Islet inflammation in type 2 diabetes and physiology

Abstract

The finding of islet inflammation in type 2 diabetes (T2D) and its involvement in β cell dysfunction has further highlighted the significance of inflammation in metabolic diseases. The number of intra-islet macrophages is increased in T2D, and these cells are the main source of proinflammatory cytokines within islets. Multiple human studies of T2D have shown that targeting islet inflammation has the potential to be an effective therapeutic strategy. In this Review we provide an overview of the cellular and molecular mechanisms by which islet inflammation develops and causes β cell dysfunction. We also emphasize the regulation and roles of macrophage polarity shift within islets in the context of T2D pathology and β cell health, which may have broad translational implications for therapeutics aimed at improving islet function.

Figure 1. M1-like polarization of islet macrophages plays important roles in islet inflammation and β cell dysfunction in T2D.

The communication between islet macrophages and β cells via hIAPP, chemokines (e.g., CCL2 and CXCL1), and proinflammatory cytokines (e.g., IL-1β) initiate and amplify the M1-like polarity shift of islet macrophages and islet inflammation. The inflammasome/IL-1β pathway in islet macrophages is a common pathway that causes β cell dysfunction within inflamed islets in T2D.

Figure 2. M2-like polarization of islet macrophages plays key roles in the proliferation and physiologic maintenance of β cells.

Multiple cytokines (e.g., TGF-β1, VEGFA, and CSF1) secreted from multiple cell types within islets (e.g., macrophages, β cells, and endothelial cells) form networks that contribute to a microenvironment that promotes M2-like polarization of islet macrophages. CSF1 signaling is a common mediator that maintains and promotes M2-like activation of both islet-resident and recruited macrophages. M2-like macrophages play an indispensable role in the establishment of the microenvironment necessary for β cell health. CSF1R, CSF1 receptor.

Figure 3. Overview of islet macrophage biology in the context of normal physiology and T2D pathology.

M1-like macrophages are represented by surface expression of Ly6C and MHC-II and gene expression of Nlrp3, Il1b, Tnf, and Nos2. M1-like macrophages are induced by such factors as FFAs, hIAPPs, and endocannabinoids, and at least some M1-like macrophages are recruited through CCL2 signaling. M2-like macrophages are represented by surface expression of CD206 and CD301 and gene expression of Il10, Arg1, and Tgfb1. At least some M2-like macrophages self-renew or are recruited through CSF1 signaling. In the sterile islet inflammation observed in T2D, islet macrophages’ polarization is seamlessly regulated as a continuum, rather than as distinct bimodal M1 and M2 polarization. Studies of the regulation of islet macrophage polarization, characterizations of subsets of heterogeneous islet macrophages, and analyses of the mechanisms by which these polarized macrophages exert their physiologic and pathologic effects on islet biology have the potential for translation to T2D therapeutics.