Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities


Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia.

Key points

  • Macrophages are the primary immune cells involved in obesity-associated islet inflammation in both mice and humans.

  • Obesity reprogrammes the islet immune microenvironment by inducing the local replication of islet-resident macrophages or by recruiting circulating monocytes.

  • Islet macrophages in obese mice display multiple functions, including decreasing β-cell insulin secretion and stimulating β-cell proliferation.

  • In the normal, lean state, islet macrophages promote islet development and maintenance of normal glucose-stimulated insulin secretion.

  • Islet macrophages are potential therapeutic targets to modulate β-cell function in individuals with obesity and/or type 2 diabetes mellitus.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Macrophages dominate obesity-associated islet inflammation.
Fig. 2: Interactions of islet macrophages and β-cells in obesity.


  1. 1.

    da Rocha Fernandes, J. et al. IDF Diabetes Atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res. Clin. Pract. 117, 48–54 (2016).

    PubMed  Google Scholar 

  2. 2.

    Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

    CAS  PubMed  Google Scholar 

  3. 3.

    Magkos, F. et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab. 23, 591–601 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Saisho, Y. Importance of beta cell function for the treatment of type 2 diabetes. J. Clin. Med. 3, 923–943 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Kitamura, T. The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 9, 615–623 (2013).

    CAS  PubMed  Google Scholar 

  6. 6.

    Biden, T. J., Boslem, E., Chu, K. Y. & Sue, N. Lipotoxic endoplasmic reticulum stress, beta cell failure, and type 2 diabetes mellitus. Trends Endocrinol. Metab. 25, 389–398 (2014).

    CAS  PubMed  Google Scholar 

  7. 7.

    Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

    CAS  PubMed  Google Scholar 

  8. 8.

    Lackey, D. E. & Olefsky, J. M. Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12, 15–28 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

    Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).

    CAS  PubMed  Google Scholar 

  10. 10.

    Eguchi, K. et al. Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell. Metab. 15, 518–533 (2012). This study shows that SFAs induce β-cells to produce chemokines that recruit pro-inflamamtory monocytes and macrophages, which impair β-cell function.

    CAS  PubMed  Google Scholar 

  11. 11.

    Boni-Schnetzler, M. & Meier, D. T. Islet inflammation in type 2 diabetes. Semin. Immunopathol. 41, 501–513 (2019).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ying, W. et al. Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab. 29, 457–474 e455 (2019). This study reports that resident macrophages drive obesity-associated islet inflammation through local proliferation and that the accumulated islet macrophages affect both β-cell proliferation and function.

    CAS  PubMed  Google Scholar 

  13. 13.

    Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    CAS  PubMed  Google Scholar 

  14. 14.

    Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  15. 15.

    Geutskens, S. B., Otonkoski, T., Pulkkinen, M. A., Drexhage, H. A. & Leenen, P. J. Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro. J. Leukoc. Biol. 78, 845–852 (2005).

    CAS  PubMed  Google Scholar 

  16. 16.

    Banaei-Bouchareb, L. et al. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J. Leukoc. Biol. 76, 359–367 (2004).

    CAS  PubMed  Google Scholar 

  17. 17.

    Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015). This study provides a comprehensive view of the origin, phenotype, turnover and gene expression of macrophages in exocrine pancreas and the islets.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Mathis, D. Immunological goings-on in visceral adipose tissue. Cell Metab. 17, 851–859 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    McLaughlin, T., Ackerman, S. E., Shen, L. & Engleman, E. Role of innate and adaptive immunity in obesity-associated metabolic disease. J. Clin. Invest. 127, 5–13 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Sell, H., Habich, C. & Eckel, J. Adaptive immunity in obesity and insulin resistance. Nat. Rev. Endocrinol. 8, 709–716 (2012).

    CAS  PubMed  Google Scholar 

  21. 21.

    Shalapour, S. & Karin, M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J. Clin. Invest. 125, 3347–3355 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    CAS  PubMed  Google Scholar 

  23. 23.

    Murray, P. J. & Wynn, T. A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ehses, J. A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007). This study provides clear evidence showing an increase in the number of macrophages in the islets of humans with T2DM and animal models of obesity and T2DM.

    CAS  PubMed  Google Scholar 

  25. 25.

    Kamata, K. et al. Islet amyloid with macrophage migration correlates with augmented beta-cell deficits in type 2 diabetic patients. Amyloid 21, 191–201 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Zhao, H. L. et al. Prevalence and clinicopathological characteristics of islet amyloid in Chinese patients with type 2 diabetes. Diabetes 52, 2759–2766 (2003).

