Minireview: Emerging Concepts in Islet Macrophage Biology in Type 2 Diabetes

Abstract

Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for β-cell formation during development and support β-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional β-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes.

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

“…6A, B; Shih et al 2002). Cluster C7 is enriched in genes with immune function and likely represents innate cells such as macrophages or dendritic cells (Supplemental Table S3), which have been previously reported to reside in islets and are critical for proper development (Xiao et al 2014;Morris 2015). Our data also revealed an interplay between hormone-producing cells and vascular cells (cluster C9).…”

Islet inflammation in type 2 diabetes

“…These innate immune system cells are quite heterogeneous, possess functional plasticity and may exert contradictory actions [7,23]. An attempt has been made to describe these differences by classifying macrophages as being 'classically' activated (M1 macrophages) or 'alternatively' activated (M2 macrophages).…”

“…An attempt has been made to describe these differences by classifying macrophages as being 'classically' activated (M1 macrophages) or 'alternatively' activated (M2 macrophages). Although these two classes are likely to represent the polar ends of a much broader activation spectrum, it is nevertheless assumed that M1 macrophages produce proinflammatory cytokines and are cytotoxic, whereas M2 macrophages contribute to resolving inflammation and promoting tissue repair through several mechanisms, including phagocytosis of apoptotic cells and remodelling the extracellular matrix [7,23]. In addition, macrophages have been described in the human pancreas at 6-12 weeks of development, suggesting a contribution to pancreas development in humans [28], as more clearly shown in rodents [7].…”

“…Islet cells themselves can produce some of these molecules when exposed to high concentrations of glucose [13] or the fatty acid palmitate [12,15], conditions used to mimic a diabetic micro-environment. However, macrophages are likely to be the dominant producers of some toxic cytokines, such as IL-1β [7,40]. Whatever the source, the effects of cytokines on beta cell function and survival depend on several other factors, including, in particular, their concentrations and combinations.…”

“…However, dysregulated or prolonged inflammation states have been associated with many diseases, including type 2 diabetes [1]. Early connections between inflammation, obesity and type 2 diabetes were made in the 1990s, in both rodent models and humans [2,3], and later substantiated by a large body of evidence (see [4][5][6][7] for recent reviews). Then, it was observed that pancreatic islet cells may also show signs of inflammation, including immune cell infiltration [8][9][10] and increased expression of cytokines and chemokines [11][12][13].…”