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OBJECTIVE Mortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased [...]

OBJECTIVE--It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the HFE genotype. [...]

OBJECTIVE--Metabolic activation of the innate immune system governed by interleukin (IL)-1β contributes to β-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1β antibody. We evaluated the [...]

Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F[(ab').sub.2] fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-lβ mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-IRA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-[V7.sup.+] T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation. Diabetes 61:145-154, 2012, Immunologics can reverse diabetes in the NOD model of type 1 diabetes (TID), and they have shown efficacy in clinical trials (1-4). However, there is a substantial variability in the [...]

OBJECTIVE--Interleukin (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 [...]

OBJECTIVE--Proinfiammatory cytokines are cytotoxic to β-cells and have been implicated in the pathogenesis of type 1 diabetes and islet graft failure. The importance of the intrinsic mitochondrial apoptotic pathway in cytoldne-induced B-cell death is unclear. Here, cytokine activation of the intrinsic apoptotic pathway and the role of the two proapoptotic Bcl-2 proteins, Bad and Bax, were examined in β-cells. RESEARCH DESIGN AND METHODS--Human and rat islets and INS-1 cells were exposed to a combination of proinflammatory cytokines (interleukin-lβ, interferon-γ and/or tumor necrosis factor-α). Activation of Bad was determined by Ser136 dephosphorylation, mitochondrial stress by changes in mitochondrial metabolic activity and cytochrome c release, downstream apoptotic signaling by activation of caspase-9 and -3, and DNA fragmentation. The inhibitors FK506 and V5 were used to investigate the role of Bad and Bax activation, respectively. RESULTS--We found that proinflammatory cytokines induced calcineurin-dependent dephosphorylation of Bad Ser136, mitochondrial stress, cytochrome c release, activation of caspase-9 and -3, and DNA fragmentation. Inhibition of Bad Ser136 dephosphorylation or Bax was found to inhibit cytokine-induced intrinsic proapoptotic signaling. CONCLUSIONS--Our findings demonstrate that the intrinsic mitochondrial apoptotic pathway contributes significantly to cytokine-induced β-cell death and suggest a functional role of calcineurin-mediated Bad Ser136 dephosphorylation and Bax activity in cytokine-induced apoptosis. Diabetes 58: 1807-1815, 2009, Proinflammatory cytokines, particularly interleukin (IL)-1β in combination with interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α, have been implicated in the elimination of β-cells in type 1 diabetes (1). However, the [...]

OBJECTIVE--β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). [...]

The pathogenesis of type 1 diabetes is not clearly understood, but it is generally accepted that type 1 diabetes is an immune-mediated disease caused by inflammation in the islets of [...]

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)-1[beta], 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-6[alpha] 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., Since ancient Greece, differences in lethality and distinct clinical features have led physicians to discern between two main diabetic phenotypes. But it has only been since 1974 that what we [...]

The pubertal peak in onset of type 1 diabetes occurs earlier in girls than boys. We postulated that this sex difference might be mediated in part by estrogen or by genes regulated by estrogen, such as the interleukin-6 (IL6) gene. Previous studies concerning the role of an estrogen-sensitive single nucleotide polymorphism (SNP) in the IL6 promoter in type 1 diabetes have proved contradictory. We therefore selected a large, genetically homogenous population-based cohort, analyzed by age at onset and sex, to test the hypothesis that the IL6-174G>C SNP affects age at onset of type 1 diabetes in females but not in males. We found that the IL6-174CC genotype was significantly less frequent in females diagnosed after than in those diagnosed before the age of 10 years (19 vs. 13%, P = 0.016). No genotype difference was observed in males stratified for age at onset. Among children diagnosed after age 10, the median age of onset was 11.9 years (intraquartile range 10.7-14.6) in 34 girls homozygous for IL6-174C compared with 13.2 years (11.6-15.4) in 229 girls with other genotypes and 13.5 years (12.0-15.6) in 339 males with any IL6-174 genotype (P = 0.012). These data support the hypothesis that pubertal changes may contribute to accelerated onset of type 1 diabetes in genetically susceptible females. This phenomenon may be orchestrated by the action of estrogen on the IL6 promoter., The peak age at onset of type 1 diabetes occurs between the ages of 8 and 14 years in females but not until ~2 years later in males (1). This [...]

