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...