Interleukin-1 beta targeted therapy for type 2 diabetes

Since having been cloned in 1984, IL-1β has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1β is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases and type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure and type 2 diabetes. Macrophage are the primary source of IL-1, but epidermal, epithelial, lymphoid and vascular tissues also synthesize IL-1. IL-1β production and secretion have also been reported from pancreatic islets. Insulin-producing β-cells within pancreatic islets are specifically prone to IL-β-induced destruction and loss of function. Macrophage-derived IL-1β production in insulin-sensitive organs, leads to progression of inflammation and induction of insulin resistance in obesity. We summarize the mechanisms involved in inflammation and specifically the IL-1β signals that lead to the progression of insulin resistance and diabetes. We highlight recent clinical studies and experiments in animals and isolated islets using IL-1β as a potential target for the therapy of type 2 diabetes.

[1]  K. Maedler,et al.  XOMA 052, an anti-IL-1{beta} monoclonal antibody, improves glucose control and {beta}-cell function in the diet-induced obesity mouse model. , 2010, Endocrinology.

[2]  T. Mandrup-Poulsen,et al.  The anti‐interleukin‐1 in type 1 diabetes action trial—background and rationale , 2009, Diabetes/metabolism research and reviews.

[3]  K. Maedler,et al.  Purinergic P2X7 receptors regulate secretion of interleukin-1 receptor antagonist and beta cell function and survival , 2009, Diabetologia.

[4]  C. Dinarello,et al.  Immunological and inflammatory functions of the interleukin-1 family. , 2009, Annual review of immunology.

[5]  Eric J. Brunner,et al.  Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes , 2009, Diabetes Care.

[6]  J. Carvalheira,et al.  Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity , 2009, The Journal of Neuroscience.

[7]  D. R. Laybutt,et al.  Cytokine-Induced β-Cell Death Is Independent of Endoplasmic Reticulum Stress Signaling , 2008, Diabetes.

[8]  Philip A Kern,et al.  Adipocytokines and the metabolic complications of obesity. , 2008, The Journal of clinical endocrinology and metabolism.

[9]  P. Halban,et al.  Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. , 2008, The Journal of clinical endocrinology and metabolism.

[10]  S. Brownell,et al.  Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. , 2008, Cytokine.

[11]  Byung-Hyun Park,et al.  Making insulin-deficient type 1 diabetic rodents thrive without insulin , 2008, Proceedings of the National Academy of Sciences.

[12]  J. Olefsky,et al.  Insulin sensitivity: modulation by nutrients and inflammation. , 2008, The Journal of clinical investigation.

[13]  S. G. Rønn,et al.  Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection , 2008, Diabetologia.

[14]  J. Myers,et al.  The MAPK kinase kinase-1 is essential for stress-induced pancreatic islet cell death. , 2008, Endocrinology.

[15]  L. Castellani,et al.  The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. , 2008, Endocrinology.

[16]  N. Kaiser,et al.  Impaired Glucose-Stimulated Insulin Secretion Is Coupled With Exocrine Pancreatic Lesions in the Cohen Diabetic Rat , 2008, Diabetes.

[17]  P. Butler,et al.  Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. , 2008, Endocrine reviews.

[18]  J. Olefsky,et al.  Inflammation and insulin resistance , 2008, FEBS letters.

[19]  M. Karin,et al.  JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. , 2007, Cell metabolism.

[20]  S. Volpato,et al.  Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. , 2007, Journal of psychiatric research.

[21]  L. Salmena,et al.  Distinct In Vivo Roles of Caspase-8 in β-Cells in Physiological and Diabetes Models , 2007, Diabetes.

[22]  H. Ellingsgaard,et al.  Increased Number of Islet-Associated Macrophages in Type 2 Diabetes , 2007, Diabetes.

[23]  S. Malozowski,et al.  Interleukin-1-receptor antagonist in type 2 diabetes mellitus. , 2007, The New England journal of medicine.

[24]  J. Beckmann,et al.  The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis , 2007, Diabetologia.

[25]  G. Forloni,et al.  JNK signalling: a possible target to prevent neurodegeneration. , 2007, Current pharmaceutical design.

