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Barsanti C, Lenzarini F, Kusmic C. Diagnostic and prognostic utility of non-invasive imaging in diabetes management. World J Diabetes 2015; 6:792-806. [PMID: 26131322 PMCID: PMC4478576 DOI: 10.4239/wjd.v6.i6.792] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 12/23/2014] [Accepted: 04/14/2015] [Indexed: 02/05/2023] Open
Abstract
Medical imaging technologies are acquiring an increasing relevance to assist clinicians in diagnosis and to guide management and therapeutic treatment of patients, thanks to their non invasive and high resolution properties. Computed tomography, magnetic resonance imaging, and ultrasonography are the most used imaging modalities to provide detailed morphological reconstructions of tissues and organs. In addition, the use of contrast dyes or radionuclide-labeled tracers permits to get functional and quantitative information about tissue physiology and metabolism in normal and disease state. In recent years, the development of multimodal and hydrid imaging techniques is coming to be the new frontier of medical imaging for the possibility to overcome limitations of single modalities and to obtain physiological and pathophysiological measurements within an accurate anatomical framework. Moreover, the employment of molecular probes, such as ligands or antibodies, allows a selective in vivo targeting of biomolecules involved in specific cellular processes, so expanding the potentialities of imaging techniques for clinical and research applications. This review is aimed to give a survey of characteristics of main diagnostic non-invasive imaging techniques. Current clinical appliances and future perspectives of imaging in the diagnostic and prognostic assessment of diabetic complications affecting different organ systems will be particularly addressed.
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Calderari S, Irminger JC, Giroix MH, Ehses JA, Gangnerau MN, Coulaud J, Rickenbach K, Gauguier D, Halban P, Serradas P, Homo-Delarche F. Regenerating 1 and 3b gene expression in the pancreas of type 2 diabetic Goto-Kakizaki (GK) rats. PLoS One 2014; 9:e90045. [PMID: 24587207 PMCID: PMC3936001 DOI: 10.1371/journal.pone.0090045] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 01/27/2014] [Indexed: 02/06/2023] Open
Abstract
Regenerating (REG) proteins are associated with islet development, β-cell damage, diabetes and pancreatitis. Particularly, REG-1 and REG-3-beta are involved in cell growth/survival and/or inflammation and the Reg1 promoter contains interleukin-6 (IL-6)-responsive elements. We showed by transcriptome analysis that islets of Goto-Kakizaki (GK) rats, a model of spontaneous type 2 diabetes, overexpress Reg1, 3α, 3β and 3γ, vs Wistar islets. Goto-Kakizaki rat islets also exhibit increased cytokine/chemokine expression/release, particularly IL-6. Here we analyzed Reg1 and Reg3β expression and REG-1 immuno-localization in the GK rat pancreas in relationship with inflammation. Isolated pancreatic islets and acinar tissue from male adult Wistar and diabetic GK rats were used for quantitative RT-PCR analysis. REG-1 immunohistochemistry was performed on paraffin sections with a monoclonal anti-rat REG-1 antibody. Islet cytokine/chemokine release was measured after 48 h-culture. Islet macrophage-positive area was quantified on cryostat sections using anti-CD68 and major histocompatibility complex (MHC) class II antibodies. Pancreatic exocrine-to-endocrine Reg1 and Reg3β mRNA ratios were markedly increased in Wistar vs GK rats. Conversely, both genes were upregulated in isolated GK rat islets. These findings were unexpected, because Reg genes are expressed in the pancreatic acinar tissue. However, we observed REG-1 protein labeling in acinar peri-ductal tissue close to islets and around large, often disorganized, GK rat islets, which may retain acinar cells due to their irregular shape. These large islets also showed peri-islet macrophage infiltration and increased release of various cytokines/chemokines, particularly IL-6. Thus, IL-6 might potentially trigger acinar REG-1 expression and secretion in the vicinity of large diabetic GK rat islets. This increased acinar REG-1 expression might reflect an adaptive though unsuccessful response to deleterious microenvironment.