OBJECTIVE--To evaluate the perinatal outcome and the frequency of maternal complications in pregnancies of women with type 2 diabetes during 1996-2001. RESEARCH DESIGN AND METHODS--Medical records of 61 consecutive singleton [...]

Cytokines and free radicals are mediators of β-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1β (IL-1β) + γ-interferon (IFN-γ) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic β-cells. We have previously shown, by microarray analysis of primary β-cells, that IL-1β + IFN-γ decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump [Ca.sup.2+] ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress-related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). In the present study we show that cytokine-induced apoptosis and necrosis in primary rat β-cells and INS-1E cells largely depends on NO production. IL-1β + IFN-γ via NO synthesis, markedly decreased SERCA2b protein expression and depleted ER [Ca.sup.2+] stores. Of note, β-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER [Ca.sup.2+] depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α) and PRK (RNA-dependent protein kinase)-like ER kinase (PERK)/activating transcription factor 4 (ATF4), but not ATF6. In contrast, the ER stress-inducing agent thapsigargin triggered these four pathways in parallel. In conclusion, our results suggest that the IL-1β + IFN-γ-induced decrease in SERCA2b expression, with subsequent depletion of ER [Ca.sup.2+] and activation of the ER stress pathway, is a potential contributory mechanism to β-cell death., The endoplasmic reticulum (ER) is a highly dynamic organelle, responsible for modification and sorting of newly synthesized proteins and [Ca.sup.2+] storage and signaling (1). The resting free [Ca.sup.2+] concentration in [...]

Increasing evidence indicates that a progressive decrease in the functional [beta]-cell mass is the hallmark of both type 1 and type 2 diabetes. The underlying causes, [beta]-cell apoptosis and impaired secretory function, seem to be partly mediated by macrophage production of interleukin (IL)-1[beta] and/or high-glucose-induced p-cell production of IL-1[beta] Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion. Therefore, we studied the effect of diazoxide and of the novel potassium channel opener NN414, selective for the [beta]-cell potassium channel SUR1/Kir6.2, on glucose- and IL-1[beta]-induced apoptosis and impaired function in human [beta]-cells. Exposure of human islets for 4 days to 11.1 and 33.3 mmol/l glucose, 2 ng/ml IL-1[beta], or 10 and 100 [micro]mol/l of the sulfonylurea tolbutamide induced [beta]-cell apoptosis and impaired glucose-stimulated insulin secretion. The deleterious effects of glucose and IL-1[beta] were blocked by 200 [micro]mol/l diazoxide as well as by 3 and 30 [micro]mol/l NN414. By Western blotting with phosphospecific antibodies, glucose and IL-1[beta] were shown to activate the extracellular signal-regulated kinase (ERK) 1/2, an effect that was abrogated by 3 [micro]mol/l NN414. Similarly, 1 [micro]mol/l of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor PD098059 or 1 [micro]mol/l of the L-type [Ca.sup.2+] channel blocker nimodipine prevented glucose- and IL-1[beta]-induced ERK activation, [beta]-cell apoptosis, and impaired function. Finally, islet release of IL-1[beta] in response to high glucose could be abrogated by nimodipine, NN414, or PD098059. Thus, in human islets, glucose- and IL-1[beta]-induced [beta]-cell secretory dysfunction and apoptosis are [Ca.sup.2+] influx and ERK dependent and can be prevented by the [beta]-cell selective potassium channel opener NN414., There is now general agreement that both impaired [beta]-cell function and decreased [beta]-cell mass contribute to the insulin deficiency observed in patients with type 2 diabetes (1-11). Therefore, in the [...]