[26]  M. Taniguchi,et al.  Successful Islet Transplantation to Two Recipients From a Single Donor by Targeting Proinflammatory Cytokines in Mice , 2007, Transplantation.

[27]  M. Kurrer,et al.  The Fas pathway is involved in pancreatic β cell secretory function , 2007, Proceedings of the National Academy of Sciences.

[28]  M. Karin,et al.  NF-κB prevents β cell death and autoimmune diabetes in NOD mice , 2007, Proceedings of the National Academy of Sciences.

[29]  S. G. Rønn,et al.  Diabetes and Suppressors of Cytokine Signaling Proteins , 2007, Diabetes.

[30]  E. Montanya,et al.  Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome , 2007, Diabetologia.

[31]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[32]  L. Chambless,et al.  Increased Concentrations of C-Reactive Protein and IL-6 but not IL-18 Are Independently Associated With Incident Coronary Events in Middle-Aged Men and Women: Results From the MONICA/KORA Augsburg Case–Cohort Study, 1984–2002 , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[33]  H. Ellingsgaard,et al.  Low Concentration of Interleukin-1β Induces FLICE-Inhibitory Protein–Mediated β-Cell Proliferation in Human Pancreatic Islets , 2006, Diabetes.

[34]  Herbert Tilg,et al.  Adipocytokines: mediators linking adipose tissue, inflammation and immunity , 2006, Nature Reviews Immunology.

[35]  S. Lenzen,et al.  Beta cell death in hyperglycaemic Psammomys obesus is not cytokine-mediated , 2006, Diabetologia.

[36]  S. Grey,et al.  Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection. , 2006, Diabetes.

[37]  F. Ortis,et al.  Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. , 2006, Molecular endocrinology.

[38]  B. Neel,et al.  Neuronal PTP1B regulates body weight, adiposity and leptin action , 2006, Nature Medicine.

[39]  P. Cohen,et al.  Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. , 2006, Molecular endocrinology.

[40]  M. Dolz,et al.  Islet Inflammation and Fibrosis in a Spontaneous Model of Type 2 Diabetes, the GK Rat , 2006, Diabetes.

[41]  C. Kahn,et al.  Critical nodes in signalling pathways: insights into insulin action , 2006, Nature Reviews Molecular Cell Biology.

[42]  W. Kiess,et al.  Adipocytokines: leptin--the classical, resistin--the controversical, adiponectin--the promising, and more to come. , 2005, Best practice & research. Clinical endocrinology & metabolism.

[43]  H. Ellingsgaard,et al.  Mechanisms of β-Cell Death in Type 2 Diabetes , 2005 .

[44]  Nils Welsh,et al.  Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. , 2005, Diabetes.

[45]  M. Bugliani,et al.  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? , 2005, Diabetes.

[46]  L. Velloso,et al.  Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. , 2005, Endocrinology.

[47]  R. Lehmann,et al.  Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt , 2005, Diabetologia.

[48]  N. Rothwell,et al.  Interleukin-1 and neuronal injury , 2005, Nature Reviews Immunology.

[49]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[50]  F. Ortis,et al.  Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. , 2005, Diabetes.

[51]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[52]  C. Brosnan,et al.  The cytokine IL‐1β transiently enhances P2X7 receptor expression and function in human astrocytes , 2005, Glia.

[53]  Esko Vanninen,et al.  Multiple Abnormalities in Glucose and Energy Metabolism and Coordinated Changes in Levels of Adiponectin, Cytokines, and Adhesion Molecules in Subjects With Metabolic Syndrome , 2004, Circulation.

[54]  E. Van Obberghen,et al.  The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. , 2004, Diabetes.

[55]  H. Münzberg,et al.  Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. , 2004, Endocrinology.

[56]  D. Maysinger,et al.  Cross-talk between phosphatidylinositol 3-kinase/AKT and c-jun NH2-terminal kinase mediates survival of isolated human islets. , 2004, Endocrinology.

[57]  P. Halban,et al.  Pioglitazone and sodium salicylate protect human β-cells against apoptosis and impaired function induced by glucose and interleukin-1β , 2004 .

