The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells

Defects in insulin secretion, resulting from loss of function or destruction of pancreatic beta-cells, trigger diabetes. Interleukin (IL)-1beta is a proinflammatory cytokine that is involved in type 1 and type 2 diabetes development and impairs beta-cell survival and function. Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival.     

基于生物信息学探讨骨质疏松症与2型糖尿病的关系

目的基于生物信息学探讨骨质疏松症与2型糖尿病的关系。方法通过五大疾病数据库(Disgenet、TTD、OMIM、Drugbank、KEGG数据库)和分析平台(DAVID数据库)对骨质疏松症和2型糖尿病的相关基因进行分析筛选,并对筛选结果进行基因富集分析以及KEGG通路分析。结果通过五大疾病数据库及相关文献筛选分别选出与骨质疏松症和2型糖尿病相关基因336个和316个,并将数据导入DAVID数据库进行基因富集分析以及KEGG通路分析,结果骨质疏松症与2型糖尿病相关通路集中在PI3K-Akt信号通路、FoxO信号通路、HIF-1信号通路、AMPK信号通路、Rap1信号通路、Jak-STAT信号通路、Ras信号通路、NF-kappa B信号通路、T细胞信号通路、TNF信号通路、VEGF信号通路、脂肪细胞因子信号通路、fc-εri信号通路。结论骨质疏松症与2型糖尿病均是涵盖众多差异表达基因的复杂代谢性疾病,两种疾病均存在庞大的基因表达网络,涉及众多信号通路。从通路分析结果中可以看出,两种疾病复杂基因网络背景下依然存在一些高度重合的差异基因表达,所涉及的信号通路能够同时对两种疾病产生调控作用,这提示两种疾病分子机制存在密切关联,并可能是药物同时干预两种疾病的靶点所在。     

Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes

Involvement of gut immune system has been implicated in the pathogenesis of type 1 diabetes. However, few studies have been performed on the gut mucosa from patients with type 1 diabetes. Thus, we characterized the stage of immune activation in jejunal biopsy samples from 31 children with type 1 diabetes by immunohistochemistry, in situ hybridization, and RT-PCR. We found enhanced expressions of HLA-DR, HLA-DP, and intercellular adhesion molecule-1 by immunohistochemistry even on structurally normal intestine of patients with type 1 diabetes and no signs of celiac disease. In addition, the densities of IL-1 alpha- and IL-4-positive cells detected by immunohistochemistry and IL-4 mRNA-expressing cells evaluated by in situ hybridization were increased in the lamina propria in patients with type 1 diabetes and normal mucosa. Instead, the densities of IL-2, gamma-interferon (IFN-gamma), and tumor necrosis factor alpha-positive cells, the density of IFN-gamma mRNA positive cells, and the amounts of IFN-gamma mRNA detected by RT-PCR correlated with the degree of celiac disease in patients with type 1 diabetes. Our study supports the hypothesis that a link exists between the gut immune system and type 1 diabetes.     

Interleukin-6 and diabetes: the good, the bad, or the indifferent?

Inflammatory mechanisms play a key role in the pathogenesis of type 1 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years in advance of disease onset. This low-grade inflammation has been proposed to be involved in the pathogenetic processes causing type 2 diabetes. Mediators of inflammation such as tumor necrosis factor-alpha, interleukin (IL)-1beta, the IL-6 family of cytokines, IL-18, and certain chemokines have been proposed to be involved in the events causing both forms of diabetes. IL-6 has in addition to its immunoregulatory actions been proposed to affect glucose homeostasis and metabolism directly and indirectly by action on skeletal muscle cells, adipocytes, hepatocytes, pancreatic beta-cells, and neuroendocrine cells. Here we argue that IL-6 action-in part regulated by variance in the IL-6 and IL-6alpha receptor genes-contributes to, but is probably neither necessary nor sufficient for, the development of both type 1 and type 2 diabetes. Thus, the two types of diabetes are also in this respect less apart than apparent. However, the mechanisms are not clear, and we therefore propose future directions for studies in this field.     

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets?

