Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

[1]  T. Mandrup-Poulsen,et al.  The role of interleukin-1 in the pathogenesis of IDDM , 1996, Diabetologia.

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

[3]  S. Grundy,et al.  Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes , 1985, Diabetologia.

[4]  S. Xiao,et al.  Apoptosis-inducing Membrane Vesicles , 2001, The Journal of Biological Chemistry.

[5]  D. Eizirik,et al.  Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. , 2001, Diabetes.

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

[7]  D. Eizirik,et al.  Cytokine induction of Fas gene expression in insulin-producing cells requires the transcription factors NF-kappaB and C/EBP. , 2001, Diabetes.

[8]  T. Wilkin The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes , 2001, Diabetologia.

[9]  G. Melino,et al.  High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. , 2001, Diabetes.

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

[11]  C. Mathieu,et al.  Monocyte chemoattractant protein-1 is expressed in pancreatic islets from prediabetic NOD mice and in interleukin-1β-exposed human and rat islet cells , 2001, Diabetologia.

[12]  D. Eizirik,et al.  beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes. , 2001, Diabetes.

[13]  C Benoist,et al.  beta-Cell death during progression to diabetes. , 2001, Nature.

[14]  K. Maedler,et al.  Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. , 2001, Diabetes.

[15]  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.

[16]  Dongbo Liu,et al.  Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-). , 2000, Diabetes.

[17]  P. Morel,et al.  Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. , 2000, Transplantation.

[18]  P. Robbins,et al.  Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. , 2000, The Journal of biological chemistry.

[19]  G. Holländer,et al.  Nitric oxide production and Fas surface expression mediate two independent pathways of cytokine-induced murine beta-cell damage. , 2000, Diabetes.

[20]  D. Finegood,et al.  Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes? , 2000, Diabetes.

[21]  L. Kuller,et al.  Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. , 2000, Diabetes.

[22]  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.

[23]  F. Bertuzzi,et al.  Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose. , 1999, Diabetes.

[24]  E. Cerasi,et al.  Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. , 1999, Diabetes.

[25]  M. Karin How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex. , 1999, Oncogene.

[26]  B. Zhivotovsky,et al.  Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. , 1998, The Journal of biological chemistry.

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

[28]  J. Corbett,et al.  Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. , 1998, Journal of immunology.

[29]  J. Davoust,et al.  Processing of engulfed apoptotic bodies yields T cell epitopes. , 1997, Journal of immunology.

[30]  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.

[31]  C. Ricordi,et al.  Improved Human Islet Isolation Using a New Enzyme Blend, Liberase , 1997, Diabetes.

[32]  C. Möller,et al.  Long-term effects of aminoguanidine on insulin release and biosynthesis: evidence that the formation of advanced glycosylation end products inhibits B cell function. , 1997, Endocrinology.

[33]  K. Yamada,et al.  Mouse islet cell lysis mediated by interleukin-1-induced Fas , 1996, Diabetologia.

[34]  N. Welsh,et al.  Cytokines activate the nuclear factor kappa B (NF-kappa B) and induce nitric oxide production in human pancreatic islets. , 1996, FEBS letters.

[35]  M. Mcdaniel,et al.  Interleukin-1 beta-induced nitric oxide synthase expression by rat pancreatic beta-cells: evidence for the involvement of nuclear factor kappa B in the signaling mechanism. , 1995, Endocrinology.

[36]  L. Olson,et al.  Differentiating Glucose Toxicity From Glucose Desensitization: A New Message From the Insulin Gene , 1994, Diabetes.

[37]  E. Cerasi,et al.  Hyperproinsulinemia and insulin deficiency in the diabetic Psammomys obesus. , 1994, Endocrinology.

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

[39]  N. Blau,et al.  Nitric oxide synthase is not a constituent of the antimicrobial armature of human mononuclear phagocytes. , 1993, The Journal of infectious diseases.

[40]  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.

[41]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[42]  G. Korbutt,et al.  Prolonged exposure of human pancreatic islets to high glucose concentrations in vitro impairs the beta-cell function. , 1992, The Journal of clinical investigation.

[43]  R. Robertson,et al.  Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. , 1992, The Journal of clinical investigation.

[44]  M. Rowley,et al.  Antibodies to Glutamic Acid Decarboxylase Discriminate Major Types of Diabetes Mellitus , 1992, Diabetes.

[45]  M. Mcdaniel,et al.  Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin-1 beta-induced inhibition of insulin secretion. , 1991, The Journal of biological chemistry.

[46]  E. Cerasi,et al.  Monolayer culture of adult rat pancreatic islets on extracellular matrix: modulation of B-cell function by chronic exposure to high glucose. , 1991, Endocrinology.

[47]  P. Lacy,et al.  Activation of intraislet lymphoid cells causes destruction of islet cells. , 1991, The American journal of pathology.

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

[49]  R. DeFronzo,et al.  Glucose Toxicity , 1990, Diabetes Care.

[50]  R. Robertson Type II Diabetes, Glucose “Non-Sense,” and Islet Desensitization , 1989, Diabetes.

[51]  Camillo Ricordi,et al.  Automated Method for Isolation of Human Pancreatic Islets , 1988, Diabetes.

[52]  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.

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

[54]  J. Leahy,et al.  Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions. , 1986, The Journal of clinical investigation.

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