[58]  P. Halban,et al.  Extracellular matrix protects pancreatic beta-cells against apoptosis: role of short- and long-term signaling pathways. , 2004, Diabetes.

[59]  D. Crossman,et al.  Secretion of Intracellular IL-1 Receptor Antagonist (Type 1) Is Dependent on P2X7 Receptor Activation1 , 2004, The Journal of Immunology.

[60]  J. Flier,et al.  Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3 , 2004, Nature Medicine.

[61]  M. Carty,et al.  Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. , 2004, Diabetes.

[62]  P. Halban,et al.  Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[63]  C. Stansberg,et al.  The interleukin 1 receptor family. , 2004, Developmental and comparative immunology.

[64]  S. Bandinelli,et al.  Diverse Effect of Inflammatory Markers on Insulin Resistance and Insulin‐Resistance Syndrome in the Elderly , 2004, Journal of the American Geriatrics Society.

[65]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[66]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[67]  K. Iverfeldt,et al.  The role of endogenous interleukin-1 in stress-induced adrenal activation and adrenalectomy-induced adrenocorticotropic hormone hypersecretion. , 2003, Endocrinology.

[68]  I. Goshen,et al.  Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic, pharmacological and developmental aspects , 2003, Pain.

[69]  Kathrin Maedler,et al.  Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes , 2003, Journal of Molecular Medicine.

[70]  P. Heinke,et al.  Prevention of autoimmune diabetes in NOD mice by troglitazone is associated with modulation of ICAM-1 expression on pancreatic islet cells and IFN-gamma expression in splenic T cells. , 2003, Biochemical and biophysical research communications.

[71]  V. Giusti,et al.  Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. , 2003, Diabetes.

[72]  Z. Bloomgarden,et al.  Inflammation and insulin resistance. , 2003, Diabetes care.

[73]  O. Wagner,et al.  Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes. , 2002, Diabetes.

[74]  M. White,et al.  SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2* , 2002, The Journal of Biological Chemistry.

[75]  E. Araki,et al.  Endoplasmic reticulum stress-mediated apoptosis in pancreatic β-cells , 2002, Apoptosis.

[76]  C. Mathieu,et al.  Interleukin-1 receptor antagonist inhibits primary non-function and prolongs graft survival time of xenogeneic islets transplanted in spontaneously diabetic autoimmune NOD mice , 2002 .

[77]  R. Robertson,et al.  Inhibition of Interleukin-1β-Induced COX-2 and EP3 Gene Expression by Sodium Salicylate Enhances Pancreatic Islet β-Cell Function , 2002 .

[78]  A. Golay,et al.  IL-1 receptor antagonist serum levels are increased in human obesity: a possible link to the resistance to leptin? , 2002, The Journal of clinical endocrinology and metabolism.

[79]  L. Carpenter,et al.  Inhibition of Protein Kinase C δ Protects Rat INS-1 Cells Against Interleukin-1β and Streptozotocin-Induced Apoptosis , 2002 .

[80]  F. Pociot,et al.  Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-γ-mediated toxicity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[81]  M. Donath,et al.  Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. , 2001, Diabetes.

[82]  John C. Lee,et al.  Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis. , 2001, Biochemical pharmacology.

[83]  J. Corbett,et al.  Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1 , 2001, The Journal of Biological Chemistry.

[84]  C. Gabay,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Leptin Directly Induces the Secretion of Interleukin 1 Receptor Antagonist in Human Monocytes* , 2022 .

[85]  N. Sarvetnick,et al.  A Mechanism for IL-10-Mediated Diabetes in the Nonobese Diabetic (NOD) Mouse: ICAM-1 Deficiency Blocks Accelerated Diabetes1 2 , 2000, The Journal of Immunology.

[86]  N. Rothwell,et al.  Interleukin 1 in the brain: biology, pathology and therapeutic target , 2000, Trends in Neurosciences.

[87]  M. Trucco,et al.  Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I , 2000, Gene Therapy.

[88]  L. Carpenter,et al.  Protein Kinase Cδ Activation by Interleukin-1β Stabilizes Inducible Nitric-oxide Synthase mRNA in Pancreatic β-Cells* , 2000, The Journal of Biological Chemistry.

