BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. RESULTS: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].). T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of Reprints and permissions information is available online at www.nature.com/reprints/index.html.

Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived inflammatory factors. Increased islet-associated immune cells were observed in human type 2 diabetic patients, high-fat-fed C57BL/6J mice, the GK rat, and the db/db mouse. When cultured islets were exposed to a type 2 diabetic milieu or when islets were isolated from high-fat-fed mice, increased isletderived inflammatory factors were produced and released, including interleukin (IL)-6, IL-8, chemokine KC, granulocyte colony-stimulating factor, and macrophage inflammatory protein 1␣. The specificity of this response was investigated by direct comparison to nonislet pancreatic tissue and ␤-cell lines and was not mimicked by the induction of islet cell death. Further, this inflammatory response was found to be biologically functional, as conditioned medium from human islets exposed to a type 2 diabetic milieu could induce increased migration of monocytes and neutrophils. This migration was blocked by IL-8 neutralization, and IL-8 was localized to the human pancreatic ␣-cell. Therefore, islet-derived inflammatory factors are regulated by a type 2 diabetic milieu and may contribute to the macrophage infiltration of pancreatic islets that we observe in type 2 diabetes. Diabetes 56:2356-2370, 2007 A ctivation of the innate immune system has long been reported in obesity, insulin resistance, and type 2 diabetics and is characterized by increased circulating levels of acute-phase proteins and of cytokines and chemokines (1-5). However, the notion that excess circulating nutrients may stimulate the ␤-cell to produce chemokines remains unexplored, and immune cell infiltration has not been shown in islets of type 2 diabetic patients.One of the most classical chemotactic agents in immunology is the CXC family chemokine, interleukin (IL)-8 (CXCL8) (6). IL-8 is produced by leukocytes, fibroblasts, and endothelial and epithelial cells and is commonly associated with infections, graft rejection, allergy, asthma, cancer, and atherosclerosis. In addition to its effect on neutrophils, the chemotactic effect of IL-8 also is important in mediating monocyte migration (7-9). The rodent does not express IL-8. Instead, the rodent functional homolog of IL-8 is thought to be chemokine KC (CXCL1, or Gro-␣ in the rat), which also has been reported to induce granulocyte and monocyte migration (9). Chemokine KC is thought to be an ortholog of human CXCL1. Circulating levels of IL-8 are elevated in type 2 diabetic individuals (10,11), in whom IL-8 has been implicated in systemic insulin resistance and atherosclerosis (12,13).Thus, we hypothesized that pancreatic islets in type 2 diabetes are characterized by increased macrophage infiltration and that a type 2 diabetic milieu could promote chemokine production in pancreatic islets. ...

A decrease in the number of functional insulin-producing ␤-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ␤-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ␤-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K ؉ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ␤-cell secretory function and cell turnover. Thus, the mechanisms regulating ␤-cell proliferation, apoptosis, and function are inseparable processes. Diabetes 54 (Suppl. 2):S108 -S113, 2005 F or many years, the contribution of a reduction in ␤-cell mass to the development of type 2 diabetes was heavily debated. Recently, several publications have convincingly confirmed this hypothesis (1-3), leading to a rapid overemphasis of this etiological factor. Indeed, other mechanisms contributing to the failure of the ␤-cell to produce enough insulin appear more and more neglected. While we strongly believe that ␤-cell destruction is an important etiological factor in the development and progression of type 2 diabetes, in this review, we will highlight evidence that this is not dissociable from an intrinsic secretory defect. We will show that pathways regulating ␤-cell turnover are also implicated in ␤-cell insulin secretory function. It follows that adaptive mechanisms of function and mass share common regulatory pathways and will therefore act in concert. Depending on the prevailing concentration and the intracellular pathways activated, some factors may be deleterious to ␤-cell mass while enhancing insulin secretion, protective to the ␤-cell while inhibiting function, or even protective to the ␤-cell while enhancing function. It will become apparent that the failure of the ␤-cell in type 2 diabetes is akin to a multifactorial equation, with an overall negative result.Thus, although we will review the factors and mechanisms regulating ␤-cell mass individually, only in a minority of diabetic patients does one single etiological factor underlie the failure of the ␤-cell. In addition to maturityonset diabetes of the young, another example of this is autoimmune-mediated destruction of ␤-cells in young lean individuals. However, given that the incidence of type 1 diabetes increases with obesity (4), that insulin resistance is a risk factor for the progression of this condition (5), and that ϳ50% of the general population carry the same genetic predisposition (6), this example already implicates multiple etiological factors. Recognition of ␤-cell destruction not only in type 1 but also in type 2 diabetes led us to recently propose a unif...

Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1␤. In the periphery, increased expression of IL-1␤ was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1␤ or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1␤, IL-6, TNF␣, KC, MCP-1, and MIP-1␣) and islet CD68 ؉ , MHC II ؉ , and CD53 ؉ immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1␤ activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1␤ may drive tissue inflammation that impacts on both ␤ cell functional mass and insulin sensitivity in type 2 diabetes.interleukin-1 ͉ metabolic stress ͉ pancreatic islet ͉ insulin resistance ͉ beta cells

OBJECTIVEInterleukin (IL)-1 impairs insulin secretion and induces β-cell apoptosis. Pancreatic β-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and β-cell function and reduces inflammatory markers in patients with type 2 diabetes. Here we investigated the durability of these responses.RESEARCH DESIGN AND METHODSAmong 70 ambulatory patients who had type 2 diabetes, A1C >7.5%, and BMI >27 kg/m2 and were randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blind 39-week follow-up study. Primary outcome was change in β-cell function after anakinra withdrawal. Analysis was done by intention to treat.RESULTSThirty-nine weeks after anakinra withdrawal, the proinsulin-to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by −0.07 [95% CI −0.14 to −0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (−3.2 mg/l [−6.2 to −1.1], P = 0.014) and in IL-6 (−1.4 ng/l [−2.6 to −0.3], P = 0.036) were maintained until the end of study.CONCLUSIONSIL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal.

Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced ␤-cell function and mass, an increased proportion of ␣-cells relative to ␤-cells, and ␣-cell dysfunction. Here we show that the ␣ cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the ␣-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates ␣-cell proliferation, prevents apoptosis due to metabolic stress, and regulates ␣-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased ␣-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of ␣-cell mass display decreased fasting glucagon levels. However, despite these ␣-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic ␣-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional ␤-cell compensation to increased metabolic demand.alpha-cell mass ͉ beta-cell function ͉ high-fat diet ͉ pancreatic islet

Onset of Type 2 diabetes occurs when the pancreatic beta-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, beta-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in beta-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.