Different degrees of beta-cell failure and apoptosis are present in type 1 and type 2 diabetes. It has been recently suggested that high glucose-induced beta-cell apoptosis in type 2 diabetes shares a final common pathway with type 1 diabetes, involving interleukin-1beta (IL-1beta) production by beta-cells, nuclear factor-kappaB (NF-kappaB) activation, and death via Fas-FasL. The aim of this study was to test whether human islet exposure to high glucose in vitro, or to the type 2 diabetes environment in vivo, induces IL-1beta expression and consequent activation of NF-kappaB-dependent genes. Human islets were isolated from five normoglycemic organ donors. The islets were cultured for 48 h to 7 days at 5.6, 11, or 28 mmol/l glucose. For comparative purposes, islets were also exposed to IL-1beta. Gene mRNA expression levels were assessed by real-time RT-PCR in a blinded fashion. Culture of the human islets at 11 and 28 mmol/l glucose induced a four- to fivefold increase in medium insulin as compared with 5.6 mmol/l glucose, but neither IL-1beta nor IL-1 receptor antagonist (IL-1ra) expression changed. IL-1beta and IL-1ra protein release to the medium was also unchanged. Stimulated human monocytes, studied in parallel, released >50-fold more IL-1beta than the islets. There was also no glucose-induced islet Fas expression. Expression of the NF-kappaB-dependent genes IkappaB-alpha and monocyte chemoattractant protein (MCP)-1 was induced in human islets by IL-1beta but not by high glucose. In a second set of experiments, human islets were isolated from seven type 2 diabetic patients and eight control subjects. The findings on mRNA levels were essentially the same as in the in vitro experiments, namely the in vivo diabetic state did not induce IL-1beta, Fas, or MCP-1 expression in human islets, and also did not modify IL-1ra expression. The present findings suggest that high glucose in vitro, or the diabetic milieu in vivo, does not induce IL-1beta production or NF-kappaB activation in human islets. This makes it unlikely that locally produced IL-1beta is an important mediator of glucotoxicity to human islets and argues against the IL-1beta-NF-kappaB-Fas pathway as a common mediator for beta-cell death in type 1 and type 2 diabetes.     

Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.     

Amyloid-β induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway

Epidemiological studies indicate that patients with Alzheimer's disease (AD) have an increased risk of developing type 2 diabetes mellitus (T2DM), and experimental studies suggest that AD exacerbates T2DM, but the underlying mechanism is still largely unknown. This study aims to investigate whether amyloid-β (Aβ), a key player in AD pathogenesis, contributes to the development of insulin resistance, as well as the underlying mechanism. We find that plasma Aβ40/42 levels are increased in patients with hyperglycemia. APPswe/PSEN1dE9 transgenic AD model mice with increased plasma Aβ40/42 levels show impaired glucose and insulin tolerance and hyperinsulinemia. Furthermore, Aβ impairs insulin signaling in mouse liver and cultured hepatocytes. Aβ can upregulate suppressors of cytokine signaling (SOCS)-1, a well-known insulin signaling inhibitor. Knockdown of SOCS-1 alleviates Aβ-induced impairment of insulin signaling. Moreover, JAK2/STAT3 is activated by Aβ, and inhibition of JAK2/STAT3 signaling attenuates Aβ-induced upregulation of SOCS-1 and insulin resistance in hepatocytes. Our results demonstrate that Aβ induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway and have implications toward resolving insulin resistance and T2DM.     

T-cell production of an inducible interleukin-10 transgene provides limited protection from autoimmune diabetes.

In a number of animal models of spontaneous autoimmune diabetes, pathogenesis has been highly correlated with autoreactive T-cell production of the type 1 cytokine interferon-gamma (IFN-gamma), while protection from disease was associated with type 2 cytokines such as interleukin (IL)-4. Curiously, in some models, diabetes is associated with unexpected cytokine patterns; for example, diabetes can develop in NOD mice lacking a functional IFN-gamma gene. In another situation, acceleration of diabetes occurs in transgenic mice with constitutive beta-cell expression of the type 2 cytokine IL-10. IL-10 has generally been associated with immunosuppression, including the modulation of class II expression on antigen-presenting cells and the generation of regulatory CD4 T-cells. Because it is possible that unregulated expression of any cytokine might lead to unphysiological effects in vivo, we tested the notion that an inducible T-cell-specific IL-10 transgene might yet mediate a more physiological protection from autoimmune diabetes. Our results show that indeed, regulated T-cell production of IL-10 does not accelerate diabetes and instead can provide significant protection from disease. These results help rectify the apparent discrepancies between the effect of IL-10 on various models of autoimmune diabetes.     