[89]  W. Arend,et al.  Biological role of interleukin 1 receptor antagonist isoforms , 2000, Annals of the rheumatic diseases.

[90]  C. Dinarello.  The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1. , 2000, The New England journal of medicine.

[91]  D. Eizirik,et al.  Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. , 2000, European cytokine network.

[92]  N. Morgan,et al.  Dissociation between Fas expression and induction of apoptosis in human islets of Langerhans , 2000, Diabetes, obesity & metabolism.

[93]  N. Rothwell,et al.  Potential mechanisms of interleukin-1 involvement in cerebral ischaemia , 1999, Journal of Neuroimmunology.

[94]  P. Robbins,et al.  Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro. , 1999, Diabetes.

[95]  C. Ricordi,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1999 by The Endocrine Society Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Me , 2022 .

[96]  J. Corbett,et al.  IL-1 produced and released endogenously within human islets inhibits beta cell function. , 1998, The Journal of clinical investigation.

[97]  Detlef Balschun,et al.  A neuromodulatory role of interleukin-1β in the hippocampus , 1998 .

[98]  M. Su,et al.  Interleukin-1β-induced Rat Pancreatic Islet Nitric Oxide Synthesis Requires Both the p38 and Extracellular Signal-regulated Kinase 1/2 Mitogen-activated Protein Kinases* , 1998, The Journal of Biological Chemistry.

[99]  N. Morgan,et al.  Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1beta and Fas ligation. , 1998, Diabetes.

[100]  C. Ricordi,et al.  Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. , 1998, Diabetes.

[101]  M. Mcdaniel,et al.  Evidence for the presence of type I IL-1 receptors on β-cells of islets of Langerhans , 1997 .

[102]  G. Stassi,et al.  Nitric Oxide Primes Pancreatic β Cells for Fas-mediated Destruction in Insulin-dependent Diabetes Mellitus , 1997, The Journal of experimental medicine.

[103]  B. Thorens,et al.  Inhibition of glucose‐induced insulin secretion by long‐term preexposure of pancreatic islets to leptin , 1997, FEBS letters.

[104]  D. Eizirik,et al.  IL‐1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non‐obese diabetic (NOD) mice , 1997, Clinical and experimental immunology.

[105]  N. Welsh,et al.  Cytokines activate the nuclear factor κB (NF‐κB) and induce nitric oxide production in human pancreatic islets , 1996 .

[106]  K. Docherty,et al.  Glucose Stimulates the Activity of the Guanine Nucleotide-exchange Factor eIF-2B in Isolated Rat Islets of Langerhans (*) , 1996, The Journal of Biological Chemistry.

[107]  M. Todaro,et al.  Expression of apoptosis-inducing CD95 (Fas/Apo-1) on human beta-cells sorted by flow-cytometry and cultured in vitro. , 1995, Transplantation proceedings.

[108]  R. Holden,et al.  Interleukin-1β: A common cause of alzheimer's disease and diabetes mellitus , 1995 .

[109]  M. Dardenne,et al.  Localization and characterization of interleukin-1 receptors in the islets of Langerhans from control and nonobese diabetic mice. , 1995, Endocrinology.

[110]  S. Dower,et al.  Interleukin-1 receptors. , 1994, European cytokine network.

[111]  F. Nicoletti,et al.  Protection from experimental autoimmune diabetes in the non‐obese diabetic mouse with soluble interleukin‐1 receptor , 1994, European journal of immunology.

[112]  D. Eizirik,et al.  Interleukin-1 receptor antagonist prevents low dose streptozotocin induced diabetes in mice. , 1994, Biochemical and biophysical research communications.

[113]  M. Field,et al.  Effect of 15-Deoxyspergualin on Immediate Function and Long-Term Survival of Transplanted Islets in Murine Recipients of a Marginal Islet Mass , 1994, Diabetes.

[114]  P. Lacy.  The intraislet macrophage and type I diabetes. , 1994, The Mount Sinai journal of medicine, New York.

[115]  D. Eizirik,et al.  Treatment With an Interleukin-1 Receptor Antagonist Protein Prolongs Mouse Islet Allograft Survival , 1993, Diabetes.