OBJECTIVE -- The use of cyclosporin in recent-onset type 1 diabetes has demonstrated the potential for immune intervention in the treatment and prevention of the disease. However, a proportion of [...]

Proinflammatory cytokines are implicated as effector molecules in the pathogenesis of IDDM. Interleukin-6 (IL-6) alone or in combination with IL-1Β inhibits glucose-stimulated insulin release from isolated rat pancreatic islets by [...]

In type 1 diabetes, an immune-mediated process leads to the destruction of pancreatic Β-cells. In the last decade, considerable progress has been made in understanding the cellular and biochemical pathogenic [...]

The aim of this study was to investigate whether strain-dependent differences in β-cell sensitivity to interleukin (IL) 1β exist in vitro and in vivo and if so, whether these differences [...]

An inducible nitric oxide (NO) synthase isoform (iNOS) is specifically induced in the β-cells of interleukin (IL)-1β-exposed rat islets, suggesting a role for NO in the pathogenesis of type I [...]

Interleukin (IL)-1β-mediated damage to β-cells in isolated islets of Langerhans depends upon de novo synthesis of proteins that have not been fully identified. Further, IL-1β-induced and tumor necrosis factor α-induced [...]

We have investigated whether glutamic acid decarboxylase (GAD) autoantibodies ([GAD.sub.65] Ab) were affected by cyclosporin therapy and were related to subsequent non-insulin-requiring remission and loss of glucagon-stimulated C-peptide response in [...]

Interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 [...]

Nicotinamide (NA) prevents macrophage- and interleukin-1 (IL-1)-mediated β-cell damage in vitro as well as diabetes development in animal models of insulin-dependent diabetes mellitus (IDDM). IL-1β-mediated inhibition of insulin release and [...]

OBJECTIVE--We tested the hypothesis that elevated transferrin saturation is associated with an increased risk of any form of diabetes, as well as type 1 or type 2 diabetes separately. RESEARCH [...]

Cytokines are protein mediators of intercellular stress communication with autocrine, paracrine, and endocrine modes of action. Hormones differ from cytokines by being produced in specialized glandular organs, by not all [...]

There is growing evidence that insulin-dependent diabetes mellitus (IDDM) is caused by an immunemediated destruction of the pancreatic Β-cells [1,2]. Recent studies of immunosuppression with cyclosporin in patients and experimental [...]

[CD4.sup.+] T-cells play a central role in IDDM pathogenesis (1). Hence, gene polymorphisms that modulate the [CD4.sup.+] T-cell response to antigen presentation may confer susceptibility to IDDM. The CD4 receptor [...]

Pancreatic Β-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 [...]

Interleukin-1[Beta] (IL-1[Beta]) treatment of neonatal rat islets for 24 h induces changes in the expression of 105 of 2,200 proteins, as determined previously by two-dimensional (2D) gel electrophoresis. Nitric oxide [...]

To characterize the differentiation events that selectively target insulin-producing cells to interleukin (IL)1Β--induced apoptosis, we studied IL-1Β signaling via mitogen-activated protein kinase (MAPK) and stress-activated protein kinase in 2 pancreatic [...]

Pancreatic [Beta]-cells are more sensitive to several toxins (e.g., streptozotocin, alloxan, cytokines) than the other three endocrine cell types in the islets of Langerhans. Cytokine-induced free radicals in [Beta]-cells may [...]

Interaction of Β-Cell Activity and IL-1 Concentration and Exposure Time in Isolated Rat Islets of Langerhans This study was designed to test the hypothesis that target-cell activity influences the degree [...]