高龄老人慢性病与骨质疏松症的相关性研究进展

近年来研究表明,骨质疏松的发生常与一些慢性疾病相关。笔者通过分析高龄老人常见的几种慢性疾病如阿尔茨海默病、脑梗死、慢性肾脏病、2型糖尿病及动脉粥样硬化这几种疾病中骨质疏松症的研究进展,探讨骨质疏松与这几种疾病之间的关系。在以上几种疾病中引起骨质疏松症的因素包括:(1)TNF-a和IL-6等炎症因子可通过抑制疾病共有的信号通路Wnt途径;(2)由于高龄老人常见的慢性病与骨质疏松有共同的危险因素,如年龄、性别、吸烟、糖尿病、高血压等;(3)高龄老人由于器官退行性改变,导致消化道吸收和消化功能减退,造成钙、维生素D、雌激素等骨合成的原料缺乏;(4)高龄老人常合并多种基础疾病,导致自身户外活动受限,缺乏光照、缺少锻炼,体质量指数下降及营养不良等在骨质疏松的形成中扮演重要角色。综上所述,骨质疏松症的发生常与多种因素相关,对于合并有其他多种慢性疾病的高龄老人来说,发生骨质疏松的风险较高,应当加强骨密度的监测,早诊断、早治疗,避免骨折的发生。     

Association of non-HLA genes with type 1 diabetes autoimmunity

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.     

beta-cell apoptosis: stimuli and signaling

Pancreatic beta-cells are sensitive to a number of proapoptotic stimuli. Thus, apoptosis is an important part of the physiological neonatal remodeling of the endocrine pancreas, and a number of pathological stimuli involved in type 1 and type 2 diabetes have been shown to elicit beta-cell apoptosis. Factors of relevance to type 1 diabetes include proinflammatory cytokines, nitric oxide, and reactive oxygen species as well as Fas ligand. Recent findings that free fatty acids, glucose, sulfonylurea, and amylin cause beta-cell apoptosis in vitro suggest that programmed cell death may also be involved in the pathogenesis of type 2 diabetes. Furthermore, there is evidence favoring a convergence in signaling pathways toward common effectors of beta-cell apoptosis elicited by stimuli implicated in the pathogenesis of type 1 and type 2 diabetes. Therefore, recent studies involving the stimuli and signaling pathways of beta-cell apoptosis-in particular, mitogen- and stress-activated protein kinases-will be reviewed. It is concluded that immunological, inflammatory, and metabolic signals cause beta-cell apoptosis, and the possibility that these signals converge toward a common beta-cell death signaling pathway should be investigated further.     

A 1alpha,25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice

Type 1 diabetes is a chronic progressive autoimmune disease characterized by mononuclear cell infiltration, dominated by interleukin-12 (IL-12)-dependent Th1 cells, of the pancreatic islets, with subsequent destruction of insulin-producing beta-cells. Here, we demonstrate that treatment of adult nonobese diabetic (NOD) mice with an analog of 1alpha,25-dihydroxyvitamin D(3), an immunomodulatory agent preventing dendritic cell maturation, decreases lipopolysaccharide-induced IL-12 and gamma-interferon production, arrests Th1 cell infiltration and progression of insulitis, and inhibits diabetes development at nonhypercalcemic doses. Arrest of disease progression is accompanied by an enhanced frequency in the pancreatic lymph nodes of CD4(+)CD25(+) regulatory T-cells that are able to inhibit the T-cell response to the pancreatic autoantigen insulinoma-associated protein 2 and to significantly delay disease transfer by pathogenic CD4(+)CD25(-) cells. Thus, a short treatment of adult NOD mice with an analog of 1,25-dihydroxyvitamin D(3) inhibits IL-12 production, blocks pancreatic infiltration of Th1 cells, enhances CD4(+)CD25(+) regulatory cells, and arrests the progression of type 1 diabetes, suggesting its possible application in the treatment of human autoimmune diabetes.     

Peripheral hyperinsulinemia promotes tau phosphorylation in vivo

Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer's disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. Phospho-FoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.     

Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice

Sirolimus is an immunosuppressant that inhibits interleukin (IL)-2 signaling of T-cell proliferation but not IL-2-induced T-cell apoptosis. Therefore, we hypothesized that administration of IL-2, together with sirolimus, might shift T-cell proliferation to apoptosis and prevent autoimmune destruction of islet beta-cells. We found that sirolimus and IL-2 therapy of female NOD mice, beginning at age 10 weeks, was synergistic in preventing diabetes development, and disease prevention continued for 13 weeks after stopping sirolimus and IL-2 therapy. Similarly, sirolimus and IL-2 were synergistic in protecting syngeneic islet grafts from recurrent autoimmune destruction after transplantation in diabetic NOD mice, and diabetes did not recur after stopping sirolimus and IL-2 combination therapy. Immunocytochemical examination of islet grafts revealed significantly decreased numbers of leukocytes together with increased apoptosis of these cells in mice treated with sirolimus and IL-2, whereas beta-cells were more numerous, and significantly fewer were apoptotic. In addition, Th1-type cells (gamma-interferon-positive and IL-2(+)) were decreased the most, and Th2-type cells (IL-4(+) and IL-10(+)) and Th3-type cells (transforming growth factor-beta1(+)) were increased the most in islet grafts of sirolimus and IL-2-treated mice. We conclude that 1) combination therapy with sirolimus and IL-2 is synergistic in protecting islet beta-cells from autoimmune destruction; 2) diabetes prevention continues after withdrawal of therapy; and 3) the mechanism of protection involves a shift from Th1- to Th2- and Th3-type cytokine-producing cells, possibly due to deletion of autoreactive Th1 cells.     

Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training

Skeletal muscle insulin resistance plays a key role in the pathogenesis of type 2 diabetes. It recently has been hypothesized that excessive activity of the inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB) inflammatory pathway is a mechanism underlying skeletal muscle insulin resistance. However, it is not known whether IkappaB/NFkappaB signaling in muscle from subjects with type 2 diabetes is abnormal. We studied IkappaB/NFkappaB signaling in vastus lateralis muscle from six subjects with type 2 diabetes and eight matched control subjects. Muscle from type 2 diabetic subjects was characterized by a 60% decrease in IkappaB beta protein abundance, an indicator of increased activation of the IkappaB/NFkappaB pathway. IkappaB beta abundance directly correlated with insulin-mediated glucose disposal (Rd) during a hyperinsulinemic (40 mU x m(-2) x min(-1))-euglycemic clamp (r = 0.63, P = 0.01), indicating that increased IkappaB/NFkappaB pathway activity is associated with muscle insulin resistance. We also investigated whether reversal of this abnormality could be a mechanism by which training improves insulin sensitivity. In control subjects, 8 weeks of aerobic exercise training caused a 50% increase in both IkappaB alpha and IkappaB beta protein. In subjects with type 2 diabetes, training increased IkappaB alpha and IkappaB beta protein to levels comparable with that of control subjects, and these increments were accompanied by a 40% decrease in tumor necrosis factor alpha muscle content and a 37% increase in insulin-stimulated glucose disposal. In summary, subjects with type 2 diabetes have reduced IkappaB protein abundance in muscle, suggesting excessive activity of the IkappaB/NFkappaB pathway. Moreover, this abnormality is reversed by exercise training.     

Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice

OBJECTIVE

Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes.

RESEARCH DESIGN AND METHODS

We generated IL-21R–deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes.

RESULTS

Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R^−/− NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R^−/− NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds.

CONCLUSIONS

This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes.The nonobese diabetic (NOD) mouse model is the most well-characterized animal model of human type 1 diabetes and has provided important insights into the etiology and pathogenesis of this increasingly prevalent autoimmune disease (1). Rigorous genetic analysis of the NOD background has revealed the existence of multiple defined chromosomal regions known as insulin-dependent diabetes (idd) loci that confer susceptibility to or protection from the development of type 1 diabetes (2). Of the ∼15 regions identified, idd3 is of particular importance, because congenic NOD lines containing alleles from protected strains at this locus are significantly less susceptible to diabetes. To date, idd3 is the most potent disease modifying the non–major histocompatibility complex (MHC) locus (3). Therefore, some of the genes within the idd3 interval must play a crucial role in regulating immune destruction of pancreatic β-cells.Among the several candidate genes within the idd3 locus, interleukin (IL)-21 is of particular interest, because dysregulated IL-21 production and signaling has been found in the NOD mouse (4). IL-21 belongs to the type 1 cytokine family, which includes potent immune modulators such as IL-2, IL-4, IL-7, and IL-15, whose high-affinity receptor complexes all use the common γc receptor subunit (5,6). The specificity of IL-21 signaling is achieved through its specific interaction with the IL-21 receptor subunit, which forms a heterodimer with the γc subunit (7). This receptor complex delivers IL-21 signals to a variety of immune cells including CD4⁺ and CD8⁺ T-cells, B-cells, NK cells, NKT cells, and dendritic cells (8–13), all of which can play some role in the pathogenesis of type 1 diabetes in the NOD mouse (14–20). Therefore, the aim of our present study was to better understand the role of IL-21 in type 1 diabetes. We demonstrate that loss of IL-21 signaling, via knockout of the IL-21 receptor, completely abrogates diabetes development on the NOD background. In addition, we demonstrate that overexpression of IL-21 in pancreatic β-cells induces a high incidence of spontaneous type 1 diabetes on the normally diabetes-resistant C57Bl/6 genetic background. Together, these findings clearly underline the potent prodiabetogenic activity of IL-21.