[116]  F. Pociot,et al.  Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. , 1993, Cytokine.

[117]  M. Mcdaniel,et al.  Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[118]  S. Dower,et al.  Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. , 1992, Journal of immunology.

[119]  W. Fiers,et al.  Is amyloidogenesis during Alzheimer's disease due to an IL-1-/IL-6-mediated 'acute phase response' in the brain? , 1991, Immunology today.

[120]  D. Dunn,et al.  Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts , 1990, The Journal of experimental medicine.

[121]  G. Warnock,et al.  Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture. , 1990, The Journal of clinical endocrinology and metabolism.

[122]  H. W. Harris,et al.  Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[123]  D. Eizirik.  Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. , 1988, Acta endocrinologica.

[124]  J. Nerup,et al.  The bimodal effect of interleukin 1 on rat pancreatic beta-cells--stimulation followed by inhibition--depends upon dose, duration of exposure, and ambient glucose concentration. , 1988, Acta endocrinologica.

[125]  C. Dinarello,et al.  Biology of interleukin 1 , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[126]  A. Rabinovitch,et al.  Destruction of Rat Islet Cell Monolayers by Cytokines: Synergistic Interactions of Interferon-γ, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1 , 1988, Diabetes.

[127]  B. Mach,et al.  A urine inhibitor of interleukin 1 activity affects both interleukin 1 alpha and 1 beta but not tumor necrosis factor alpha. , 1987, Journal of immunology.

[128]  J. Lowenthal,et al.  A urine inhibitor of interleukin 1 activity that blocks ligand binding. , 1987, Journal of immunology.

[129]  J. Nerup,et al.  Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans , 1987, Diabetologia.

[130]  P. Libby,et al.  Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells , 1987, The Journal of experimental medicine.

[131]  J. Nerup,et al.  Low concentrations of interleukin-1 stimulate and high concentrations inhibit insulin release from isolated rat islets of Langerhans. , 1986, Acta endocrinologica.

[132]  J. Nerup,et al.  Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. , 1986, Science.

[133]  J. Nerup,et al.  Cytokines Cause Functional and Structural Damage to Isolated Islets of Langerhans , 1985, Allergy.

[134]  A. C. Webb,et al.  Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[135]  C. Dinarello,et al.  Molecular basis of fever in humans. , 1982, The American journal of medicine.

[136]  W. Rathmann,et al.  Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist ( IL-1 Ra ) precede the onset of type 2 diabetes ( Whitehall II Study ) , 2008 .

[137]  J. Nerup,et al.  Affinity-purified human Interleukin I is cytotoxic to isolated islets of Langerhans , 2006, Diabetologia.

[138]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[139]  E. Montanya,et al.  Adenoviral overexpression of interleukin-1 receptor antagonist protein increases β-cell replication in rat pancreatic islets , 2005, Gene Therapy.

[140]  A. Hevener,et al.  IKK-beta links inflammation to obesity-induced insulin resistance. , 2005, Nature medicine.

[141]  A. K. Cardozo,et al.  High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NFκB , 2005, Diabetologia.

[142]  H. Thomas,et al.  IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. , 2004, Diabetes.

[143]  A. Chervonsky,et al.  Caspase-1 is not required for type 1 diabetes in the NOD mouse. , 2004, Diabetes.

[144]  P. Halban,et al.  Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. , 2004, The Journal of clinical endocrinology and metabolism.

[145]  R. Robertson,et al.  Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function. , 2002, Diabetes.

[146]  D. Schorderet,et al.  Cell-Permeable Peptide Inhibitors of JNK: Novel Blockers of β-Cell Death , 2001 .

[147]  F. Pitossi,et al.  A neuromodulatory role of interleukin-1beta in the hippocampus. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[148]  N. Barshes,et al.  islet transplantation: implications for intrahepatic grafts , 2022 .

[149]  Nils Welsh,et al.  Interleukin-1 (cid:98) -induced Ceramide and Diacylglycerol Generation May Lead to Activation of the c-Jun NH 2 -terminal Kinase and the Transcription Factor ATF2 in the Insulin-producing Cell Line RINm5F* , 1996 .