The cytokines interleukin (IL)-I and interferon (IFN)-[gamma] are believed to be mediators of immune-mediated [beta]-cell destruction in type 1 diabetes. Inhibition of the nuclear factor (NF)-[kappa]B and mitogen-activated protein kinase (MAPK) pathways protects [beta]-cells against cytokine-induced apoptosis, partly because of inhibition of inducible nitric oxide synthase expression and nitric oxide (NO) generation. We have previously shown that suppressor of cytokine signaling (SOCS)-3 prevents cytokine-induced NO production and apoptosis in a [beta]-cell line. The aim of this study was to investigate by microarray the gene pattern induced by IL-1 and its suppression by SOCS-3 in a [beta]-cell line. Furthermore, we also investigated whether SOCS-3 inhibits the NF-[kappa]B and MAPK pathways, NO production, and apoptosis induction in primary rat [beta]-cells. By microarray analysis (Affymetrix U34A Array), we found that IL-1 stimulation (150 pg/ml, 6 h) upregulated 23 annotated genes, 15 of which were inhibited by SOCS-3. Interestingly, of these 15 genes, 9 have previously been reported to be NF-[kappa]B dependent. Using an adenovirus expression approach, we found by Western blotting that SOCS-3 inhibited I[kappa]B degradation and MAPK activation in dispersed rat islets cultures exposed to IL-1 (250 pg/ml, 15 min). In addition, both NO production and apoptosis induction by IL-1 + IFN-[gamma] (250 and 10 ng/ml, 24 h) were suppressed 50% by SOCS-3. In conclusion, we show that expression of SOCS-3 inhibits NF-[kappa]B-dependent gene transcription in a [beta]-cell line and inhibits I[kappa]B degradation and MAPK activation in primary rat [beta]-cells. These findings elucidate the signaling pathways involved in the mechanism by which SOCS-3 reduces cytokine-induced toxicity in [beta]-cells., Peter E. Heding, (1) Sif Groth Ronn, (1) Mogens Kruhoffer, (2) Torben Falck Orntoft, (2) Helle Frobose, (1) Allan Ertman Karlsen, (1) Jorn Nerup, (1) Thomas Mandrup-Poulsen, (1) Nils Billestrup [...]

By the induction of apoptosis in pancreatic [beta]-cells, interleukin (IL)-1[beta] is believed to be an important mediator of the [beta]-cell destruction leading to type 1 diabetes. The apoptotic effect of IL-1[beta] is primarily mediated by Jun N[H.sub.2]-terminal kinase (JNK), because inhibition of JNK activity completely blocks IL-1[beta]-induced [beta]-cell apoptosis. The growth arrest and DNA damage-inducible gene (gadd45[beta]) has been reported to inhibit JNK activation via inhibition of the upstream kinase MKK7. The aim was to investigate gadd45[beta] regulation by IL-1[beta] in [beta]-cells and non-[beta]-cells and to evaluate the involvement of gaddA5[beta] in [beta]-cell JNK signaling. The methods used were quantitative RT-PCR on RNA isolated from cells exposed to cytokines and Western blotting. IL-1[beta] caused a minor induction of gadd45[beta] mRNA in two [beta]-cell lines (INS-1E and [beta]TC3) compared with IL-1[beta]-exposed NIH-3T3 fibroblasts (11- and 4-fold vs. 120-fold, respectively), indicating insufficient gadd45[beta] induction by IL-1[beta] in [beta]-cells. As a preliminary evaluation of gadd45[beta] involvement in [beta]-cell JNK signaling, pools of overexpressing INS-1E and [beta]TC3 cells (transfection efficiency ~50%) were exposed to IL-1[beta]. gadd45[beta] overexpression reduced 1L-1[beta]-induced JNK activation by 42 and 63% in INS-1E and [beta]TC3 cells, respectively. This identifies gadd45[beta] as a [beta]-cell JNK inhibitor, and the impact of this inhibition on cytokine-induced [beta]-cell apoptosis will be further investigated., Claus M. Larsen, (1) Guido Franzoso, (2) Nils Billestrup, (1) Thomas Mandrup-Poulsen (1,3) From the (1) Steno Diabetes Center, Gentofte, Denmark; the (2) University of Chicago, Chicago, Illinois; and the [...]