Islet inflammation: a unifying target for diabetes treatment?

Abstract

In the past decade, islet inflammation has emerged as a contributor to the loss of functional β cell mass in both type 1 (T1D) and type 2 diabetes (T2D). Evidence supports the idea that overnutrition and insulin resistance result in the production of proinflammatory mediators by β cells. In addition to compromising β cell function and survival, cytokines may recruit macrophages into islets, thus augmenting inflammation. Limited but intriguing data imply a role of adaptive immune response in islet dysfunction in T2D. Clinical trials have validated anti-inflammatory therapies in T2D, whereas immune therapy for T1D remains challenging. Further research is required to improve our understanding of islet inflammatory pathways and to identify more effective therapeutic targets for T1D and T2D.

Figure 1. Dysfunctional adipose tissue in obesity drives β cell inflammation and T2D

Excess caloric intake progressively induces weight gain and fat accretion leading to obesity. Adipose tissue (AT) is responsible for storage of ~90% of the FFA load following feeding, and therefore, substantial adipocyte remodeling involving primarily hypertrophy and some degree of hyperplasia occurs to accommodate the increasing demand for triglyceride storage. Hypertrophic adipocytes have significantly reduced response to insulin and become progressively more lipolytic liberating excessive FFA. Gene expression of inflammatory proteins and peptides increases resulting in elevated production of cytokines, chemokines, and other inflammatory mediators, such as 12LO. The latter, in turn, contributes to immune cell recruitment and activation within AT, including T cells (CD4⁺ and CD8⁺), MΦ, natural killer cells (NK), and dendritic cells (DC). Once in AT, immune cells are an additional source of pro-inflammatory mediators. The array of the adipokines secreted by the adipocytes also changes with increased production of leptin and reduced adiponectin. All of these circulating factors act in an endocrine manner and induce dysfunction in the pancreatic β cells. Elevated FFAs induce lipotoxicity, oxidative stress, mitochondrial dysfunction, and ER stress in the β cells; elevated leptin, coupled with leptin resistance in β cells, may contribute to reduced insulin secretion. Insulin secretion is further reduced by inflammatory mediators originating from either AT or locally produced by the islets and by the infiltrating immune cells. Adiponectin has beneficial effects via AdipoR1 and 2 receptors, which reduce oxidative stress and ER stress in the β cell. Reduced adiponectin expression in obesity minimizes its beneficial effects. Higher demand for insulin due to insulin resistance negatively affects β cells through ER stress and islet expansion. The recruitment of MΦ is also thought to amplify inflammation and islet dysfunction in obesity. It is yet to be determined whether other immune cells are involved in islet inflammation in T2D. The overall inflammatory responses in β cells in obesity contribute to reduced functional β cell mass leading to T2D, when combined with systemic insulin resistance.

Figure 2. Major inflammatory mediators and signaling pathways involved in β-cell demise

The major triggers of inflammation in islets are shared with the ones that induce inflammation in AT, liver and muscle: excess saturated FFA, lipid mediators such as lipoxygenase products (12-HETE), increased glucose, and pro-inflammatory cytokines and chemokines. IAPP is so far acknowledged as an islet specific inflammatory mediator, and is produced and secreted solely by the β cell. Inflammatory mediators activate cellular stress: saturated FFA and glucose increase ER stress (via CHOP/IRE α1). IL-1β increases the expression of NOX1/4 activating NADPH oxidase and DMT1, which increases iron transport; both lead to an increase in ROS, and together with IAPP, contribute to increased oxidative stress. 12(S)-HETE, produced by 12LO activates the G-protein coupled receptor GPR31, and induces downstream inflammatory signals. Cytokines produced locally or from circulation also activate inflammatory pathways via specific cytokine receptors in β cells. In response to cytokine receptors JAK/TYK, p38MAPK and JNK are activated; also JNK is phosphorylated in response to TLR4 activation or IAPP intracellular aggregation; p38MAPK is activated downstream of GPR31; ROS activate JNK, p38MAPK or NF-κB; activation of MyD88/TRIF downstream of TLR4 also leads to NF-κB activation; other transcription factors activated downstream of kinases are c-Jun, AP2 (downstream of JNK) and STAT3/4/5/(downstream of p38MAPK and JAK/Tyk). A positive feedback loop is operational in the β cell in which inflammatory mediators extrinsic to β cells converge in activating transcription of various cytokines, chemokines, and other inflammatory mediators that in turn act in an autocrine manner to exacerbate the inflammatory response. Also, intracellularly, there is extensive cross talk between signaling molecules involved in oxidative stress, ER stress, mitochondrial dysfunction, and inflammatory responses.