer, F.W.; Zhou, B.; Tan, B.; Zhu, G.; Deng, J.; Yin, Y. Glutamine metabolism in macrophages: A novel target for obesity/type 2 diabetes. Adv. Nutr., 2019, 10(2), 321-330.
[http://dx.doi.org/10.1093/advances/nmy084]
[60]
Wang, Y.; Wu, Y.; Sailike, J.; Sun, X.; Abuduwaili, N.; Tuoliuhan, H.; Yusufu, M.; Nabi, X.H. Fourteen composite probiotics alleviate type 2 diabetes through modulating gut microbiota and modifying M1/M2 phenotype macrophage in db/db mice. Pharmacol. Res., 2020, 161, 105150.
[http://dx.doi.org/10.1016/j.phrs.2020.105150] [PMID: 32818655]

Rights & Permissions Print Cite
Article Metrics
62
2
© 2024 Bentham Science Publishers | Privacy Policy