    CAS  PubMed  Google Scholar 

  27. 27.

    Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. Islet-associated macrophages in type 2 diabetes. Diabetologia 52, 1686–1688 (2009).

    CAS  PubMed  Google Scholar 

  28. 28.

    Marselli, L. et al. Beta-cell inflammation in human type 2 diabetes and the role of autophagy. Diabetes Obes. Metab. 15, 130–136 (2013).

    CAS  PubMed  Google Scholar 

  29. 29.

    Butcher, M. J. et al. Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes. Diabetologia 57, 491–501 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Donath, M. Y., Storling, J., Berchtold, L. A., Billestrup, N. & Mandrup-Poulsen, T. Cytokines and beta-cell biology: from concept to clinical translation. Endocr. Rev. 29, 334–350 (2008).

    CAS  PubMed  Google Scholar 

  31. 31.

    Eguchi, K. & Nagai, R. Islet inflammation in type 2 diabetes and physiology. J. Clin. Invest. 127, 14–23 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    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. 95, 149–160 (2014).

    PubMed  Google Scholar 

  33. 33.

    Perdiguero, E. G. & Geissmann, F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2–8 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ginhoux, F. & Jung, S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat. Rev. Immunol. 14, 392–404 (2014).

    CAS  PubMed  Google Scholar 

  35. 35.

    Braune, J. et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity. J. Immunol. 198, 2927–2934 (2017).

    CAS  PubMed  Google Scholar 

  36. 36.

    Haase, J. et al. Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. Diabetologia 57, 562–571 (2014).

    CAS  PubMed  Google Scholar 

  37. 37.

    Amano, S. U. et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19, 162–171 (2014).

    CAS  PubMed  Google Scholar 

  38. 38.

    Tardelli, M. et al. Osteopontin is a key player for local adipose tissue macrophage proliferation in obesity. Mol. Metab. 5, 1131–1137 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    CAS  PubMed  Google Scholar 

  40. 40.

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    CAS  PubMed  Google Scholar 

  43. 43.

    Maedler, K. et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Boni-Schnetzler, M. et al. Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. Endocrinology 150, 5218–5229 (2009).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ye, R. et al. Intracellular lipid metabolism impairs beta cell compensation during diet-induced obesity. J. Clin. Invest. 128, 1178–1189 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Amar, S., Zhou, Q., Shaik-Dasthagirisaheb, Y. & Leeman, S. Diet-induced obesity in mice causes changes in immune responses and bone loss manifested by bacterial challenge. Proc. Natl Acad. Sci. USA 104, 20466–20471 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Zhang, Q. et al. NF-kappaB dynamics discriminate between TNF doses in single cells. Cell Syst. 5, 638–645.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Turner, D. A. et al. Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells. J. Cell Sci. 123, 2834–2843 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Stephens, J. M., Lee, J. & Pilch, P. F. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J. Biol. Chem. 272, 971–976 (1997).

    CAS  PubMed  Google Scholar 

  50. 50.

    McGillicuddy, F. C. et al. Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes 60, 1688–1698 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Aamodt, K. I. & Powers, A. C. Signals in the pancreatic islet microenvironment influence beta-cell proliferation. Diabetes Obes. Metab. 19, 124–136 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Weitz, J. R. et al. Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. Diabetologia 61, 182–192 (2018).

    CAS  PubMed  Google Scholar 

  53. 53.

    Westwell-Roper, C. Y., Ehses, J. A. & Verchere, C. B. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 63, 1698–1711 (2014).

    CAS  PubMed  Google Scholar 

  54. 54.

    Kratz, M. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 20, 614–625 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Lumeng, C. N., DelProposto, J. B., Westcott, D. J. & Saltiel, A. R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57, 3239–3246 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Li, P. et al. Functional heterogeneity of CD11c-positive adipose tissue macrophages in diet-induced obese mice. J. Biol. Chem. 285, 15333–15345 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Rodriguez-Calvo, T., Ekwall, O., Amirian, N., Zapardiel-Gonzalo, J. & von Herrath, M. G. Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 63, 3880–3890 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Dalmas, E. et al. Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47, 928–942 e7 (2017).

    CAS  PubMed  Google Scholar 

  59. 59.

    Brissova, M. et al. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes beta cell regeneration. Cell Metab. 19, 498–511 (2014). This study demonstrates the importance of endothelial cell-derived VEGF in regulating β-cell proliferation and insulin secretion.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Porte, D. Jr., Baskin, D. G. & Schwartz, M. W. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes 54, 1264–1276 (2005).

