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Review
. 2012 Mar;2(3):a007724.
doi: 10.1101/cshperspect.a007724.

Connecting type 1 and type 2 diabetes through innate immunity

Justin I Odegaard  1 , Ajay Chawla
Affiliations
Review

Connecting type 1 and type 2 diabetes through innate immunity

Justin I Odegaard et al. Cold Spring Harb Perspect Med. 2012 Mar.

Abstract

The escalating epidemic of obesity has driven the prevalence of both type 1 and 2 diabetes mellitus to historically high levels. Chronic low-grade inflammation, which is present in both type 1 and type 2 diabetics, contributes to the pathogenesis of insulin resistance. The accumulation of activated innate immune cells in metabolic tissues results in release of inflammatory mediators, in particular, IL-1β and TNFα, which promote systemic insulin resistance and β-cell damage. In this article, we discuss the central role of innate immunity and, in particular, the macrophage in insulin sensitivity and resistance, β-cell damage, and autoimmune insulitis. We conclude with a discussion of the therapeutic implications of this integrated understanding of diabetic pathology.

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Figures

Figure 1.
Figure 1.
Insulin resistance damages β-cells and leads to autoimmune insulitis. (A) In lean, insulin-sensitive individuals, normal insulin secretion is sufficient to induce robust uptake of glucose from the circulation by skeletal muscle and adipose tissue, to inhibit free fatty acid (FFA) release from adipose tissue, and to suppress hepatic gluconeogenesis. In such individuals, the adipose tissue macrophages and Kupffer cells have an alternative bias, resulting in expression of interleukin-1 receptor antagonist (IL1-Ra) and suppression of IL-1β. The resulting serologic state is characterized by relatively low concentrations of insulin, glucose, FFAs, and inflammatory mediators (e.g., IL-1β) and high levels of regulatory cytokines (e.g., IL-1Ra). (B) In contrast, insulin resistance abrogates insulin’s peripheral effects, resulting in reduced glucose uptake, unsuppressed hepatic gluconeogenesis, and enhanced FFA release from adipose tissue. Under these conditions, adipose tissue macrophages and Kupffer cell populations are classically activated, expressing high levels of pro-inflammatory mediators such as IL-1β, TNFα, and nitric oxide, while suppressing production of tolerogenic peptides, such as IL-10 and IL-1Ra. The serum is thus characterized by progressively higher levels of insulin, glucose, FFAs, and inflammatory mediators and reduced levels of tolerogenic peptides. Escalating insulin resistance eventually results in levels of glucose, saturated fatty acids, and inflammatory mediators that are directly toxic to β-cells (among other tissues). β-Cell damage and concomitant innate immune activation within the islet initiate β-cell-specific cytotoxic T lymphocyte (CTL) responses, which further damage the beleaguered β-cells. (Blue) Processes associated with insulin sensitivity; (red) those associated with insulin resistance. The arrow weight indicates relative flux through individual pathways.
Figure 2.
Figure 2.
Stress kinases mediate insulin resistance. Anabolic actions of insulin are mediated via the insulin receptor, which becomes autophosphorylated following binding to insulin. This allows for docking and tyrosine phosphorylation of insulin receptor substrate (IRS) proteins, which subsequently activate the downstream insulin signaling pathways. On the other hand, serine phosphorylation of IRS-1 and IRS-2 by stress-activated kinases JNK1 and IKKβ potently inhibits insulin signaling, resulting in cellular insulin resistance. Moreover, transcriptional activation of inflammatory genes by AP-1 and NF-κB, the transcription factors activated by the stress kinases, promotes insulin resistance in an autocrine and paracrine manner in metabolic tissues. In obesity, the increased influx of glucose and free fatty acids and production of ROS induces ER stress, resulting in activation of JNK signaling, whereas obesity-induced inflammation activates JNK and IKKβ signaling to promote insulin resistance. (This figure is from Odegaard and Chawla 2011; reprinted, with express permission, from the authors.)
Figure 3.
Figure 3.
Obesity results in recruitment of macrophages into adipose tissue, which promotes adipose tissue inflammation and insulin resistance. Obesity results in increased levels of circulating saturated fatty acids, which activate Toll-like receptors 2/4 (TLR2/4) to promote classical activation of adipose tissue macrophages. Secretion of inflammatory cytokines, such as IL-1β and TNF-α, by adipose tissue macrophages inhibits insulin action in adipocytes. Moreover, activation of the NLRP3-containing inflammasomes, potentially by ceramides, augments the release IL-1β by classically activated macrophages. Cross talk between adipocytes and adipose tissue macrophages perpetuates these inflammatory cascades via release of chemokines, cytokines, and fatty acids. Ccl2 and osteopontin (OPN) are two chemoattractants implicated in the recruitment of Ly6C+CCR2+ inflammatory monocytes, which differentiate into classically activated adipose tissue macrophages. CD5-like antigen (CD5L), a peptide released by macrophages that is incorporated into adipocytes via CD36-mediated endocytosis, potentiates lipolysis of triglycerides in adipocytes. This establishes a feed-forward loop in which the released fatty acids induce chemokine expression, potentiating monocyte and macrophage recruitment into adipose tissue. By inhibiting the IL-4- and PPARγ-driven program of alternative activation, mineralocorticoid (MR) signaling contributes to classical activation of adipose tissue macrophages. (This figure is from Chawla et al. 2011; reprinted, with express permission, from the author.)
Figure 4.
Figure 4.
Cross talk between innate and adaptive immune cells in obese adipose tissue. Overnutrition results in necrotic death of engorged adipocytes, resulting in recruitment of classically activated macrophages to clear cellular debris. These classically activated macrophages, which express molecules associated with antigen-presenting cells (MHC class II, CD1d, costimulatory molecules, and CD11c), are potentially capable of presenting necrotic cell-derived antigens to T-cells and B-cells. This will activate adaptive immunity, resulting in clonal expansion of CD4+Th1 cells and recruitment of CD8+ T-cells. Secretion of chemotactic factors by CD8+ T-cells and IFNγ by CD4+Th1 cells increases recruitment and classical activation of adipose tissue macrophages, respectively, thereby establishing a vicious cycle of inflammation. The concomitant reduction in numbers of immunosuppressive Treg cells contributes to the adipose tissue inflammation and insulin resistance. Lastly, B-cells, which are capable of presenting antigens to naive T-cells, infiltrate obese adipose tissue and secrete IgG2c antibodies, factors that worsen insulin resistance. (This figure is from Chawla et al. 2011; reprinted, with express permission, from the author.)
Figure 5.
Figure 5.
Amelioration of obesity-induced insulin resistance by alternatively activated macrophages. Adipose tissue of lean animals is populated by alternatively activated macrophages, which promote insulin sensitivity in adipocytes by attenuating inflammation and releasing IL-10. Production of IL-4 and IL-13 by eosinophils sustains alternative macrophage activation of adipose tissue macrophages, which can be distinguished by their expression of alternative activation markers CD206, CD301, and Arg1. Transcriptional synergy between STAT6, peroxisome proliferator-activated receptors δ/γ (PPARδ/γ), and Krupple-like factor 4 (KLF4) sustains alternative activation of adipose tissue macrophages. Factors derived from lean adipose tissue, such as adiponectin and unsaturated ω3-fatty acids, synergize with IL-4 signaling to enhance alternative activation and dampen NF-κB-driven classical activation of adipose tissue macrophages. (This figure is from Chawla et al. 2011; reprinted, with express permission, from the author.)
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