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MESH Headings
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Chemokines/blood
- Chemokines/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Gene Expression Regulation
- Islets of Langerhans/metabolism
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Lithostathine/genetics
- Lithostathine/metabolism
- Macrophages/metabolism
- Male
- Pancreatitis-Associated Proteins
- Rats
- Rats, Wistar
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Affiliation(s)
- Sophie Calderari
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Jean-Claude Irminger
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
| | - Marie-Hélène Giroix
- Equipe associée au Centre National de la Recherche Scientifique (CNRS) 4413-Unité de Biologie Fonctionnelle et Adaptative (BFA), Team 1 (Biologie et Pathologie du Pancréas Endocrine (B2PE)), Université Paris-Diderot Sorbonne-Paris-Cité, Paris, France
| | - Jan A. Ehses
- Department of Surgery, Faculty of Medicine, University of British Columbia and Child and Family Research Institute, Vancouver, BC, Canada
| | - Marie-Noëlle Gangnerau
- Equipe associée au Centre National de la Recherche Scientifique (CNRS) 4413-Unité de Biologie Fonctionnelle et Adaptative (BFA), Team 1 (Biologie et Pathologie du Pancréas Endocrine (B2PE)), Université Paris-Diderot Sorbonne-Paris-Cité, Paris, France
| | - Josiane Coulaud
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Katharina Rickenbach
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
| | - Dominique Gauguier
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Philippe Halban
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
| | - Patricia Serradas
- INSERM UMRS 872, Team 9, CRC, Université Pierre et Marie Curie, Paris 6, Paris, France
| | - Françoise Homo-Delarche
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS 872, Team 6, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie, Paris 6, Paris, France
- * E-mail:
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Portha B, Giroix MH, Tourrel-Cuzin C, Le-Stunff H, Movassat J. The GK rat: a prototype for the study of non-overweight type 2 diabetes. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2012; 933:125-59. [PMID: 22893405 DOI: 10.1007/978-1-62703-068-7_9] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of β-cell secretory dysfunction and/or decreased β-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustrate to what extent the Goto Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK abnormalities so far identified is proposed in this perspective, together with their time-course and interactions. A special focus is given toward the pathogenesis of defective β-cell number and function in the GK model. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (1) several susceptibility loci containing genes responsible for some diabetic traits; (2) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas and the major insulin target tissues; and (3) environmentally induced loss of β-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammation, and oxidative stress.
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Affiliation(s)
- Bernard Portha
- Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), Université Paris-Diderot, CNRS EAC 4413, Paris, France.
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Medarova Z, Greiner DL, Ifediba M, Dai G, Bolotin E, Castillo G, Bogdanov A, Kumar M, Moore A. Imaging the pancreatic vasculature in diabetes models. Diabetes Metab Res Rev 2011; 27:767-72. [PMID: 22069257 PMCID: PMC3721374 DOI: 10.1002/dmrr.1249] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Vascular parameters, such as vascular volume, flow, and permeability, are important disease biomarkers for both type 1 and type 2 diabetes. Therefore, it is essential to develop approaches to monitor the changes in pancreatic microvasculature non-invasively. METHODS Here, we describe the application of the long-circulating, paramagnetic T1 contrast agent, protected Graft Copolymer bearing covalently linked gadolinium diethylenetriaminepentaacetic acid residues and labelled with fluorescein (PGC-GdDTPA-F) for the non-invasive semi-quantitative evaluation of vascular changes in diabetic models using magnetic resonance imaging. RESULTS We observed a significantly higher accumulation of protected graft copolymer bearing covalently linked gadolinium diethylenetriaminepentaacetic acid residues and labelled with fluorescein in the pancreata of BBDR rats induced to develop diabetes, as compared to non-diabetic controls at 1 h post-injection. No differences were seen in the blood pool, kidney, or muscle, indicating that the effect is specific to the diabetic pancreas. Fluorescence microscopy revealed a marked increase in contrast agent availability in the pancreas with the development of the pathology. Similar changes were noted in the homozygous Leprdb mouse model of type 2 diabetes. This effect appeared to result both from the increase of vascular volume and permeability. CONCLUSIONS High-molecular weight paramagnetic blood volume contrast agents are valuable for the in vivo definition of pancreatic microvasculature dynamics by magnetic resonance imaging. The increase in vascular volume and permeability, associated with diabetic inflammation, can be monitored non-invasively and semi-quantitatively by magnetic resonance imaging in diabetic BBDR rats. This imaging strategy represents a valuable research tool for better understanding of the pathologic process.
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Affiliation(s)
- Zdravka Medarova
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Dale L. Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Marytheresa Ifediba
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Guangping Dai
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | | | | | - Alexei Bogdanov
- Departments of Radiology and Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Mohanraja Kumar
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
| | - Anna Moore
- Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
- Correspondence to: Anna Moore, Molecular Imaging Laboratory, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Bldg.75, 13th St., Charlestown, MA 02129, USA
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Portha B, Lacraz G, Chavey A, Figeac F, Fradet M, Tourrel-Cuzin C, Homo-Delarche F, Giroix MH, Bailbé D, Gangnerau MN, Movassat J. Islet structure and function in the GK rat. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 654:479-500. [PMID: 20217511 DOI: 10.1007/978-90-481-3271-3_21] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of beta-cell secretory dysfunction and/or decreased beta-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustrate to what extent the Goto-Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK islet abnormalities so far identified is proposed in this perspective. The pathogenesis of defective beta-cell number and function in the GK model is also discussed. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (i) several susceptibility loci containing genes responsible for some diabetic traits (distinct loci encoding impairment of beta-cell metabolism and insulin exocytosis, but no quantitative trait locus for decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas (decreased beta-cell neogenesis and proliferation) transmitted over generations; and (iii) loss of beta-cell differentiation related to chronic exposure to hyperglycaemia/hyperlipidaemia, islet inflammation, islet oxidative stress, islet fibrosis and perturbed islet vasculature.
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Affiliation(s)
- Bernard Portha
- Laboratoire B2PE, Unité BFA, Université Paris-Diderot et CNRS EAC4413, F - 75205 Paris Cedex13, France.