    CAS  PubMed  Google Scholar 

  61. 61.

    Halban, P. A. et al. Beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37, 1751–1758 (2014). This paper briefly summarizes recent knowledge on the mechanisms underlying β-cell failure in T2DM.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Donath, M. Y., Boni-Schnetzler, M., Ellingsgaard, H., Halban, P. A. & Ehses, J. A. Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends Endocrinol. Metab. 21, 261–267 (2010).

    CAS  PubMed  Google Scholar 

  63. 63.

    Burns, S. M. et al. High-throughput luminescent reporter of insulin secretion for discovering regulators of pancreatic beta-cell function. Cell Metab. 21, 126–137 (2015).

    CAS  PubMed  Google Scholar 

  64. 64.

    Westwell-Roper, C., Denroche, H. C., Ehses, J. A. & Verchere, C. B. Differential activation of innate immune pathways by distinct islet amyloid polypeptide (IAPP) aggregates. J. Biol. Chem. 291, 8908–8917 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Dasu, M. R., Devaraj, S. & Jialal, I. High glucose induces IL-1beta expression in human monocytes: mechanistic insights. Am. J. Physiol. Endocrinol. Metab. 293, E337–E346 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Riera-Borrull, M. et al. Palmitate conditions macrophages for enhanced responses toward inflammatory stimuli via JNK activation. J. Immunol. 199, 3858–3869 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    Kim, H. E. et al. Tumour necrosis factor-alpha-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx. J. Endocrinol. 198, 549–560 (2008).

    CAS  PubMed  Google Scholar 

  68. 68.

    Cardozo, A. K. et al. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes 54, 452–461 (2005).

    CAS  PubMed  Google Scholar 

  69. 69.

    Major, C. D. & Wolf, B. A. Interleukin-1beta stimulation of c-Jun NH2-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. Diabetes 50, 2721–2728 (2001).

    CAS  PubMed  Google Scholar 

  70. 70.

    Ammendrup, A. et al. The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes 49, 1468–1476 (2000).

    CAS  PubMed  Google Scholar 

  71. 71.

    Bonny, C., Oberson, A., Negri, S., Sauser, C. & Schorderet, D. F. Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes 50, 77–82 (2001).

    CAS  PubMed  Google Scholar 

  72. 72.

    Welsh, N. Interleukin-1 beta-induced ceramide and diacylglycerol generation may lead to activation of the c-Jun NH2-terminal kinase and the transcription factor ATF2 in the insulin-producing cell line RINm5F. J. Biol. Chem. 271, 8307–8312 (1996).

    CAS  PubMed  Google Scholar 

  73. 73.

    Bouzakri, K. et al. Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells. Diabetes 57, 1195–1204 (2008).

    CAS  PubMed  Google Scholar 

  74. 74.

    Kawamori, D. et al. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J. Biol. Chem. 281, 1091–1098 (2006).

    CAS  PubMed  Google Scholar 

  75. 75.

    Kaneto, H. et al. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J. Biol. Chem. 277, 30010–30018 (2002).

    CAS  PubMed  Google Scholar 

  76. 76.

    Kim-Muller, J. Y. et al. Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab. 20, 593–602 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Grunnet, L. G. et al. Proinflammatory cytokines activate the intrinsic apoptotic pathway in beta-cells. Diabetes 58, 1807–1815 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Cardozo, A. K., Kruhoffer, M., Leeman, R., Orntoft, T. & Eizirik, D. L. Identification of novel cytokine-induced genes in pancreatic beta-cells by high-density oligonucleotide arrays. Diabetes 50, 909–920 (2001).

    CAS  PubMed  Google Scholar 

  79. 79.

    Weir, G. C., Laybutt, D. R., Kaneto, H., Bonner-Weir, S. & Sharma, A. Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes 50, S154–S159 (2001).

    CAS  PubMed  Google Scholar 

  80. 80.

    Welsh, N. et al. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54, 3238–3244 (2005).

    CAS  PubMed  Google Scholar 

  81. 81.

    Vomund, A. N. et al. Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc. Natl Acad. Sci. USA 112, E5496–E5502 (2015). This study shows evidence that intra-islet macrophages take up intact insulin-containing vesicles from β-cells.

    CAS  PubMed  Google Scholar 

  82. 82.

    Yamashita, Y. M., Inaba, M. & Buszczak, M. Specialized intercellular communications via cytonemes and nanotubes. Annu. Rev. Cell. Dev. Biol. 34, 59–84 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Baeyens, L., Hindi, S., Sorenson, R. L. & German, M. S. Beta-cell adaptation in pregnancy. Diabetes Obes. Metab. 18, 63–70 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Hull, R. L. et al. Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation. Diabetologia 48, 1350–1358 (2005).

