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. The dominant immune cell type causing pancreatic islet inflammation in individuals with obesity and/or type 2 diabetes mellitus is the macrophage. In this Review, we focus on the characteristics of inflammation in obese or type 2 diabetes mellitus islets and the consequences of this with respect to β-cell function. 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.