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Jonas JC, Bensellam M, Duprez J, Elouil H, Guiot Y, Pascal SMA. Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes Obes Metab 2009; 11 Suppl 4:65-81. [PMID: 19817790 DOI: 10.1111/j.1463-1326.2009.01112.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Pancreatic beta-cells exposed to high glucose concentrations display altered gene expression, function, survival and growth that may contribute to the slow deterioration of the functional beta-cell mass in type 2 diabetes. These glucotoxic alterations may result from various types of stress imposed by the hyperglycaemic environment, including oxidative stress, endoplasmic reticulum stress, cytokine-induced apoptosis and hypoxia. The glucose regulation of oxidative stress-response and integrated stress-response genes in cultured rat islets follows an asymmetric V-shaped profile parallel to that of beta-cell apoptosis, with a large increase at low glucose and a moderate increase at high vs. intermediate glucose concentrations. These observations suggest that both types of stress could play a role in the alteration of the functional beta-cell mass under states of prolonged hypoglycaemia and hyperglycaemia. In addition, beta-cell demise under glucotoxic conditions may also result from beta-cell hypoxia and, in vivo, from their exposure to inflammatory cytokines released locally by non-endocrine islet cells. A better understanding of the relative contribution of each type of stress to beta-cell glucotoxicity and of their pathophysiological cause in vivo may lead to new therapeutic strategies to prevent the slow deterioration of the functional beta-cell mass in glucose intolerant and type 2 diabetic patients.
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Affiliation(s)
- J C Jonas
- Université catholique de Louvain, Brussels, Belgium.
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Ehses JA, Ellingsgaard H, Böni-Schnetzler M, Donath MY. Pancreatic islet inflammation in type 2 diabetes: from alpha and beta cell compensation to dysfunction. Arch Physiol Biochem 2009; 115:240-7. [PMID: 19645635 DOI: 10.1080/13813450903025879] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Evidence in support of the concept of local pancreatic islet inflammation as a mechanism of beta cell failure in type 2 diabetes is accumulating. Observations in human islets from type 2 diabetic patients and rodent models of the disease indicate the increased presence of IL-1 driven cytokines and chemokines in pancreatic islets, concomitant with immune cell infiltration. Inflammation is the body's protective response to harmful stimuli and tissue damage. However, under chronic stress (e.g. metabolic stress in obesity and type 2 diabetes) the body's own defensive response may become deleterious to tissue function. Here, we summarize the current evidence that islet inflammation is a feature of type 2 diabetes, and discuss its role with respect to alpha and beta cell compensation and eventual beta cell failure.
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Affiliation(s)
- Jan A Ehses
- Division of Endocrinology, Diabetes and Nutrition, Center for Integrated Human Physiology, University Hospital of Zürich, 8091 Zürich, Switzerland.
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Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F. Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat. PLoS One 2009; 4:e6963. [PMID: 19742300 PMCID: PMC2737103 DOI: 10.1371/journal.pone.0006963] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2009] [Accepted: 08/03/2009] [Indexed: 02/07/2023] Open
Abstract
Background Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra). Methodology/Principal Findings Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia. Conclusions/Significance GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the β-cell microenvironment and contribute to progressive type 2 diabetic β-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent β-cell dysfunction in type 2 diabetes.
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Affiliation(s)
- Grégory Lacraz
- Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France
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Lacraz G, Figeac F, Movassat J, Kassis N, Coulaud J, Galinier A, Leloup C, Bailbé D, Homo-Delarche F, Portha B. Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses. PLoS One 2009; 4:e6500. [PMID: 19654863 PMCID: PMC2715861 DOI: 10.1371/journal.pone.0006500] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Accepted: 07/03/2009] [Indexed: 01/13/2023] Open
Abstract
Background Oxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic β-cells. Here, we have evaluated islet OS status and β-cell response to ROS using the GK/Par rat as a model of type 2 diabetes. Methodology/Principal Findings Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1) gene expression was analyzed by qRT-PCR; 2) insulin secretion rate was measured; 3) ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4) antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H2O2 or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels) of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment. Conclusions The GK/Par model illustrates the effectiveness of adaptive response to OS by β-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par β-cell secretory dysfunction.
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Affiliation(s)
- Grégory Lacraz
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Florence Figeac
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Jamileh Movassat
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Nadim Kassis
- Equipe HERGE, Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Josiane Coulaud
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Anne Galinier
- UMR 5241, CNRS and Université P. Sabatier, CHU Rangueil, Toulouse, France
| | - Corinne Leloup
- UMR 5241, CNRS and Université P. Sabatier, CHU Rangueil, Toulouse, France
| | - Danielle Bailbé
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Françoise Homo-Delarche
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
| | - Bernard Portha
- Equipe B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptative), Université Paris-Diderot et CNRS EAC7059, Paris, France
- * E-mail:
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IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci U S A 2009; 106:13998-4003. [PMID: 19666548 DOI: 10.1073/pnas.0810087106] [Citation(s) in RCA: 274] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1beta. In the periphery, increased expression of IL-1beta was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1beta or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1beta, IL-6, TNFalpha, KC, MCP-1, and MIP-1alpha) and islet CD68(+), MHC II(+), and CD53(+) immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.
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