    CAS  PubMed  Google Scholar 

  85. 85.

    Peyot, M. L. et al. Beta-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta-cell mass. Diabetes 59, 2178–2187 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325–332 (2008).

    CAS  PubMed  Google Scholar 

  87. 87.

    Stamateris, R. E., Sharma, R. B., Hollern, D. A. & Alonso, L. C. Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression. Am. J. Physiol. Endocrinol. Metab. 305, E149–E159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Mosser, R. E. et al. High-fat diet-induced beta-cell proliferation occurs prior to insulin resistance in C57BL/6J male mice. Am. J. Physiol. Endocrinol. Metab. 308, E573–E582 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Alonso, L. C. et al. Glucose infusion in mice: a new model to induce beta-cell replication. Diabetes 56, 1792–1801 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Levitt, H. E. et al. Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice. Diabetologia 54, 572–582 (2011).

    CAS  PubMed  Google Scholar 

  91. 91.

    Porat, S. et al. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab. 13, 440–449 (2011).

    CAS  PubMed  Google Scholar 

  92. 92.

    Assmann, A., Ueki, K., Winnay, J. N., Kadowaki, T. & Kulkarni, R. N. Glucose effects on beta-cell growth and survival require activation of insulin receptors and insulin receptor substrate 2. Mol. Cell Biol. 29, 3219–3228 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Garcia-Ocana, A. et al. Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J. Biol. Chem. 275, 1226–1232 (2000).

    CAS  PubMed  Google Scholar 

  94. 94.

    Araujo, T. G. et al. Hepatocyte growth factor plays a key role in insulin resistance-associated compensatory mechanisms. Endocrinol. 153, 5760–5769 (2012).

    CAS  Google Scholar 

  95. 95.

    Demirci, C. et al. Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus. Diabetes 61, 1143–1152 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Xiao, X. et al. M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7. Proc. Natl Acad. Sci. USA 111, E1211–E1220 (2014). This study reveals that M2-like macrophages and the SMAD7 pathway can increase β-cell mass.

    CAS  PubMed  Google Scholar 

  97. 97.

    Riley, K. G. et al. Macrophages are essential for CTGF-mediated adult beta-cell proliferation after injury. Mol. Metab. 4, 584–591 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Chen, H. et al. PDGF signalling controls age-dependent proliferation in pancreatic beta-cells. Nature 478, 349–355 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Jaguin, M., Fardel, O. & Lecureur, V. AhR-dependent secretion of PDGF-BB by human classically activated macrophages exposed to DEP extracts stimulates lung fibroblast proliferation. Toxicol. Appl. Pharmacol. 285, 170–178 (2015).

    CAS  PubMed  Google Scholar 

  100. 100.

    Onogi, Y. et al. PDGFRbeta regulates adipose tissue expansion and glucose metabolism via vascular remodeling in diet-induced obesity. Diabetes 66, 1008–1021 (2017).

    CAS  PubMed  Google Scholar 

  101. 101.

    Shimokado, K. et al. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell 43, 277–286 (1985).

    CAS  PubMed  Google Scholar 

  102. 102.

    Zhou, X. et al. Circuit design features of a stable two-cell system. Cell 172, 744–757.e17 (2018).

    CAS  PubMed  Google Scholar 

  103. 103.

    Donath, M. Y., Dalmas, E., Sauter, N. S. & Boni-Schnetzler, M. Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab. 17, 860–872 (2013).

    CAS  PubMed  Google Scholar 

  104. 104.

    Burke, S. J. et al. Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet beta-cell de-differentiation. Mol. Metab. 14, 95–107 (2018). This study reports that knockout of the β-cell IL-1β receptor in mice can result in dedifferentiation of β-cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Maedler, K. et al. Low concentration of interleukin-1 beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets. Diabetes 55, 2713–2722 (2006). This study shows an improvement in β-cell proliferation by a low concentration of IL-1β.

    CAS  PubMed  Google Scholar 

  106. 106.

    Nordmann, T. M. et al. The role of inflammation in beta-cell dedifferentiation. Sci. Rep. 7, 6285 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150, 1223–1234 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Boni-Schnetzler, M. et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta-cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Boni-Schnetzler, M. et al. Beta cell-specific deletion of the IL-1 receptor antagonist impairs beta cell proliferation and insulin secretion. Cell Rep. 22, 1774–1786 (2018). This study provides evidence supporting an important role of β-cell-derived IL-1Ra on β-cell function and maintenance.

