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

Abstract

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.

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

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Acknowledgements

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.).

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Correspondence to Jerrold M. Olefsky.

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Glossary

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.

Osteopetrosis

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

Insulitis

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.

Metaflammation

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.

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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). https://doi.org/10.1038/s41574-019-0286-3

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