IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice.

AIMS/HYPOTHESIS: Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to beta cell dysfunction in type 2 diabetes. Human but not non-amyloidogenic rodent IAPP induces islet macrophage proIL-1ß synthesis. We evaluated the effect of IL-1 receptor antagonist (IL-1Ra) on islet inflammation and dysfunction in a mouse model of type 2 diabetes with amyloid formation. METHODS: Lean and obese male mice (A/a or A(vy)/A at the agouti locus, respectively) with or without beta cell human IAPP expression (hIAPP(Tg/0)) were treated with PBS or IL-1Ra (50 mg kg(-1) day(-1)) from 16 weeks of age. Intraperitoneal glucose and insulin tolerance tests were performed after 8 weeks. Pancreases were harvested for histology and gene expression analysis. RESULTS: Aggregation of human IAPP was associated with marked upregulation of proinflammatory gene expression in islets of obese hIAPP(Tg/0) mice, together with amyloid deposition and fasting hyperglycaemia. IL-1Ra improved glucose tolerance and reduced plasma proinsulin:insulin in both lean and obese hIAPP(Tg/0) mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean hIAPP (Tg/0) mice, suggesting a feed-forward mechanism by which islet inflammation promotes islet amyloid at the early stages of disease. IL-1Ra limited Il1a, Il1b, Tnf and Ccl2 expression in islets from obese hIAPP(Tg/0) mice, suggesting an altered islet inflammatory milieu. CONCLUSIONS/INTERPRETATION: These data provide the first in vivo evidence­using a transgenic mouse model with amyloid deposits resembling those found in human islets­that IAPP-induced beta cell dysfunction in type 2 diabetes may be mediated by IL-1. Anti-IL-1 therapies may limit islet inflammation and dysfunction associated with amyloid formation.

Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1ß production and ß-cell dysfunction.

Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1ß secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and ß-cell dysfunction. In cultured islets, macrophages (F4/80(+)CD11b(+)CD11c(+) cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1ß, tumor necrosis factor-α, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1ß synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with ß-cell human IAPP (hIAPP) expression had impaired glucose tolerance, elevated islet Il1b mRNA, and decreased Il10 and Il1rn expression following high-fat feeding. Islet macrophages were the major source of these transcripts and expressed increased cell surface Ly6C and CD11c in hIAPP transgenic mice. Clodronate liposome-mediated depletion of islet macrophages improved glucose tolerance and blocked proinflammatory gene expression in hIAPP-expressing mice, despite increasing the amount of islet amyloid. These data provide the first evidence that IAPP aggregates skew resident islet macrophages toward a proinflammatory phenotype and suggest a mechanism by which anti-inflammatory therapies may protect ß-cells from IAPP-induced islet dysfunction.

Death and dysfunction of transplanted ß-cells: lessons learned from type 2 diabetes?

ß-Cell replacement by islet transplantation is a potential curative therapy for type 1 diabetes. Despite advancements in islet procurement and immune suppression that have increased islet transplant survival, graft function progressively declines, and many recipients return to insulin dependence within a few years posttransplant. The progressive loss of ß-cell function in islet transplants seems unlikely to be explained by allo- and autoimmune-mediated mechanisms alone and in a number of ways resembles ß-cell failure in type 2 diabetes. That is, both following transplantation and in type 2 diabetes, islets exhibit decreased first-phase glucose-stimulated insulin secretion, impaired proinsulin processing, inflammation, formation of islet amyloid, signs of oxidative and endoplasmic reticulum stress, and ß-cell death. These similarities suggest common mechanisms may underlie loss of insulin production in both type 2 diabetes and islet transplantation and point to the potential for therapeutic approaches used in type 2 diabetes that target the ß-cell, such as incretin-based therapies, as adjuncts for immunosuppression in islet transplantation.

Npas4 is a novel activity-regulated cytoprotective factor in pancreatic ß-cells.

Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic ß-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel ß-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by ß-cell depolarizing agents. Npas4 tempers ß-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose-stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate-induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves ß-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function.