    CAS  PubMed  Google Scholar 

  110. 110.

    Dror, E. et al. Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat. Immunol. 18, 283–292 (2017). This study indicates the physiological role of macrophage-derived IL-1β in mediating postprandial β-cell insulin secretion.

    CAS  PubMed  Google Scholar 

  111. 111.

    Hajmrle, C. et al. Interleukin-1 signaling contributes to acute islet compensation. JCI Insight 1, e86055 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Kelpe, C. L. et al. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J. Biol. Chem. 278, 30015–30021 (2003).

    CAS  PubMed  Google Scholar 

  113. 113.

    Lang, F., Ullrich, S. & Gulbins, E. Ceramide formation as a target in beta-cell survival and function. Expert Opin. Ther. Targets 15, 1061–1071 (2011).

    CAS  PubMed  Google Scholar 

  114. 114.

    Cunha, D. A. et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes 61, 2763–2775 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Thompson, P. J. et al. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060.e10 (2019). This study demonstrates the critical role of senescent β-cells in triggering the occurrence of T1DM.

    CAS  PubMed  Google Scholar 

  117. 117.

    Sone, H. & Kagawa, Y. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48, 58–67 (2005).

    CAS  PubMed  Google Scholar 

  118. 118.

    Aguayo-Mazzucato, C. et al. Beta cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 25, 898–910.e5 (2017).This study reveals the development of senescent β-cells that affect insulin secretion in obesity and/or T2DM.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Donath, M. Y. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13, 465–476 (2014).

    CAS  PubMed  Google Scholar 

  120. 120.

    Goldfine, A. B. et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 159, 1–12 (2013).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    CAS  PubMed  Google Scholar 

  122. 122.

    Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J. Am. Coll. Cardiol. 71, 2392–2401 (2018). This study provides a critical assessment of the effect of canakinumab on major cardiovascular events among individuals with and without diabetes mellitus.

    CAS  PubMed  Google Scholar 

  123. 123.

    Kataria, Y., Ellervik, C. & Mandrup-Poulsen, T. Treatment of type 2 diabetes by targeting interleukin-1: a meta-analysis of 2921 patients. Semin. Immunopathol. 41, 413–425 (2019).

    PubMed  Google Scholar 

  124. 124.

    Gordon, S. & Pluddemann, A. Tissue macrophages: heterogeneity and functions. BMC Biol. 15, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

Download references


The authors acknowledge the support of the US National Institute of Diabetes and Digestive and Kidney Diseases (DK063491 and DK101395 to J.M.O., and DK114427 to W.F.), the US National Institute of Diabetes and Digestive and Kidney Diseases K99/R00 award (1K99DK115998 to W.Y.), the University of California San Diego (UCSD)/ University of California Los Angeles (UCLA) Diabetes Research Center Pilot and Feasibility grants (to W.Y., Y.S.L, and W.F.), and the UCSD Clinical and Translational Research Institute (CTRI) UL1 TR000100 (to W.F.).

Author information




The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Jerrold M. Olefsky.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Yolk sac-derived primitive haematopoiesis

The generation of blood-lineage cells, including primitive erythroid cells, platelets and macrophages, in the extra-embryonic yolk sac during early embryonic development.


A rare inherited syndrome characterized by increased bone density due to a defect of osteoclasts, a specialized population of macrophages that can resorb bone.


Islet-specific inflammation characterized by the infiltration of various types of immune cell into pancreatic islets, more commonly used to describe the islet inflammation preceding or accompanying type 1 diabetes mellitus.

Islet amyloid polypeptide

(IAPP). An islet hormone that is co-secreted with insulin from β-cells and forms islet amyloids.


Low-grade inflammation induced by overnutrition, which occurs in metabolic tissue (primarily adipose tissue, liver, muscle and pancreatic islets), causes dysregulation of immune cells and inflammatory responses.

Type 2 innate lymphoid cells

(ILC2s). A subgroup of innate lymphoid cells characterized by the lack of rearranged receptors and production of type 2 cytokines such as IL-5 and IL-13.

Transwell plate chambers

Devices designed to study cell migration and cell–cell interaction, which are permeable to soluble factors but prevent the migration or contact of cells between the upper and lower chambers.

IL-1 receptor antagonist

(IL-1Ra). A member of the IL-1 family of cytokines that binds to the IL-1 receptor but does not induce intracellular signalling.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ying, W., Fu, W., Lee, Y.S. et al. The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities. Nat Rev Endocrinol 16, 81–90 (2020).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing