Descriptor: "MESH: Diabetes Mellitus, Experimental" - Searchworks@Jio Institute Digital Library Search Results

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33 results on '"MESH: Diabetes Mellitus, Experimental"'

1. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

Author: Ophélie Pereira, Jean Personnaz, Céline Saint-Laurent, Toshiyuki Araki, Maithé Tauber, Jean-Pierre Salles, Philippe Valet, Adélaïde Gélineau, Mickaël Canouil, Romain Paccoud, Armelle Yart, Jacques Weill, Jean-Philippe Pradere, Mylène Tajan, Cédric Dray, Enzo Piccolo, Sophie Le Gonidec, Inès Baba, Thomas Edouard, Emmanuel L. Gautier, Haoussa Askia, Philippe Froguel, Benjamin G. Neel, Nicolas Beton, Simon Deleruyelle, Johanna Auriau, Sophie Branka, Alizée Dortignac, Maxime Branchereau, Isabelle Castan, Christophe Heymes, Rémy Burcelin, Julie Charpentier, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), ANR-17-CE14-0009,CAPTOR,Contrôler la fonction des progéniteurs du tissu adipeux pour améliorer les désordres métaboliques de l'obésité(2017), and ANR-17-CE14-0023,TARGETKC,Homéostasie et rôles des cellules de Kupffer dans la stéatohépatite(2017)
Subjects: MESH: Inflammation, medicine.medical_specialty, endocrine system diseases, education, Inflammation, Type 2 diabetes, MESH: Mice, Knockout, Diabetes Mellitus, Experimental, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, MESH: Diabetes Mellitus, Experimental, medicine, Animals, Humans, Glucose homeostasis, MESH: Animals, Macrophage homeostasis, MESH: Mice, 030304 developmental biology, Mice, Knockout, 0303 health sciences, MESH: Humans, business.industry, Macrophages, Monocyte, nutritional and metabolic diseases, MESH: Macrophages, General Medicine, medicine.disease, 3. Good health, MESH: Insulin Resistance, medicine.anatomical_structure, Endocrinology, Adipose Tissue, Diabetes Mellitus, Type 2, Lipotoxicity, Insulin Resistance, medicine.symptom, business, MESH: Adipose Tissue, 030217 neurology & neurosurgery, MESH: Diabetes Mellitus, Type 2
Abstract: Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with constitutive inflammation of tissues involved in the regulation of glucose metabolism. Bone marrow transplantation and macrophage depletion improved glucose homeostasis and decreased metaflammation in the mice, highlighting a key role of macrophages. In-depth analysis of bone marrow-derived macrophages in vitro and liver macrophages showed that hyperactive SHP2 promoted a proinflammatory phenotype, modified resident macrophage homeostasis, and triggered monocyte infiltration. Consistent with a role of SHP2 in promoting inflammation-driven insulin resistance, pharmaceutical SHP2 inhibition in obese diabetic mice improved insulin sensitivity even better than conventional antidiabetic molecules by specifically reducing metaflammation and alleviating macrophage activation. Together, these results reveal that SHP2 hyperactivation leads to inflammation-triggered metabolic impairments and highlight the therapeutical potential of SHP2 inhibition to ameliorate insulin resistance.
Published: 2021

2. Inflammation-linked adaptations in dermal microvascular reactivity accompany the development of obesity and type 2 diabetes

Author: Nguyen-Tu, Marie-Sophie, Nivoit, Pierre, Oréa, Valérie, Lemoine, Sandrine, Acquaviva, Cécile, Pagnon-Minot, Aurélie, Fromy, Bérengère, Sethi, Jaswinder, Sigaudo-Roussel, Dominique, Fromy, Berengere, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Biologie et de Pathologie Est - CBPE, NOVOTEC, University of Southampton, M.-S.N.-T. was supported by the University of Lyon 1 and the study was supported by a grant from Fondation Lyon 1 and from DEFISENS-TACT MI CNRS. J.K.S. was supported by the British Heart Foundation (Award number PG/10/038/28359) and funded by the Wellcome Trust (Grant number 206453/Z/17/Z)., We thank Jocelyne Vial (Anexpeau facility, Lyon) for her kind help in treating the animals and we are very grateful to Nicolas Gadot (Anipath facility, Lyon)., Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université de Lyon, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de Maladies Héréditaires du Métabolisme, Centre de Biologie Et de Pathologie Est - Bron Centre médical, and Institut de biologie et chimie des protéines [Lyon] (IBCP)
Subjects: Male, MESH: Inflammation, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], Adipose Tissue, White, Mice, Obese, Article, Diabetes Mellitus, Experimental, MESH: Vasodilation, Mice, MESH: Mice, Inbred C57BL, MESH: Diabetes Mellitus, Experimental, Animals, MESH: Obesity, MESH: Animals, Obesity, MESH: Mice, MESH: Mice, Obese, ComputingMilieux_MISCELLANEOUS, Skin, Inflammation, MESH: Cytokines, [SDV.BA]Life Sciences [q-bio]/Animal biology, MESH: Adiponectin, MESH: Male, Mice, Inbred C57BL, Vasodilation, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH: Microvessels, Diabetes Mellitus, Type 2, MESH: Adipose Tissue, White, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Microvessels, Cytokines, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Adiponectin, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Diabetes Mellitus, Type 2
Abstract: International audience; Background/ObjectivesThe increased prevalence of obesity has prompted great strides in our understanding of specific adipose depots and their involvement in cardio-metabolic health. However, the impact of obesity on dermal white adipose tissue (dWAT) and dermal microvascular functionality remains unclear. This study aimed to investigate the temporal changes that occur in dWAT and dermal microvascular functionality during the development of diet-induced obesity and type 2 diabetes in mice.MethodsMetabolic phenotyping of a murine model of hypercaloric diet (HCD)-induced obesity and type 2 diabetes was performed at three time points that reflected three distinct stages of disease development; 2 weeks of HCD-overweight-metabolically healthy, 4 weeks of HCD-obese-prediabetic and 12 weeks of HCD-obese-type 2 diabetic mice. Expansion of dWAT was characterized histologically, and changes in dermal microvascular reactivity were assessed in response to pressure and the vasodilators SNP and Ach.ResultsHCD resulted in a progressive expansion of dWAT and increased expression of pro-inflammatory markers (IL1β and COX-2). Impairments in pressure-induced (PIV) and Ach-induced (endothelium-dependent) vasodilation occurred early, in overweight-metabolically healthy mice. Residual vasodilatory responses were NOS-independent but sensitive to COX inhibition. These changes were associated with reductions in NO and adiponectin bioavailability, and rescued by exogenous adiponectin or hyperinsulinemia. Obese-prediabetic mice continued to exhibit impaired Ach-dependent vasodilation but PIV appeared normalized. This normalization coincided with elevated endogenous adiponectin and insulin levels, and was sensitive to NOS, COX and PI3K, inhibition. In obese-type 2 diabetic mice, both Ach-stimulated and pressure-induced vasodilatory responses were increased through enhanced COX-2-dependent prostaglandin response.ConclusionsWe demonstrate that the development of obesity, metabolic dysfunction and type 2 diabetes, in HCD-fed mice, is accompanied by increased dermal adiposity and associated metaflammation in dWAT. Importantly, these temporal changes are also linked to disease stage-specific dermal microvascular reactivity, which may reflect adaptive mechanisms driven by metaflammation.
Published: 2019

3. Erythropoietin Restores C-Fiber Function and Prevents Pressure Ulcer Formation in Diabetic Mice

Author: James Javellaud, Vincent Sarrazy, Nicole Oudart, L. Botelle, Loriane Gourloi, Claire Demiot, Jean-Michel Achard, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Laboratoire de Chimie des Substances Naturelles (LCSN), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), and Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Vasodilation, Pharmacology, Biochemistry, MESH: Dose-Response Relationship, Drug, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: Diabetes Mellitus, Experimental, MESH: Animals, Skin, MESH: Treatment Outcome, Pressure Ulcer, 0303 health sciences, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Recombinant Proteins, 3. Good health, Dose–response relationship, Treatment Outcome, medicine.anatomical_structure, Nociception, Anesthesia, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, medicine.drug, MESH: Pressure Ulcer, Endothelium, Dermatology, Streptozocin, Diabetes Mellitus, Experimental, Magnetics, 03 medical and health sciences, MESH: Skin, Diabetes mellitus, MESH: Nerve Fibers, Unmyelinated, medicine, Animals, MESH: Magnetics, MESH: Erythropoietin, Erythropoietin, MESH: Mice, Molecular Biology, 030304 developmental biology, Nerve Fibers, Unmyelinated, Dose-Response Relationship, Drug, business.industry, MESH: Streptozocin, Cell Biology, Neurovascular bundle, Streptozotocin, medicine.disease, MESH: Male, Disease Models, Animal, MESH: Disease Models, Animal, business, 030217 neurology & neurosurgery
Abstract: International audience; Pressure-induced vasodilatation (PIV), a cutaneous physiological neurovascular (C-fiber/endothelium) mechanism, is altered in diabetes and could possibly contribute to pressure ulcer development. We wanted to determine whether recombinant human erythropoietin (rhEPO), which has protective neurovascular effects, could prevent PIV alteration and pressure ulcer formation. We developed a skin pressure ulcer model in mice by applying two magnetic plates to the dorsal skin. This induced significant stage 2 ulcers (assessed visually and histologically) in streptozotocin-treated mice with 8 weeks of diabetes compared with very few in controls. Control and streptozotocin mice received either no treatment or systematic rhEPO (3,000 UI kg(-1) intraperitoneally, twice a week) during the last 2 weeks of diabetes. After 8 weeks of diabetes, we assessed ulcer development, PIV, endothelium-dependent vasodilation, C-fiber-mediated nociception threshold, and skin innervation density. Pretreatment with rhEPO fully prevented ulcer development in streptozotocin mice and also fully restored C-fiber nociception, skin innervation density, and significantly improved PIV, but had no effect on endothelium-dependent vasodilation. Our finding that rhEPO treatment protects the skin against pressure-induced ulcers in diabetic mice encourages evaluation of the therapeutic potential for non-hematopoietic analogs of EPO in preventing neuropathic diabetic ulcers.
Published: 2011

4. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice.: LEPROTs decrease growth hormone signaling

Author: Céline Cudejko, Eric Bauge, Jean-Pierre Salles, Réjane Paumelle, Thierry Touvier, Bernard Bailleul, Olivier Briand, Bart Staels, Sandrine Caron, Francoise Conte-Auriol, Yves Rouillé, Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Signal Transduction, Suppressor of Cytokine Signaling Proteins, MESH: Recombinant Proteins, MESH: Hepatocytes, Mice, 0302 clinical medicine, STAT5 Transcription Factor, MESH: Diabetes Mellitus, Experimental, Glucose homeostasis, MESH: Animals, Receptor, SOCS2, STAT5, 0303 health sciences, biology, Intracellular Signaling Peptides and Proteins, Fasting, General Medicine, MESH: Suppressor of Cytokine Signaling Proteins, Recombinant Proteins, Liver, Female, RNA Interference, Signal transduction, MESH: Receptors, Somatotropin, Signal Transduction, Research Article, Genetically modified mouse, medicine.medical_specialty, MESH: Rats, MESH: Mice, Transgenic, Transgene, MESH: RNA Interference, MESH: Fasting, Mice, Transgenic, MESH: Carrier Proteins, 030209 endocrinology & metabolism, Cell Line, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, 030304 developmental biology, MESH: Humans, MESH: STAT5 Transcription Factor, Receptors, Somatotropin, MESH: Male, Rats, MESH: Cell Line, Mice, Inbred C57BL, Endocrinology, Membrane protein, Growth Hormone, MESH: Growth Hormone, Hepatocytes, biology.protein, Carrier Proteins, MESH: Female, MESH: Liver
Abstract: International audience; Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions. However, the mechanisms controlling hepatic GH resistance are currently unknown. Here, we investigated the role of 2 tetraspanning membrane proteins, leptin receptor overlapping transcript (LEPROT; also known as OB-RGRP) and LEPROT-like 1 (LEPROTL1), in controlling GH sensitivity. Transgenic mice expressing either human LEPROT or human LEPROTL1 displayed growth retardation, reduced plasma IGF1 levels, and impaired hepatic sensitivity to GH, as measured by STAT5 phosphorylation and Socs2 mRNA expression. These phenotypes were accentuated in transgenic mice expressing both proteins. Moreover, gene silencing of either endogenous Leprot or Leprotl1 in H4IIE hepatocytes increased GH signaling and enhanced cell-surface GH receptor. Importantly, we found that both LEPROT and LEPROTL1 expression were regulated in the mouse liver by physiologic and pathologic changes in glucose homeostasis. Together, these data provide evidence that LEPROT and LEPROTL1 influence liver GH signaling and that regulation of the genes encoding these proteins may constitute a molecular link between nutritional signals and GH actions on body growth and metabolism.
Published: 2009

5. Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

Author: Rémy Burcelin, Claude Knauf, Nathalie M. Delzenne, Rodrigo Bibiloni, Audrey M. Neyrinck, Patrice D. Cani, Aurélie Waget, Simon, Marie Francoise, Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology (PMNT-73/69), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Nutrition and Health, Nestlé Research Center | Centre de recherche Nestlé [Lausanne], Nestlé S.A.-Nestlé S.A., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and Nestlé Research Center
Subjects: Male, MESH: Inflammation, MESH: Bifidobacterium, Lipopolysaccharide, Endocrinology, Diabetes and Metabolism, Mice, Obese, Adipose tissue, Type 2 diabetes, MESH: Bacteroides, MESH: Base Sequence, Gut flora, medicine.disease_cause, MESH: Genotype, Feces, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Diabetes Mellitus, Experimental, Bacteroides, MESH: Obesity, MESH: Animals, Cecum, MESH: Mice, Obese, 2. Zero hunger, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Feces, MESH: Crosses, Genetic, Anti-Bacterial Agents, 3. Good health, RNA, Bacterial, Female, medicine.symptom, MESH: RNA, Bacterial, medicine.medical_specialty, Genotype, 030209 endocrinology & metabolism, Inflammation, Biology, digestive system, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Anti-Bacterial Agents, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Obesity, MESH: Mice, Crosses, Genetic, 030304 developmental biology, Intestinal permeability, Base Sequence, MESH: Cecum, medicine.disease, biology.organism_classification, Endotoxemia, MESH: Male, Mice, Inbred C57BL, Lactobacillus, Endocrinology, chemistry, MESH: Endotoxemia, Immunology, Bifidobacterium, MESH: Female, MESH: Lactobacillus, Oxidative stress
Abstract: OBJECTIVE—Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. RESEARCH DESIGN AND METHODS—We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect. RESULTS—We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat–fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14−/− mutant mice mimicked the metabolic and inflammatory effects of antibiotics. CONCLUSIONS—This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.
Published: 2008

6. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Author: Françoise Praddaude, Christiane Pecher, Julien Allard, Isabelle Renaud, Marie Buléon, Eric Cellier, Jean-Pierre Girolami, Ivan Tack, Marc Conti, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie 1, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Simon, Marie Francoise, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Signal Transduction, Male, MAPK/ERK pathway, Receptor, Bradykinin B2, Physiology, MESH: Random Allocation, medicine.medical_treatment, Kidney Glomerulus, Angiotensin-Converting Enzyme Inhibitors, MESH: Rats, Sprague-Dawley, Receptor, IGF Type 1, Rats, Sprague-Dawley, Random Allocation, chemistry.chemical_compound, MESH: Receptor, IGF Type 1, Bradykinin B2 Receptor Antagonists, MESH: Diabetes Mellitus, Experimental, MESH: Animals, Diabetic Nephropathies, chemistry.chemical_classification, Glutathione peroxidase, MESH: Angiotensin-Converting Enzyme Inhibitors, Kinin, Receptor antagonist, MESH: Albuminuria, MESH: Receptors, Transforming Growth Factor beta, Tissue Kallikreins, Signal Transduction, medicine.medical_specialty, MESH: Rats, MESH: Diabetic Nephropathies, medicine.drug_class, MESH: Tissue Kallikreins, Bradykinin, Peptidyl-Dipeptidase A, Streptozocin, Diabetes Mellitus, Experimental, Receptor, Platelet-Derived Growth Factor beta, Growth factor receptor, Internal medicine, MESH: Receptors, Growth Factor, medicine, Albuminuria, Animals, Receptors, Growth Factor, cardiovascular diseases, MESH: Receptor, Bradykinin B2, MESH: Bradykinin, Growth factor, MESH: Streptozocin, MESH: Kidney Glomerulus, MESH: Male, Rats, IRS1, MESH: Peptidyl-Dipeptidase A, Endocrinology, chemistry, MESH: Receptor, Platelet-Derived Growth Factor beta, Receptors, Transforming Growth Factor beta
Abstract: International audience; Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-beta1 (TGF-beta-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-beta-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.
Published: 2007

7. Interferon-α as a Mediator of Polyinosinic:Polycytidylic Acid–Induced Type 1 Diabetes

Author: Johanna Paronen, Maki Nakayama, George S. Eisenbarth, Jean Jasinski, Edwin Liu, Brooke Hensley, Dongmei Miao, Devasenan Devendra, Marcella Li, Evie Melanitou, Hiroaki Moriyama, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], and This research was supported by grants from the National Institutes of Health (NIH) (DK 055969, DK 062718, and AI 055466), the Autoimmunity Prevention Center U19 (AI 050864), the Diabetes Endocrine Research Center (P30 DK57516), the American Diabetes Association, the Juvenile Diabetes Foundation, and the Children’s Diabetes Foundation. D.D. is supported by an Eli Lilly fellowship award, and E.L. is supported by an NIH grant (DK 06405).
Subjects: CD4-Positive T-Lymphocytes, Aging, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Gene Expression, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], CD8-Positive T-Lymphocytes, Mice, chemistry.chemical_compound, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Interferon, polyinosinic:polycytidylic acid, MESH: Diabetes Mellitus, Experimental, MESH: Aging, MESH: Animals, Receptor, Mice, Inbred BALB C, MESH: CD4-Positive T-Lymphocytes, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: CD8-Positive T-Lymphocytes, Cytokine, rat insulin promoter, MESH: Interferon-alpha, medicine.drug, MESH: Gene Expression, MESH: Mice, Transgenic, MESH: Mice, Inbred BALB C, Mice, Transgenic, poly I:C, Biology, MESH: Poly I-C, Diabetes Mellitus, Experimental, Islets of Langerhans, Immune system, Mediator, MESH: Mice, Inbred C57BL, Internal Medicine, medicine, Animals, IFN interferon, MESH: Mice, Type 1 diabetes, Innate immune system, MESH: Islets of Langerhans, Interferon-alpha, medicine.disease, Mice, Inbred C57BL, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Poly I-C, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, chemistry, RIP, Polyinosinic:polycytidylic acid, Immunology
Abstract: International audience; A number of studies and clinical case reports have implicated interferon (IFN)-alpha as a potential mediator of type 1 diabetes pathogenesis. Administration of polyinosinic:polycytidylic acid (poly I:C), a mimic of viral double-stranded RNA, induces diabetes in C57BL/6 mice expressing the B7.1 costimulatory molecule in islets. We investigated the potential role of IFN-alpha in this disease model. The quantitative correlation between IFN-alpha levels and time to diabetes, diabetes prevention with anti-IFN-alpha antibody, and ability of IFN-alpha itself to induce diabetes are consistent with the hypothesis that poly I:C in this model acts by induction of IFN-alpha in a genetically susceptible host. Numerous recent studies highlight the importance of the innate immune system and toll receptors in determining adaptive immune responses, and we speculate that for type 1 diabetes, viral and other environmental factors may act through induction of IFNs.
Published: 2005

8. Early pre-diabetic state alters adaptation of myocardial glucose metabolism during ischemia in rats

Author: Stéphane Tanguy, Catherine Ghezzi, Joël de Leiris, Corinne Berthonneche, Sandrine Morel, Marie-Claire Toufektsian, Pascale Perret, François Boucher, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Physiopathologie des adaptations cardiovasculaires à l'Exercice, Avignon Université (AU), Radiopharmaceutiques biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Internal Medicine, Yale University School of Medicine, Physiologie cardio-Respiratoire Expérimentale Théorique et Appliquée (TIMC-IMAG-PRETA), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Sandrine Morel was supported by grant from Fédération Française de Cardiologie and Merck-Lipha
Subjects: Male, pre-diabetic state, MESH: Glycogen, Clinical Biochemistry, Myocardial Ischemia, Muscle Proteins, MESH: Myocytes, Cardiac, 030204 cardiovascular system & hematology, Sarcolemma, 0302 clinical medicine, MESH: Diabetes Mellitus, Experimental, Myocytes, Cardiac, MESH: Animals, Glycolysis, Hexosephosphates, MESH: Sarcolemma, 0303 health sciences, Glucose Transporter Type 4, MESH: Hexosephosphates, General Medicine, glycolysis, Adaptation, Physiological, 3. Good health, MESH: Glucose, Protein Transport, MESH: Insulin Resistance, MESH: Monosaccharide Transport Proteins, MESH: Glycolysis, MESH: Myocardial Ischemia, glucose extraction, Glycogen, MESH: Protein Transport, medicine.medical_specialty, MESH: Myocardium, Monosaccharide Transport Proteins, MESH: Rats, Clinical chemistry, Ischemia, Fructose, ischemia, In Vitro Techniques, Carbohydrate metabolism, Biology, Diabetes Mellitus, Experimental, MESH: Prediabetic State, Prediabetic State, MESH: Muscle Proteins, 03 medical and health sciences, Insulin resistance, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Animals, Lactic Acid, Rats, Wistar, Molecular Biology, 030304 developmental biology, Myocardium, MESH: Rats, Wistar, Cell Biology, medicine.disease, MESH: Adaptation, Physiological, MESH: Male, Rats, Glucose, Endocrinology, Basal (medicine), biology.protein, GLUT4 translocation, MESH: Lactic Acid, MESH: Glucose Transporter Type 4, Insulin Resistance, MESH: Fructose, Flux (metabolism), GLUT4
Abstract: International audience; Pre-diabetic subjects with high insulin secretory capacity have double risk of cardiovascular disease compared with subjects who do not develop insulin-resistance. It is well established that the ability of the myocardium to increase its glycolytic ATP production plays a crucial role in determining cell survival under conditions of ischemia. Up to now, whether the pre-diabetic state reduces the tolerance of the heart to ischemia by affecting its ability to increase its energy production through glycolysis remains unknown. The aim of the present study was to assess whether insulin resistance affects the ability of the myocardium to increase glycolysis under ischemic conditions. Male Wistar rats were fed for 8 weeks a fructose-enriched (33%) diet to induce a pre-diabetic state. Hearts were isolated and subjected to ex-vivo low-flow (2%) ischemia for 30 min. The fructose diet increased sarcolemmal GLUT4 localisation in myocardial cells under basal conditions compared with controls. This effect was not accompanied by increased glucose utilisation. Ischemia induced the translocation of GLUT4 to the plasma membrane in controls but did not significantly modify the distribution of these transporters in pre-diabetic hearts. Glycolytic flux under ischemic conditions was significantly lower in fructose-fed rat hearts compared with controls. The reduction of glycolytic flux during ischemia in fructose-fed rat hearts was not due to metabolic inhibition downstream hexokinase II since no cardiac accumulation of glucose-6-phosphate was detected. In conclusion, our results suggest that the pre-diabetic state reduces the tolerance of the myocardium to ischemia by decreasing glycolytic flux adaptation.
Published: 2005

9. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat

Author: Christine Rouault, René Gross, Michel Derouet, Céline Cruciani-Guglielmacci, Gérard Reach, M. Manteghetti, Mohammed Taouis, Pierre Petit, Gérard Ribes, Vincent Breil, Christophe Broca, Salwa W. Rizkalla, Bernard Pau, Alain Ktorza, Unité de Recherches Avicoles (URA), Institut National de la Recherche Agronomique (INRA), Neurobiologie de l'Olfaction et de la Prise Alimentaire (NOPA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génie Biomédical et Diabète Sucré, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de physiopathologie de la nutrition (LPN), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de pharmacologie et innovation dans le diabète (CPID), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), Maladies Métaboliques, Institut de Rechercjhes SERVIER, Laboratoire de Neuroendocrinologie Moléculaire de la Prise Alimentaire, Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre d’études d’Agents Pathogènes et Biotechologies pour la Santé (CPBS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, and Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)
Subjects: insulinémie, MESH: Signal Transduction, Male, Sucrose, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Rats, Zucker, métabolisme nutritionnel, MESH: Rats, Sprague-Dawley, MESH: Isoleucine, rattus rattus, MESH: Glucose Clamp Technique, Rats, Sprague-Dawley, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, MESH: Diabetes Mellitus, Experimental, MESH: Obesity, Insulin, MESH: Animals, ComputingMilieux_MISCELLANEOUS, Euglycemic hyperinsulinemic clamp, chemistry.chemical_classification, MESH: Muscle, Skeletal, 0303 health sciences, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, biology, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Lipids, Amino acid, [SDV] Life Sciences [q-bio], MESH: Glucose, obésité, MESH: Insulin Resistance, nutrition, Liver, Biochemistry, MESH: Hyperinsulinism, Signal transduction, diabète, Signal Transduction, Niacinamide, MESH: Enzyme Activation, medicine.medical_specialty, RAT, 4-HYDROXYISOLEUCINE, MESH: Rats, 030209 endocrinology & metabolism, MESH: Insulin, [INFO] Computer Science [cs], Diabetes Mellitus, Experimental, 03 medical and health sciences, Insulin resistance, MESH: Diet, Hyperinsulinism, Physiology (medical), Internal medicine, medicine, Animals, [INFO]Computer Science [cs], Obesity, Isoleucine, Muscle, Skeletal, résistance à l'insuline, insuline, Pancreatic hormone, 030304 developmental biology, MESH: Sucrose, medicine.disease, MESH: Lipids, MESH: Male, Diet, Rats, Rats, Zucker, Enzyme Activation, Insulin receptor, Glucose, Enzyme, Endocrinology, chemistry, MESH: Phosphatidylinositol 3-Kinases, Glucose Clamp Technique, biology.protein, Insulin Resistance, MESH: Niacinamide, MESH: Liver
Abstract: International audience; ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.
Published: 2004

10. Effect of Chronic Severe Diabetes on Myocardial Stunning in the Dog

Author: J. Delaye, G Hadour, Michel de Lorgeril, Rémi Forrat, René Ferrera, Laurent Sebbag, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Pôle Médico-Chirurgical de Transplantation Cardiaque Adulte, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire d'Etudes du Comportement à Long Terme des matériaux de conditionnement (LCLT), Département de recherche sur les technologies pour l'enrichissement, le démantèlement et les déchets (DE2D), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cardioprotection, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Département de recherche sur les Procédés et Matériaux pour les Environnements complexes (DPME)
Subjects: Male, medicine.medical_specialty, MESH: Myocardial Contraction, Radioactive microsphere technique, Myocardial Infarction, Ischemia, MESH: Coronary Circulation, 030204 cardiovascular system & hematology, Diabetes Mellitus, Experimental, 030218 nuclear medicine & medical imaging, MESH: Dogs, 03 medical and health sciences, Coronary circulation, Dogs, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Coronary Circulation, Internal medicine, Diabetes mellitus, MESH: Diabetes Mellitus, Experimental, medicine, Animals, MESH: Animals, Myocardial infarction, MESH: Myocardial Stunning, Molecular Biology, Myocardial Stunning, Myocardial stunning, business.industry, Heart, medicine.disease, Myocardial Contraction, MESH: Male, 3. Good health, MESH: Heart, MESH: Myocardial Infarction, medicine.anatomical_structure, Regional Blood Flow, Coronary occlusion, Cardiology, Female, MESH: Regional Blood Flow, Cardiology and Cardiovascular Medicine, business, MESH: Female, Reperfusion injury
Abstract: International audience; In this study, we examined whether chronic severe diabetes may affect ischaemic and post-ischaemic regional myocardial dysfunction in vivo in the dog. Diabetes was chemically induced in randomized animals and major metabolic alterations were observed confirming the severity and chronicity of the diabetes. After 70 days, halothane-anaesthetized dogs underwent a 20-min coronary occlusion, followed by reperfusion. During ischaemia, global left ventricle function (dP/dtmax) was more altered (P
Published: 1998

11. Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats

Author: V. Large, Frédérique Diraison, Michel Beylot, Odile D. Peroni, Large, Valerie, Physiopathologie Metabolique et Renale, Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Glycerol, Male, Time Factors, Endocrinology, Diabetes and Metabolism, MESH: Rats, Sprague-Dawley, Cohort Studies, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: Diabetes Mellitus, Experimental, MESH: Animals, Infusions, Intravenous, MESH: Cohort Studies, 2. Zero hunger, Starvation, Carbon Isotopes, 0303 health sciences, Glycogen, MESH: Gluconeogenesis, MESH: Glucose, medicine.symptom, medicine.drug, medicine.medical_specialty, MESH: Rats, MESH: Intestinal Absorption, MESH: Starvation, 030209 endocrinology & metabolism, Carbohydrate metabolism, Biology, Tritium, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Glycerol, Internal medicine, Diabetes mellitus, medicine, Animals, MESH: Infusions, Intravenous, 030304 developmental biology, MESH: Time Factors, Gluconeogenesis, MESH: Carbon Isotopes, Metabolism, Streptozotocin, medicine.disease, MESH: Male, Rats, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Glucose, Intestinal Absorption, MESH: Tritium, chemistry, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Using a 3-hour primed-continuous infusion of [3-3H]glucose and [2-13C]glycerol, we measured glucose production, gluconeogenesis from glycerol, and total gluconeogenesis (using mass isotopomer distribution analysis [MIDA] of glucose) in postabsorptive and starved normal and streptozotocin-diabetic rats. In normal rats, 48 hours of starvation increased (P < .01) the percent contribution of both gluconeogenesis from glycerol (from 14.4% +/- 1.8% to 25.5% +/- 4.0%) and total gluconeogenesis (from 52.2% +/- 3.9% to 89.8% +/- 1.3%) to glucose production, but the absolute gluconeogenic fluxes were not modified, since glucose production decreased. Diabetic rats showed increased glucose production in the postabsorptive state; this decreased with starvation and was comparable to the of controls after 48 hours of starvation. Gluconeogenesis was increased in postabsorptive diabetic rats (69.0% +/- 1.3%, P < .05 v controls). Surprisingly, this contribution of gluconeogenesis to glucose production was not found to be increased in 24-hour starved diabetic rats (64.4% +/- 2.4%). These rats had significant liver glycogen stores, but gluconeogenesis was also low (42.8% +/- 2.1%) in 48-hour starved diabetic rats deprived of glycogen stores. Moreover, in 24-hour starved diabetic rats infused with [3-13C]lactate, gluconeogenesis was 100% when determined by comparing circulating glucose and liver pyruvate enrichment, but only 47% +/- 3% when calculated from the MIDA of glucose. Therefore, MIDA is not a valid method to measure gluconeogenesis in starved diabetic rats. This was not explained by differences in the labeling of liver and kidney triose phosphates: functional nephrectomy of starved diabetic rats decreased glucose production, but gluconeogenesis calculated by the MIDA method was only 48% +/- 3.3%. We conclude that (1) diabetic rats have increased glucose production and gluconeogenesis in the postabsorptive state; (2) starvation decreases glucose production and increases the contribution of gluconeogenesis, but MIDA is not an appropriate method in this situation; and (3) the kidneys contribute to glucose production in starved diabetic rats.
Published: 1997

12. Intravenous infusion of donor apoptotic leukocytes before transplantation delays allogeneic islet graft rejection through regulatory T cells

Author: François Kleinclauss, Francis Bonnefoy, François Mougel, Sylvain Perruche, Bernadette Kantelip, Alfred Penfornis, Philippe Saas, Sophie Borot, Stéphanie Kury-Paulin, Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], Service d'urologie, andrologie et transplantation rénale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Saas, Philippe, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Service d'urologie et transplantation rénale, and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon )
Subjects: Graft Rejection, Endocrinology, Diabetes and Metabolism, MESH : Leukocytes, Islets of Langerhans Transplantation, Apoptosis, T-Lymphocytes, Regulatory, MESH : T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, Endocrinology, Leukocytes, MESH: Diabetes Mellitus, Experimental, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Medicine, MESH : Female, MESH: Animals, 0303 health sciences, Mice, Inbred BALB C, geography.geographical_feature_category, biology, FOXP3, General Medicine, Islet, 3. Good health, Leukocyte Transfusion, MESH : Islets of Langerhans Transplantation, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Diabetes Mellitus, Experimental, medicine.drug, Allogeneic transplantation, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Inbred BALB C, MESH: Immunomodulation, MESH: Graft Rejection, MESH : Leukocyte Transfusion, Diabetes Mellitus, Experimental, Andrology, Immunomodulation, MESH: Leukocytes, 03 medical and health sciences, MESH : Mice, Internal Medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, MESH : Immunomodulation, geography, business.industry, Friend virus, MESH: Apoptosis, MESH: T-Lymphocytes, Regulatory, MESH : Graft Rejection, biology.organism_classification, Streptozotocin, medicine.disease, MESH: Leukocyte Transfusion, Transplantation, Graft-versus-host disease, MESH: Islets of Langerhans Transplantation, Immunology, MESH : Animals, business, MESH: Female, MESH : Apoptosis
Abstract: International audience; AIM: This study describes the ability of intravenous donor apoptotic leukocyte infusion before islet transplantation to delay allogeneic graft rejection and implicates regulatory T cells (T(reg)) in the effect. METHODS: Allogeneic FVB (Friend virus B-type) islet transplants were placed under the kidney capsule of BALB/c recipient mice rendered diabetic by streptozotocin. Apoptotic donor leukocytes were infused intravenously 7 days before transplantation. Foxp3/DTR/GFP transgenic C57BL/6 mice were used as recipients to show depletion of T(reg) after apoptotic cell infusion. Control mice received islet transplants without apoptotic cells. RESULTS: The graft median survival time (MST) in recipient mice was 15±1.5 days when apoptotic cells were infused 7 days prior to transplantation of a 1000-islet-containing allograft and 6±0.5 days in the control mice (P
Published: 2012

13. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota

Author: Claire Cenac, Pierre Monsan, Aurélie Waget, Pascale Klopp, Philippe Valet, Jacques Amar, Jason S. Iacovoni, Jérôme Mariette, Rémy Burcelin, Mathieu Bergé, Jérôme Lluch, Audrey Baylac, Anne Bouloumié, Sandra Grès, Christophe Klopp, Françoise Ouarné, Christine Roques, Olivier Bouchez, Vassilia Theodorou, Matteo Serino, Elodie Luche, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Adhésion Bacterienne et Formation de Biofilms, PRES Université de Toulouse, ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Plateforme Bio-informatique Toulouse Genopole®, UBIA INRA, Toulouse Genopole, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), CRITT Bio-Industrie, Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Service de Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], his work was supported by grants from Agence Nationale pour la Recherche (ANR) to RB and collaborators (ANR-Florinflam and Transflora), in part, by the European Commission's Seventh Framework programme under grant agreement No 241913 (FLORINASH) to RB and by the Benjamin Delessert Foundation to MS., European Project: 241913,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,FLORINASH(2010), Centre National de la Recherche Scientifique - CNRS (FRANCE), Ecole d'Ingénieurs de Purpan - EIP (FRANCE), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), Institut National des Sciences Appliquées de Toulouse - INSA (FRANCE), Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE), Institut universitaire de France - IUF (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), ToxAlim (Toulouse, France), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés - LISBP (Toulouse, France), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Burcelin, Remy, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Simon, Marie Francoise, The role of intestinal microflora in non-alcoholic fatty liver disease (NAFLD) - FLORINASH - - EC:FP7:HEALTH2010-01-01 - 2014-12-31 - 241913 - VALID, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, Male, mictobiota, White adipose tissue, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gut flora, Fatty Acids, Nonesterified, Intestinal absorption, Cecum, Mice, 0302 clinical medicine, gut, metabolic, background, phenotype, diet, MESH: Diabetes Mellitus, Experimental, MESH: Animals, 2. Zero hunger, 0303 health sciences, Glucose tolerance test, MESH: Muscle, Skeletal, MESH: Cytokines, MESH: Fatty Acids, Nonesterified, medicine.diagnostic_test, biology, digestive, oral, and skin physiology, Gastroenterology, food and beverages, Phenotype, Adaptation, Physiological, Intestines, medicine.anatomical_structure, High-fat diet, Liver, 030220 oncology & carcinogenesis, MESH: Permeability, Cytokines, medicine.symptom, MESH: Intestines, medicine.medical_specialty, MESH: Glucose Tolerance Test, MESH: Intestinal Absorption, Médecine humaine et pathologie, Inflammation, Gut microbiota, Diet, High-Fat, MESH: Phenotype, digestive system, Permeability, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Diabetes mellitus, Internal medicine, medicine, Animals, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Metabolic diseases, MESH: Cecum, Glucose Tolerance Test, MESH: Metagenome, medicine.disease, biology.organism_classification, MESH: Adaptation, Physiological, MESH: Male, Mice, Inbred C57BL, MESH: Diet, High-Fat, Endocrinology, Intestinal Absorption, Immunology, Metagenome, MESH: Lipopolysaccharides, MESH: Liver
Abstract: Chantier qualité GA; International audience; OBJECTIVE: The gut microbiota, which is considered a causal factor in metabolic diseases as shown best in animals, is under the dual influence of the host genome and nutritional environment. This study investigated whether the gut microbiota per se, aside from changes in genetic background and diet, could sign different metabolic phenotypes in mice. METHODS: The unique animal model of metabolic adaptation was used, whereby C57Bl/6 male mice fed a high-fat carbohydrate-free diet (HFD) became either diabetic (HFD diabetic, HFD-D) or resisted diabetes (HFD diabetes-resistant, HFD-DR). Pyrosequencing of the gut microbiota was carried out to profile the gut microbial community of different metabolic phenotypes. Inflammation, gut permeability, features of white adipose tissue, liver and skeletal muscle were studied. Furthermore, to modify the gut microbiota directly, an additional group of mice was given a gluco-oligosaccharide (GOS)-supplemented HFD (HFD+GOS). RESULTS: Despite the mice having the same genetic background and nutritional status, a gut microbial profile specific to each metabolic phenotype was identified. The HFD-D gut microbial profile was associated with increased gut permeability linked to increased endotoxaemia and to a dramatic increase in cell number in the stroma vascular fraction from visceral white adipose tissue. Most of the physiological characteristics of the HFD-fed mice were modulated when gut microbiota was intentionally modified by GOS dietary fibres. CONCLUSIONS: The gut microbiota is a signature of the metabolic phenotypes independent of differences in host genetic background and diet.
Published: 2012

14. Combined insulin treatment and intense exercise training improved basal cardiac function and Ca(2+)-cycling proteins expression in type 1 diabetic rats

Author: Ludivine Malardé, François Carré, Solène Le Douairon Lahaye, Sophie Vincent, Sami Zguira, Sophie Lemoine Morel, Françoise Rannou Bekono, Arlette Gratas-Delamarche, Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Cardiac output, fonction contractile, Time Factors, Physiology, entraînement intense en endurance, MESH: Myocardial Contraction, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Calcium-Binding Proteins, 030204 cardiovascular system & hematology, Ryanodine receptor 2, MESH: Stroke Volume, MESH: Ventricular Function, Left, Ventricular Function, Left, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, MESH: Diabetes Mellitus, Experimental, Medicine, Insulin, MESH: Animals, 0303 health sciences, Nutrition and Dietetics, General Medicine, 3. Good health, Exercise Therapy, MESH: Calcium, cardiovascular system, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Diabetes Mellitus, Type 1, Cardiac function curve, medicine.medical_specialty, système de régulation du Ca2+, MESH: Myocardium, diabète de type 1, MESH: Rats, Blotting, Western, MESH: Insulin, Sodium-Calcium Exchanger, Diabetes Mellitus, Experimental, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Tacrolimus Binding Proteins, 03 medical and health sciences, MESH: Sarcoplasmic Reticulum Calcium-Transporting ATPases, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Diabetes mellitus, Internal medicine, MESH: Hypoglycemic Agents, MESH: Blotting, Western, MESH: Exercise Therapy, Animals, Hypoglycemic Agents, Rats, Wistar, insuline, 030304 developmental biology, MESH: Tacrolimus Binding Proteins, Calcium metabolism, Type 1 diabetes, business.industry, Myocardium, MESH: Time Factors, Calcium-Binding Proteins, Ryanodine Receptor Calcium Release Channel, Stroke Volume, MESH: Rats, Wistar, medicine.disease, Myocardial Contraction, MESH: Sodium-Calcium Exchanger, MESH: Male, Rats, Endocrinology, Diabetes Mellitus, Type 1, Basal (medicine), Calcium, business
Abstract: This study investigated the effects of 8 weeks of intense exercise training combined with insulin treatment on the Ca2+-cycling protein complex expression and their functional consequences on cardiac function in type 1 diabetic rat hearts. Diabetic Wistar rats were randomly assigned into the following groups: received no treatment, insulin-treated diabetic, trained diabetic, and trained insulin-treated diabetic. A control group was also included. Insulin treatment and (or) treadmill intense exercise training were conducted over 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac expression of the main Ca2+-cycling proteins (RyR2, FKBP 12.6, SERCA2, PLB, NCX1) was assessed by Western blot. Diabetes altered basal cardiac function (±dP/dt) and decrease the expression of the main Ca2+-cycling proteins expression: RyR2, SERCA2, and NCX1 (p < 0.05). Whereas combined treatment was not able to normalize –dP/dt, it succeeded to normalize +dP/dt of diabetic rats (p < 0.05). Moreover, both insulin and intense exercise training, applied solely, increased the expression of the Ca2+-cycling proteins: RyR2, SERCA2, PLB. and NCX1 (p < 0.05). But this effect was higher when the 2 treatments were combined. These data are the first to show that combined insulin treatment and intense exercise training during diabetes synergistically act on the expression of the main Ca2+-cycling proteins, providing insights into mechanisms by which the dual treatment during diabetes improves cardiac function.
Published: 2011

15. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production

Author: Daoudi, Mehdi, Hennuyer, Nathalie, Borland, Michael, Touche, Véronique, Duhem, Christian, Gross, Barbara, Caiazzo, Robert, Kerr-Conte, Julie, Pattou, François, Peters, Jeffrey, Staels, Bart, Lestavel, Sophie, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Veterinary and Biomedical Sciences, Pennsylvania State University (Penn State), Penn State System-Penn State System, Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: PPAR-beta, MESH: Humans, diabetes, MESH: Rats, digestive, oral, and skin physiology, MESH: Glucagon-Like Peptide 1, MESH: Polymerase Chain Reaction, MESH: Gene Expression Regulation, incretin, MESH: Male, PPARβ/δ, MESH: Enteroendocrine Cells, MESH: Blood Glucose, MESH: Diabetes Mellitus, Experimental, MESH: Blotting, Western, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Disease Models, Animal, GLP-1, MESH: Mice, MESH: RNA, Messenger, MESH: Cells, Cultured
Abstract: International audience; BACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) β/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARβ/δ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARβ/δ-null, and ob/ob C57Bl/6 mice treated with the PPARβ/δ synthetic agonists GW501516 or GW0742. RESULTS: PPARβ/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARβ/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARβ/δ agonists activate the proglucagon gene transcription by interfering with the β-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARβ/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARβ/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.
Published: 2011

16. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice.: xanthine oxidase-induced muscle oxidative stress

Author: Bravard, Amélie, Bonnard, Charlotte, Durand, Annie, Chauvin, Marie-Agnès, Favier, Roland, Vidal, Hubert, Rieusset, Jennifer, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Sante et de la Recherche Medicale, National Program on Diabetes Research, Agence Nationale de la Recherche [ANR-09-JCJC-0116-01], Rhones-Alpes Region, and Servier Laboratories (Suresnes, France)
Subjects: MESH: Protein Carbonylation, oxypurinol, EXERCISE, MESH: Insulin, MESH: Xanthine Oxidase, SUPEROXIDE, MESH: Diet, MESH: Mice, Inbred C57BL, MESH: RNA, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Adenosine Triphosphate, MESH: Diabetes Mellitus, Experimental, MESH: Animals, MESH: Mice, IN-VIVO, METABOLIC SYNDROME, reactive oxygen species, MESH: Muscle, Skeletal, NITRIC-OXIDE, MESH: Oxidative Stress, diabetes, MESH: Antioxidants, MESH: Mitochondria, Muscle, INSULIN-RESISTANT MICE, MESH: Oxypurinol, DYSFUNCTION, MESH: Male, mitochondria, MESH: Enzyme Inhibitors, MESH: Microscopy, Electron, Transmission, MESH: Hydrogen Peroxide, FREE-RADICAL PRODUCTION, REACTIVE OXYGEN, NAD(P)H OXIDASE, MESH: Hyperglycemia, MESH: Diabetes Mellitus, Type 1, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Diabetes Mellitus, Type 2
Abstract: International audience; Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H(2)O(2) and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H(2)O(2) production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.
Published: 2011

17. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Author: Bravard, Amélie, Bonnard, Charlotte, Durand, Annie, Chauvin, Marie-Agnès, Favier, Roland, Vidal, Hubert, Rieusset, Jennifer, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Sante et de la Recherche Medicale, National Program on Diabetes Research, Agence Nationale de la Recherche [ANR-09-JCJC-0116-01], Rhones-Alpes Region, Servier Laboratories (Suresnes, France), and Vericel, Evelyne
Subjects: MESH: Protein Carbonylation, oxypurinol, EXERCISE, MESH: Insulin, MESH: Xanthine Oxidase, SUPEROXIDE, MESH: Diet, MESH: Mice, Inbred C57BL, MESH: RNA, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Adenosine Triphosphate, MESH: Diabetes Mellitus, Experimental, MESH: Animals, MESH: Mice, IN-VIVO, METABOLIC SYNDROME, reactive oxygen species, MESH: Muscle, Skeletal, NITRIC-OXIDE, MESH: Oxidative Stress, diabetes, MESH: Antioxidants, MESH: Mitochondria, Muscle, INSULIN-RESISTANT MICE, MESH: Oxypurinol, DYSFUNCTION, MESH: Male, mitochondria, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH: Enzyme Inhibitors, MESH: Microscopy, Electron, Transmission, MESH: Hydrogen Peroxide, FREE-RADICAL PRODUCTION, REACTIVE OXYGEN, NAD(P)H OXIDASE, MESH: Hyperglycemia, MESH: Diabetes Mellitus, Type 1, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Diabetes Mellitus, Type 2
Abstract: International audience; Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H(2)O(2) and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H(2)O(2) production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.
Published: 2011

18. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

Author: Jennifer Rieusset, Marie-Agnès Chauvin, C. Bonnard, Hubert Vidal, Annie Durand, Amélie Bravard, Roland Favier, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Institut National de la Sante et de la Recherche Medicale, National Program on Diabetes Research, Agence Nationale de la Recherche [ANR-09-JCJC-0116-01], Rhones-Alpes Region, and Servier Laboratories (Suresnes, France)
Subjects: Male, Physiology, Endocrinology, Diabetes and Metabolism, Mitochondrion, medicine.disease_cause, Antioxidants, Pathogenesis, Protein Carbonylation, chemistry.chemical_compound, Mice, 0302 clinical medicine, Adenosine Triphosphate, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Adenosine Triphosphate, MESH: Diabetes Mellitus, Experimental, Insulin, MESH: Animals, Enzyme Inhibitors, IN-VIVO, METABOLIC SYNDROME, reactive oxygen species, chemistry.chemical_classification, MESH: Muscle, Skeletal, 0303 health sciences, MESH: Oxidative Stress, diabetes, Reverse Transcriptase Polymerase Chain Reaction, MESH: Mitochondria, Muscle, 3. Good health, mitochondria, medicine.anatomical_structure, MESH: Enzyme Inhibitors, MESH: Microscopy, Electron, Transmission, MESH: Hydrogen Peroxide, FREE-RADICAL PRODUCTION, NAD(P)H OXIDASE, MESH: Diabetes Mellitus, Type 1, MESH: Diabetes Mellitus, Type 2, MESH: Protein Carbonylation, medicine.medical_specialty, Xanthine Oxidase, Oxypurinol, EXERCISE, MESH: Insulin, Biology, MESH: Xanthine Oxidase, Diabetes Mellitus, Experimental, SUPEROXIDE, 03 medical and health sciences, MESH: Diet, Microscopy, Electron, Transmission, MESH: Mice, Inbred C57BL, MESH: RNA, Physiology (medical), Internal medicine, Diabetes mellitus, medicine, Animals, Xanthine oxidase, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, Reactive oxygen species, NITRIC-OXIDE, MESH: Antioxidants, Skeletal muscle, Hydrogen Peroxide, Xanthine, medicine.disease, INSULIN-RESISTANT MICE, MESH: Oxypurinol, DYSFUNCTION, MESH: Male, Diet, Mitochondria, Muscle, Mice, Inbred C57BL, Oxidative Stress, Endocrinology, Diabetes Mellitus, Type 1, chemistry, Diabetes Mellitus, Type 2, Hyperglycemia, RNA, REACTIVE OXYGEN, MESH: Hyperglycemia, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Oxidative stress
Abstract: Reactive oxygen species (ROS) have been widely implicated in the pathogenesis of diabetes and more recently in mitochondrial alterations in skeletal muscle of diabetic mice. However, so far the exact sources of ROS in skeletal muscle have remained elusive. Aiming at better understanding the causes of mitochondrial alterations in diabetic muscle, we designed this study to characterize the sites of ROS production in skeletal muscle of streptozotocin (STZ)-induced diabetic mice. Hyperglycemic STZ mice showed increased markers of systemic and muscular oxidative stress, as evidenced by increased circulating H2O2 and muscle carbonylated protein levels. Interestingly, insulin treatment reduced hyperglycemia and improved systemic and muscular oxidative stress in STZ mice. We demonstrated that increased oxidative stress in muscle of STZ mice is associated with an increase of xanthine oxidase (XO) expression and activity and is mediated by an induction of H2O2 production by both mitochondria and XO. Finally, treatment of STZ mice, as well as high-fat and high-sucrose diet-fed mice, with oxypurinol reduced markers of systemic and muscular oxidative stress and prevented structural and functional mitochondrial alterations, confirming the in vivo relevance of XO in ROS production in diabetic mice. These data indicate that mitochondria and XO are the major sources of hyperglycemia-induced ROS production in skeletal muscle and that the inhibition of XO reduces oxidative stress and improves mitochondrial alterations in diabetic muscle.
Published: 2011

19. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production

Author: Daoudi, Mehdi, Hennuyer, Nathalie, Borland, Michael, Touche, Véronique, Duhem, Christian, Gross, Barbara, Caiazzo, Robert, Kerr-Conte, Julie, Pattou, François, Peters, Jeffrey, Staels, Bart, Lestavel, Sophie, Derudas, Marie-Hélène, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Veterinary and Biomedical Sciences, Pennsylvania State University (Penn State), Penn State System-Penn State System, Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], and CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: MESH: PPAR-beta, MESH: Humans, diabetes, MESH: Rats, digestive, oral, and skin physiology, MESH: Glucagon-Like Peptide 1, MESH: Polymerase Chain Reaction, MESH: Gene Expression Regulation, incretin, MESH: Male, PPARβ/δ, MESH: Enteroendocrine Cells, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Blood Glucose, MESH: Diabetes Mellitus, Experimental, MESH: Blotting, Western, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Disease Models, Animal, GLP-1, MESH: Mice, MESH: RNA, Messenger, MESH: Cells, Cultured
Abstract: International audience; BACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) β/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARβ/δ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARβ/δ-null, and ob/ob C57Bl/6 mice treated with the PPARβ/δ synthetic agonists GW501516 or GW0742. RESULTS: PPARβ/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARβ/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARβ/δ agonists activate the proglucagon gene transcription by interfering with the β-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARβ/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARβ/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.
Published: 2011

20. Effects of exercise training combined with insulin treatment on cardiac NOS1 signaling pathways in type 1 diabetic rats

Author: François Carré, M. S. Zguira, Solène Le Douairon Lahaye, Arlette Gratas-Delamarche, Françoise Rannou Bekono, Amélie Rébillard, Ludivine Malardé, Bernard Saïag, Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Glucose, Male, MESH: Signal Transduction, medicine.medical_treatment, MESH: Organ Size, Clinical Biochemistry, Blood Pressure, MESH: Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type I, MESH: Physical Conditioning, Animal, 030204 cardiovascular system & hematology, Ryanodine receptor 2, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, Diastole, Heart Rate, MESH: Diabetes Mellitus, Experimental, Insulin, MESH: Animals, MESH: Heart Rate, 0303 health sciences, MESH: Muscle, Skeletal, biology, MESH: Diastole, Organ Size, General Medicine, MESH: Blood Pressure, MESH: Systole, 3. Good health, Nitric oxide synthase, Type 1 diabetes, cardiovascular system, MESH: Nitric Oxide Synthase, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Citrate (si)-Synthase, MESH: Diabetes Mellitus, Type 1, Signal Transduction, Cardiac function curve, medicine.medical_specialty, MESH: Myocardium, MESH: Rats, Systole, Heart Ventricles, Citrate (si)-Synthase, MESH: Insulin, In Vitro Techniques, Diabetes Mellitus, Experimental, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physical Conditioning, Animal, Diabetes mellitus, Internal medicine, medicine, Animals, Rats, Wistar, Muscle, Skeletal, Molecular Biology, Exercise, 030304 developmental biology, business.industry, Myocardium, Body Weight, Cardiac function, Ryanodine Receptor Calcium Release Channel, Cell Biology, MESH: Rats, Wistar, medicine.disease, MESH: Male, Rats, MESH: Body Weight, Diabetes Mellitus, Type 1, Endocrinology, Basal (medicine), Receptors, Adrenergic, beta-3, biology.protein, MESH: Blood Glucose, MESH: Heart Ventricles, business, MESH: Receptors, Adrenergic, beta-3
Abstract: International audience; This study examined the effects of a dual treatment combining insulin treatment and exercise training on basal cardiac function and signaling pathways involving β3-AR, NOS1, and RyR2 in type 1 diabetic rats. Male Wistar rats were assigned into a diabetic group receiving no treatment (D), an insulin-treated diabetic (Ins), a trained diabetic (TD), and a trained insulin-treated diabetic (TIns) group. Control group (C) was included in order to confirm the deleterious effects of diabetes. Insulin treatment and/or treadmill exercise training were conducted for 8 weeks. Basal cardiac function was evaluated by Langendorff technique. Cardiac protein expression of β3-AR, NOS1, and RyR2 was assessed using Western blots. Diabetes induced a decrease of both basal diastolic and systolic (±dP/dt) cardiac function (P < 0.05). Moreover, diabetes was associated with an increase of β3-AR and NOS1 and a decrease of RyR2 expression (P < 0.05). Although combined treatment was not able to normalize -dP/dt, it succeeded to normalize +dP/dt of diabetic rats. Combined treatment led to an overexpression of RyR2. Effects of this combined treatment on +dP/dt and RyR2 were greater than the effects of insulin and exercise training, applied solely. Treatments, applied solely or in combination, resulted in a complete normalization of β3-AR and in a down-regulation of NOS1 because this protein expression in all treated diabetic rats became lower than control values (P < 0.01). Our study shows that unlike single treatments, dual treatment combining insulin treatment and exercise training was able to normalize basal systolic function of diabetic rats by a specific regulation of β3-AR-NOS1-RyR2 signaling pathways.
Published: 2011

21. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice

Author: Touvier, Thierry, Conte-Auriol, Françoise, Briand, Olivier, Cudejko, Céline, Paumelle, Réjane, Caron, Sandrine, Baugé, Eric, Rouillé, Yves, Salles, Jean-Pierre, Staels, Bart, Bailleul, Bernard, Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), and Derudas, Marie-Hélène
Subjects: MESH: Signal Transduction, MESH: Humans, MESH: Rats, MESH: Mice, Transgenic, MESH: STAT5 Transcription Factor, MESH: RNA Interference, MESH: Fasting, MESH: Carrier Proteins, MESH: Suppressor of Cytokine Signaling Proteins, MESH: Male, MESH: Cell Line, MESH: Recombinant Proteins, MESH: Hepatocytes, MESH: Mice, Inbred C57BL, MESH: Growth Hormone, MESH: Diabetes Mellitus, Experimental, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Receptors, Somatotropin, MESH: Female, MESH: RNA, Messenger, MESH: Liver
Abstract: International audience; Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions. However, the mechanisms controlling hepatic GH resistance are currently unknown. Here, we investigated the role of 2 tetraspanning membrane proteins, leptin receptor overlapping transcript (LEPROT; also known as OB-RGRP) and LEPROT-like 1 (LEPROTL1), in controlling GH sensitivity. Transgenic mice expressing either human LEPROT or human LEPROTL1 displayed growth retardation, reduced plasma IGF1 levels, and impaired hepatic sensitivity to GH, as measured by STAT5 phosphorylation and Socs2 mRNA expression. These phenotypes were accentuated in transgenic mice expressing both proteins. Moreover, gene silencing of either endogenous Leprot or Leprotl1 in H4IIE hepatocytes increased GH signaling and enhanced cell-surface GH receptor. Importantly, we found that both LEPROT and LEPROTL1 expression were regulated in the mouse liver by physiologic and pathologic changes in glucose homeostasis. Together, these data provide evidence that LEPROT and LEPROTL1 influence liver GH signaling and that regulation of the genes encoding these proteins may constitute a molecular link between nutritional signals and GH actions on body growth and metabolism.
Published: 2009

22. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice

Author: Touvier, Thierry, Conte-Auriol, Françoise, Briand, Olivier, Cudejko, Céline, Paumelle, Réjane, Caron, Sandrine, Baugé, Eric, Rouillé, Yves, Salles, Jean-Pierre, Staels, Bart, Bailleul, Bernard, Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, MESH: Humans, MESH: Rats, MESH: Mice, Transgenic, MESH: STAT5 Transcription Factor, MESH: RNA Interference, MESH: Fasting, MESH: Carrier Proteins, MESH: Suppressor of Cytokine Signaling Proteins, MESH: Male, MESH: Cell Line, MESH: Recombinant Proteins, MESH: Hepatocytes, MESH: Mice, Inbred C57BL, MESH: Growth Hormone, MESH: Diabetes Mellitus, Experimental, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Receptors, Somatotropin, MESH: Female, MESH: RNA, Messenger, MESH: Liver
Abstract: International audience; Growth hormone (GH) is a major metabolic regulator that functions by stimulating lipolysis, preventing protein catabolism, and decreasing insulin-dependent glucose disposal. Modulation of hepatic sensitivity to GH and the downstream effects on the GH/IGF1 axis are important events in the regulation of metabolism in response to variations in food availability. For example, during periods of reduced nutrient availability, the liver becomes resistant to GH actions. However, the mechanisms controlling hepatic GH resistance are currently unknown. Here, we investigated the role of 2 tetraspanning membrane proteins, leptin receptor overlapping transcript (LEPROT; also known as OB-RGRP) and LEPROT-like 1 (LEPROTL1), in controlling GH sensitivity. Transgenic mice expressing either human LEPROT or human LEPROTL1 displayed growth retardation, reduced plasma IGF1 levels, and impaired hepatic sensitivity to GH, as measured by STAT5 phosphorylation and Socs2 mRNA expression. These phenotypes were accentuated in transgenic mice expressing both proteins. Moreover, gene silencing of either endogenous Leprot or Leprotl1 in H4IIE hepatocytes increased GH signaling and enhanced cell-surface GH receptor. Importantly, we found that both LEPROT and LEPROTL1 expression were regulated in the mouse liver by physiologic and pathologic changes in glucose homeostasis. Together, these data provide evidence that LEPROT and LEPROTL1 influence liver GH signaling and that regulation of the genes encoding these proteins may constitute a molecular link between nutritional signals and GH actions on body growth and metabolism.
Published: 2009

23. Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes

Author: Hervé Dubouchaud, Karine Couturier, Luc Demaison, Martine Lanson, Xavier Leverve, Guillaume Vial, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Géophysique Interne et Tectonophysique (LGIT), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Central des Ponts et Chaussées (LCPC)-Centre National de la Recherche Scientifique (CNRS), FLAveur, VIsion et Comportement du consommateur (FLAVIC), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Hamant, Sarah, Bioenergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Géophysique Interne et Tectonophysique ( LGIT ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Laboratoire Central des Ponts et Chaussées ( LCPC ) -Institut des Sciences de la Terre ( ISTerre ), Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers ( INSU - CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ), FLAveur, VIsion et Comportement du consommateur ( FLAVIC ), Etablissement National d'Enseignement Supérieur Agronomique de Dijon ( ENESAD ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Laboratoire Central des Ponts et Chaussées (LCPC)-Institut des Sciences de la Terre (ISTerre), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers (INSU - CNRS)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), and Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)
Subjects: Male, Wistar, Guanidines, 0302 clinical medicine, MESH : 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Medicine, MESH: Animals, Acidosis, 0303 health sciences, Symporters, Heart, General Medicine, 3. Good health, MESH: Guanidines, Sodium nitroprusside, MESH : Diabetes Mellitus, Experimental, MESH: Endothelium, Vascular, Nitroprusside, medicine.medical_specialty, MESH: Dilatation, Streptozocin, 03 medical and health sciences, Heart rate, Diabetes Mellitus, Endothelium, Lactic Acid, Rats, Wistar, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Sulfones, MESH: Sodium-Hydrogen Antiporter, Cariporide, MESH : Glucose, MESH : Nitroprusside, MESH: Streptozocin, Streptozotocin, medicine.disease, MESH: Heart, 15-Hydroxy-11 alpha, MESH: Carbachol, Endocrinology, Glucose, chemistry, MESH : Endothelium, Vascular, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, MESH : Lactic Acid, MESH: Blood Glucose, Endothelium, Vascular, MESH : Monocarboxylic Acid Transporters, Blood Glucose, Clinical Biochemistry, MESH : Dilatation, 030204 cardiovascular system & hematology, chemistry.chemical_compound, Thromboxane A2, MESH: Diabetes Mellitus, Experimental, Sulfones, MESH: Monocarboxylic Acid Transporters, Sodium-Hydrogen Exchanger 1, MESH : Rats, MESH: Sulfones, MESH : Sodium-Hydrogen Antiporter, MESH : Guanidines, 9 alpha-(epoxymethano)prosta-5, MESH: Glucose, medicine.anatomical_structure, MESH : Symporters, Heart Function Tests, MESH : Heart Function Tests, medicine.symptom, medicine.drug, Monocarboxylic Acid Transporters, MESH: Symporters, Sodium-Hydrogen Exchangers, MESH: Rats, MESH : Male, Sodium-Hydrogen Antiporter, In Vitro Techniques, MESH : Rats, Wistar, Diabetes Mellitus, Experimental, Experimental, MESH : Heart, Internal medicine, Diabetes mellitus, Vascular, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Streptozocin, 030304 developmental biology, business.industry, Cell Biology, MESH: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, MESH: Rats, Wistar, MESH : Blood Glucose, Dilatation, MESH: Male, MESH: Nitroprusside, Rats, Ventricle, MESH : Carbachol, 13-dienoic Acid, Carbachol, MESH: Lactic Acid, MESH : Animals, business, MESH: Heart Function Tests
Abstract: International audience; Hyperglycemia encountered during diabetes triggers abnormalities of vascular function associated with cell acidosis and calcium overload. The purpose of this study was to determine, whether Na+/H+ exchanger (NHE-1) inhibition by cariporide protects coronary cells against the deleterious effect of hyperglycemia in the rat. In vivo hyperglycemia was triggered by streptozotocin injection. One week after, the glycemia was checked and the control and diabetic animals were treated or not with cariporide (2.5 mg/kg/day) for two weeks. Glycemia was again estimated and the hearts were perfused according to the Langendorff mode at forced flow. The left ventricle developed pressure (LVDP) and heart rate (HR) were determined with a latex balloon inserted into the left ventricle. Coronary pressure was artificially increased to 130 mmHg by infusing a thromboxane A2 analogue (U46619). This allowed the evaluation of endothelium-dependent (EDD) and endothelium-independent (EID) dilatation through bolus injections of carbamoylcholin and sodium nitroprusside, respectively. Releases of lactate and pyruvate in the coronary effluents were also determined. Diabetes did not modified LVDP, but reduced HR (-15%). This was associated with a marked decrease in EDD (-56%) and EID (-30%), while the cytosolic redox potential (estimated as the lactate/pyruvate ratio) was reduced. NHE-1 inhibition restored EDD and the lactate/pyruvate ratio without improving EID and HR. The present findings indicate that NHE-1 exchanger inhibition by cariporide protects the coronary endothelium against the deleterious effects of hyperglycemia.
Published: 2008

24. Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-beta: implications for diabetic atherosclerosis

Author: Victoria Ayala, Reinald Pamplona, Manuel Portero-Otin, Anne-Valerie Cantero, Jean-Claude Thiers, Marie Sanson, Nathalie Augé, Meyer Elbaz, Anne Nègre-Salvayre, Robert Salvayre, Régulations cellulaires: lipidoses et atherosclerose, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic Pathophysiology Research GroupDepartment of Basic Medical Sciences, Universitat de Lleida, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Glycation End Products, Advanced, Arginine, Becaplermin, MESH: Rabbits, medicine.disease_cause, Biochemistry, Guanidines, MESH: Mice, Knockout, MESH: Atherosclerosis, Mesoderm, chemistry.chemical_compound, Mice, Cell Movement, MESH: Diabetes Mellitus, Experimental, MESH: Animals, Receptor, MESH: Cell Movement, Aorta, Cells, Cultured, Mice, Knockout, Platelet-Derived Growth Factor, MESH: Mesoderm, biology, Methylglyoxal, MESH: Platelet-Derived Growth Factor, MESH: Arginine, MESH: Aorta, MESH: Myocytes, Smooth Muscle, Glyoxal, Proto-Oncogene Proteins c-sis, Protein-Tyrosine Kinases, Pyruvaldehyde, MESH: Glycosylation End Products, Advanced, MESH: Apolipoproteins E, MESH: Diabetes Complications, MESH: Guanidines, cardiovascular system, Advanced glycation end-product, Rabbits, Tyrosine kinase, Platelet-derived growth factor receptor, Biotechnology, MESH: Cells, Cultured, medicine.medical_specialty, MESH: Pyruvaldehyde, Myocytes, Smooth Muscle, MESH: Glyoxal, MESH: Protein-Tyrosine Kinases, Diabetes Mellitus, Experimental, Diabetes Complications, Receptor, Platelet-Derived Growth Factor beta, Apolipoproteins E, Internal medicine, MESH: Cell Proliferation, Genetics, medicine, Animals, Humans, Molecular Biology, MESH: Mice, Cell Proliferation, MESH: Humans, Cell growth, Atherosclerosis, Endocrinology, chemistry, biology.protein, MESH: Receptor, Platelet-Derived Growth Factor beta, Oxidative stress
Abstract: International audience; PURPOSE: Low molecular weight carbonyl compounds, such as the alpha-ketoaldehydes methylglyoxal (MGO) and glyoxal (GO), are formed under hyperglycemic conditions and behave as advanced glycation end product (AGE) precursors. They form adducts on proteins, thereby inducing cellular dysfunctions involved in chronic complications of diabetes. METHODS AND MAIN FINDINGS: Nontoxic concentrations of GO or MGO altered the PDGF-induced PDGFRbeta-phosphorylation, ERK1/2-activation, and nuclear translocation, and the subsequent proliferation of mesenchymal cells (smooth muscle cells and skin fibroblasts). This resulted mainly from inhibition of the intrinsic tyrosine kinase of PDGFRbeta and in part from altered PDGF-BB binding to PDGFRbeta. Concomitantly, the formation of AGE adducts (N(epsilon)carboxymethyl-lysine and N(epsilon)carboxyethyl-lysine) was observed on immunoprecipitated PDGFRbeta. Arginine and aminoguanidine, used as carbonyl scavengers, reversed the inhibitory effect and the formation of AGE adducts on PDGFRbeta. AGE-PDGFRbeta adducts were also detected by anti-AGE antibodies in PDGFRbeta immunopurified from aortas of diabetic (streptozotocin-treated) compared to nondiabetic apolipoprotein E-null mice. Mass spectrometry analysis of aortas demonstrated increased AGE formation in diabetic specimens. CONCLUSIONS: These data indicate that MGO and GO induce desensitization of PDGFRbeta that helps to reduce mesenchymal cell proliferation.
Published: 2007

25. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions

Author: Takeshi Takazawa, Ryozo Nagai, Hitomi Ogata, Philippe Froguel, Masato Iwabu, Tomohiro Ide, Miki Okada-Iwabu, Tetsuya Kubota, Hideki Kozono, Kazuyuki Tobe, Iseki Takamoto, Yasunori Nio, Atsushi Tsuchida, Yusuke Hada, Masaki Tsunoda, Yusuke Ito, Junji Kamon, Kazuo Hara, Masaki Kobayashi, Toshiyuki Maki, Motoharu Awazawa, Kumpei Tokuyama, Kohjiro Ueki, Katsuyoshi Kumagai, Toshimasa Yamauchi, Naoto Kubota, Kouji Murakami, Sachiko Kawamoto, Takashi Kadowaki, Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Section of Genomic Medicine, Imperial College London, Genome Centre, and Imperial College London-Hammersmith campus
Subjects: Blood Glucose, Male, Peroxisome proliferator-activated receptor, Mice, Obese, MESH: Gene Targeting, MESH: Mice, Knockout, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Diabetes Mellitus, Experimental, MESH: Animals, MESH: Mice, Obese, MESH: Receptors, Cell Surface, MESH: Lipid Metabolism, chemistry.chemical_classification, Adiponectin receptor 1, Mice, Knockout, 0303 health sciences, Adiponectin receptor 2, General Medicine, MESH: Adiponectin, AdipoRon, Gene Targeting, Receptors, Leptin, Female, Adiponectin, Receptors, Adiponectin, Protein Binding, medicine.medical_specialty, Adipokine, 030209 endocrinology & metabolism, Receptors, Cell Surface, Biology, General Biochemistry, Genetics and Molecular Biology, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, medicine, MESH: Protein Binding, Animals, MESH: Mice, 030304 developmental biology, AMPK, Lipid Metabolism, MESH: Male, Mice, Inbred C57BL, Endocrinology, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Blood Glucose, Adiponectin binding, MESH: Female
Abstract: Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.
Published: 2006

26. Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications

Author: Leo Geraci, Alberto Podjarny, Michael L. Jones, Sredy Janet, A. Thomas DiCioccio, J. Howard Jones, David E. Gunn, Michael C. Van Zandt, Diane R. Sawicki, Tatiana V. Petrova, Jorge Jacot, and Andre Mitschler, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Models, Molecular, MESH: Rats, Sprague-Dawley, Pharmacology, Crystallography, X-Ray, 01 natural sciences, Rats, Sprague-Dawley, MESH: Aldehyde Reductase, chemistry.chemical_compound, MESH: Structure-Activity Relationship, Drug Discovery, MESH: Diabetes Mellitus, Experimental, Tissue Distribution, MESH: Animals, Aldehyde Reductase, chemistry.chemical_classification, biology, Chemistry, MESH: Lens, Crystalline, Sciatic Nerve, 3. Good health, MESH: Diabetes Complications, MESH: Sciatic Nerve, Enzyme inhibitor, Molecular Medicine, MESH: Models, Molecular, MESH: Indoleacetic Acids, MESH: Rats, Stereochemistry, MESH: Thiazoles, 010402 general chemistry, Cataract, Diabetes Mellitus, Experimental, Diabetes Complications, Structure-Activity Relationship, Acetic acid, Pharmacokinetics, Diabetes mellitus, Lens, Crystalline, medicine, Animals, Humans, MESH: Tissue Distribution, Aldose reductase, MESH: Humans, Indoleacetic Acids, 010405 organic chemistry, MESH: Chronic Disease, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Crystallography, X-Ray, MESH: Male, Rats, 0104 chemical sciences, Thiazoles, Enzyme, Chronic Disease, biology.protein, Sorbitol, MESH: Cataract
Abstract: International audience; Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).
Published: 2005

27. 5-lipoxygenase expression and activity in aorta from streptozotocin-induced diabetic rats

Author: S. Vergnaud, Gaëlle Hardy, Michel Peoc'h, Françoise Stanke-Labesque, Germain Bessard, J. Lunardi, Roux-Buisson, Nathalie, Laboratoire de Pharmacologie (HP2), CHU Grenoble-Hôpital Michallon, Laboratoire d'enzymologie, CHU Grenoble, Service d'Anatomie pathologique, and Centre hospitalier Universitaire
Subjects: Male, Physiology, Aorta, Thoracic, Biochemistry, Muscle, Smooth, Vascular, chemistry.chemical_compound, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Diabetes Mellitus, Experimental, MESH: Animals, MESH: Isometric Contraction, Calcimycin, chemistry.chemical_classification, Arachidonic Acid, biology, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Enzymologic, MESH: Muscle, Smooth, Vascular, Muscle Tonus, Arachidonate 5-lipoxygenase, Arachidonic acid, medicine.drug, MESH: DNA Primers, medicine.medical_specialty, Leukotrienes, MESH: Rats, MESH: Aorta, Thoracic, chemistry.chemical_element, Calcium, In Vitro Techniques, Gene Expression Regulation, Enzymologic, Diabetes Mellitus, Experimental, Western blot, medicine.artery, Diabetes mellitus, Internal medicine, Isometric Contraction, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA Primers, Pharmacology, Aorta, MESH: Calcimycin, Arachidonate 5-Lipoxygenase, MESH: Leukotrienes, Cell Biology, Streptozotocin, medicine.disease, MESH: Muscle Tonus, MESH: Male, Rats, MESH: Arachidonic Acid, Endocrinology, Enzyme, chemistry, biology.protein, MESH: Arachidonate 5-Lipoxygenase
Abstract: International audience; We previously reported an activation of the 5-lipoxygenase pathway in aorta from streptozotocin-induced diabetic rats. The aim of this study was to investigate whether this activation was associated with an increased expression of 5-lipoxygenase, an increased cysteinyl leukotriene (CysLT) production in response to arachidonic acid or calcium ionophore A23187 and/or a hypersensitivity of the aorta to CysLTs in streptozotocin-induced diabetic rats. In aorta from diabetic and control rats, reverse transcriptase-PCR and western blot analysis with a specific 5-lipoxygenase antibody provided evidence for the presence of 5-lipoxygenase in aorta. However, the expression of 5-lipoxygenase was not significantly different between diabetic and control rats. Challenge by A23187 (10 microM) and arachidonic acid (10 microM and 0.1 mM) with or without A23187 (10 micromol/l) induced a significant increase of CysLT release (measured by enzyme immunoassay) that was in the same range in aorta from control and diabetic rats. In contrast, aortas from diabetic rats showed a greater sensitivity to LTC4 and LTD4 contractile effects. These data suggested that the activation of the 5-lipoxygenase pathway previously reported in streptozotocin-induced diabetic rats could be explained by an augmented sensitivity to CysLTs of the diabetic aorta.
Published: 2005

28. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

Author: Christian Carpéné, Philippe Valet, Charlotte Guigné, J. P. Pradères, Didier Quilliot, Gilles Ferry, Jean A. Boutin, Jean Sébastien Saulnier-Blache, Marie-Françoise Simon, Jeremie Boucher, D. Prévot, Sandra Grès, Saulnier-Blache, Jean Sébastien, Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie, Nutrition et Maladies métaboliques [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche de Croissy, Institut de Recherche Servier, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Endocrinology, Diabetes and Metabolism, Glucose uptake, medicine.medical_treatment, Adipose tissue, Impaired glucose tolerance, Mice, chemistry.chemical_compound, 0302 clinical medicine, Adipocyte, Adipocytes, MESH: Diabetes Mellitus, Experimental, MESH: Animals, Pyrophosphatases, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Gene Expression Regulation, Enzymologic, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Gene Expression Regulation, MESH: Insulin Resistance, Phosphodiesterase I, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), Autotaxin, Rosiglitazone, medicine.drug, MESH: Diabetes Mellitus, Type 2, medicine.medical_specialty, MESH: Biological Transport, MESH: Glycoproteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Deoxyglucose, Biology, Gene Expression Regulation, Enzymologic, Article, Diabetes Mellitus, Experimental, 03 medical and health sciences, Insulin resistance, Lipectomy, Multienzyme Complexes, Internal medicine, Internal Medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Adipocytes, Glycoproteins, 030304 developmental biology, MESH: Humans, Phosphoric Diester Hydrolases, Insulin, Glucose-6-Phosphate Isomerase, Biological Transport, medicine.disease, MESH: Deoxyglucose, Mice, Inbred C57BL, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, chemistry, Insulin Resistance, MESH: Autocrine Motility Factor
Abstract: AIMS/HYPOTHESIS: Autotaxin is a lysophospholipase D that is secreted by adipocytes and whose expression is substantially up-regulated in obese, diabetic db/db mice. The aim of the present study was to depict the physiopathological and cellular mechanisms involved in regulation of adipocyte autotaxin expression. METHODS: Autotaxin mRNAs were quantified in adipose tissue from db/db mice (obese and highly diabetic type 2), gold-thioglucose-treated (GTG) mice (highly obese and moderately diabetic type 2), high-fat diet-fed (HFD) mice (obese and moderately diabetic type 2), streptozotocin-treated mice (thin and diabetic type 1), and massively obese humans with glucose intolerance. RESULTS: When compared to non-obese controls, autotaxin expression in db/db mice was significantly increased, but not in GTG, HFD, or streptozotocin-treated mice. During db/db mice development, up-regulation of autotaxin occurred only 3 weeks after the emergence of hyperinsulinaemia, and simultaneously with the emergence of hyperglycaaemia. Adipocytes from db/db mice exhibited a stronger impairment of insulin-stimulated glucose uptake than non-obese and HFD-induced obese mice. Autotaxin expression was up-regulated by treatment with TNFalpha (insulin resistance-promoting cytokine), and down-regulated by rosiglitazone treatment (insulin-sensitising compound) in 3T3F442A adipocytes. Finally, adipose tissue autotaxin expression was significantly up-regulated in patients exhibiting both insulin resistance and impaired glucose tolerance. CONCLUSIONS/INTERPRETATION: The present work demonstrates the existence of a db/db-specific up-regulation of adipocyte autotaxin expression, which could be related to the severe type 2 diabetes phenotype and adipocyte insulin resistance, rather than excess adiposity in itself. It also showed that type 2 diabetes in humans is also associated with up-regulation of adipocyte autotaxin expression.
Published: 2005

29. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice

Author: Isabelle Hainault, Dalila Azzout-Marniche, Pascal Ferré, Lydia Bertry-Coussot, Dominique Bécard, Fabienne Foufelle, Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Azzout-Marniche, Dalila, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: Male, MESH : RNA, Messenger, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: CCAAT-Enhancer-Binding Proteins, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Homeostasis, Insulin, Glucose homeostasis, MESH: Animals, 0303 health sciences, MESH: Mice, Inbred CBA, Glycogen, Gene Transfer Techniques, MESH: Adenoviridae, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Transcription Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Genetic Vectors, 3. Good health, MESH : DNA-Binding Proteins, MESH : Diabetes Mellitus, Experimental, Sterol Regulatory Element Binding Protein 1, medicine.medical_specialty, MESH: Gene Expression, MESH: Gene Transfer Techniques, MESH: Insulin, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Adenoviridae, MESH: Sterol Regulatory Element Binding Protein 1, 03 medical and health sciences, MESH : Sterol Regulatory Element Binding Protein 1, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], RNA, Messenger, MESH : Gene Transfer Techniques, MESH : Injections, Intraperitoneal, MESH : Glucose, Glucokinase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH : Gene Expression, Glucose, Endocrinology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], chemistry, CCAAT-Enhancer-Binding Proteins, Mice, Inbred CBA, MESH: Liver, Transcription Factors, MESH : Transcription Factors, MESH : Insulin, MESH : Mice, Inbred CBA, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Gene Expression, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chemistry.chemical_compound, MESH: Genetic Vectors, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Diabetes Mellitus, Experimental, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Recombinant Proteins, MESH: Glucose, DNA-Binding Proteins, Liver, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Homeostasis, MESH : Homeostasis, Phosphoenolpyruvate carboxykinase, MESH: Injections, Intraperitoneal, Injections, Intraperitoneal, MESH : Recombinant Proteins, MESH : Male, Genetic Vectors, 030209 endocrinology & metabolism, Biology, Diabetes Mellitus, Experimental, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [ SDV.BBM.MN ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Diabetes mellitus, Internal medicine, MESH : Mice, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Internal Medicine, medicine, Animals, MESH : Adenoviridae, MESH: Mice, Transcription factor, MESH: RNA, Messenger, 030304 developmental biology, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH : Liver, Metabolism, MESH: Male, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH : Animals, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: DNA-Binding Proteins
Abstract: International audience; In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway. This in turn increases glycogen and triglyceride hepatic content and leads to a marked decrease in hyperglycemia in diabetic mice. We conclude that SREBP-1c has a major role in vivo in the long-term control of glucose homeostasis by insulin.
Published: 2001

30. Improved myocardial tolerance to ischaemia in the diabetic rabbit

Author: M de Lorgeril, R. Forrat, Laurent Sebbag, J. Delaye, G Hadour, René Ferrera, Cardioprotection, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Médico-Chirurgical de Transplantation Cardiaque Adulte, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire d'Etudes du Comportement à Long Terme des matériaux de conditionnement (LCLT), Département de recherche sur les technologies pour l'enrichissement, le démantèlement et les déchets (DE2D), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Département de recherche sur les Procédés et Matériaux pour les Environnements complexes (DPME), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, medicine.medical_specialty, Radioactive microsphere technique, Myocardial Infarction, Collateral Circulation, MESH: Rabbits, MESH: Coronary Circulation, 030204 cardiovascular system & hematology, Diabetes Mellitus, Experimental, 03 medical and health sciences, chemistry.chemical_compound, Coronary circulation, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Alloxan, Diabetes mellitus, Coronary Circulation, medicine, MESH: Diabetes Mellitus, Experimental, Animals, MESH: Animals, Myocardial infarction, Molecular Biology, 030304 developmental biology, MESH: Collateral Circulation, 0303 health sciences, business.industry, Heart, medicine.disease, Collateral circulation, MESH: Male, 3. Good health, MESH: Heart, MESH: Ischemic Preconditioning, Myocardial, MESH: Myocardial Infarction, medicine.anatomical_structure, chemistry, Coronary occlusion, Ischemic Preconditioning, Myocardial, Cardiology, Ischemic preconditioning, Rabbits, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; Because cardiac complications after myocardial infarction are more frequent in diabetics, we tested whether experimentally-induced diabetes may increase ischaemic myocardial injury in 23 rabbits. Diabetes was induced in randomized rabbits with the alloxan method. After 2 months, diabetic rabbits underwent a 30-min coronary occlusion followed by 3-h reperfusion and were compared with controls. Collateral flow was measured by the radioactive microsphere technique and infarct size by tetrazolium staining. Infarct size represented 28.6+/-4% of area-at-risk in controls and 16.5+/-3% in diabetics (P
Published: 1998

31. Acute myocardial infarction in dogs with experimental diabetes

Author: Forrat, R., Sebbag, L., Wiernsperger, N., Guidollet, J., Renaud, S., De Lorgeril, M., Pôle Médico-Chirurgical de Transplantation Cardiaque Adulte, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), LIPHA Sté, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: MESH: Collateral Circulation, MESH: Dogs, MESH: Hematocrit, MESH: Myocardial Infarction, MESH: Myocardium, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Diabetes Mellitus, Experimental, MESH: Myocardial Reperfusion, MESH: Animals, MESH: Coronary Circulation, MESH: Female, MESH: Male, MESH: Platelet Aggregation
Abstract: International audience; OBJECTIVE: The aim was to examine whether diabetes interferes with the development of myocardial injury in a canine ischaemia-reperfusion model. METHODS: Non-insulin-requiring diabetes was induced in dogs by the streptozotocin-alloxan method. After 75 d, the dogs were anaesthetised and myocardial infarction was provoked by occluding the left anterior descending coronary artery for 2 h followed by 6 h reperfusion. RESULTS: Diabetic dogs had higher blood glucose [9.4(SEM 1) mmol.litre-1], fructosamine [417(57) mumol.litre-1], and glycated haemoglobin [3.3(0.7)%], than control dogs [5.5(0.6), p = 0.04, 243(15), p = 0.01, and 0.7(0.2), p = 0.003, respectively], and they also had higher serum lipids (p = 0.001) and platelet aggregation (p = 0.03). Area at risk was similar in diabetic and control dogs but in contrast to controls (r = 0.78, p = 0.007), area at risk and infarct size were not correlated in diabetics (r = 0.08). In both groups, collateral flow was the major determinant of infarct size: r = -0.73 in controls (p = 0.02) and -0.97 in diabetics (p = 0.001). In spite of higher subendocardial collateral flow in diabetics [representing 21.6(6)% of the flow in the corresponding non-ischaemic zone] than in controls [11.2(6)%], infarct size was similar in both groups. However, the mean observed infarct size in the diabetic group [7.5(2.8)% of the left ventricle] was significantly (p < 0.03) larger than the mean predicted infarct size [5.2(2)%]. Multivariate analysis confirmed that diabetes, as well as collateral flow, is an independent (p = 0.03) predictor of infarct size. CONCLUSIONS: For a given collateral flow, diabetic dogs develop larger infarcts than controls. Further studies are required to investigate the biochemical mechanism(s) underlying this deleterious effect. However, this may partly explain the poor prognosis of myocardial infarction in diabetic persons.
Published: 1993

32. Acute myocardial infarction in dogs with experimental diabetes

Author: Forrat, R., Sebbag, L., Wiernsperger, N., Guidollet, J., Renaud, S., De Lorgeril, M., Pôle Médico-Chirurgical de Transplantation Cardiaque Adulte, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), LIPHA Sté, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: MESH: Collateral Circulation, MESH: Dogs, MESH: Hematocrit, MESH: Myocardial Infarction, MESH: Myocardium, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Diabetes Mellitus, Experimental, MESH: Myocardial Reperfusion, MESH: Animals, MESH: Coronary Circulation, MESH: Female, MESH: Male, MESH: Platelet Aggregation
Abstract: International audience; OBJECTIVE: The aim was to examine whether diabetes interferes with the development of myocardial injury in a canine ischaemia-reperfusion model. METHODS: Non-insulin-requiring diabetes was induced in dogs by the streptozotocin-alloxan method. After 75 d, the dogs were anaesthetised and myocardial infarction was provoked by occluding the left anterior descending coronary artery for 2 h followed by 6 h reperfusion. RESULTS: Diabetic dogs had higher blood glucose [9.4(SEM 1) mmol.litre-1], fructosamine [417(57) mumol.litre-1], and glycated haemoglobin [3.3(0.7)%], than control dogs [5.5(0.6), p = 0.04, 243(15), p = 0.01, and 0.7(0.2), p = 0.003, respectively], and they also had higher serum lipids (p = 0.001) and platelet aggregation (p = 0.03). Area at risk was similar in diabetic and control dogs but in contrast to controls (r = 0.78, p = 0.007), area at risk and infarct size were not correlated in diabetics (r = 0.08). In both groups, collateral flow was the major determinant of infarct size: r = -0.73 in controls (p = 0.02) and -0.97 in diabetics (p = 0.001). In spite of higher subendocardial collateral flow in diabetics [representing 21.6(6)% of the flow in the corresponding non-ischaemic zone] than in controls [11.2(6)%], infarct size was similar in both groups. However, the mean observed infarct size in the diabetic group [7.5(2.8)% of the left ventricle] was significantly (p < 0.03) larger than the mean predicted infarct size [5.2(2)%]. Multivariate analysis confirmed that diabetes, as well as collateral flow, is an independent (p = 0.03) predictor of infarct size. CONCLUSIONS: For a given collateral flow, diabetic dogs develop larger infarcts than controls. Further studies are required to investigate the biochemical mechanism(s) underlying this deleterious effect. However, this may partly explain the poor prognosis of myocardial infarction in diabetic persons.
Published: 1993

33. Thyrotropin releasing hormone in the pancreas of newborn rats from streptozotocin-treated mothers

Author: P. Salers, Anne Dutour, Vladimír Štrbák, L'Houcine Ouafik, Pierre Giraud, A. Randušková, Charles Oliver, Erika Resetkova, Ouafik, L'Houcine, Institute of Experimental Endocrinology, Slovak Academy of Science [Bratislava] (SAS), INSERM U 297 - Laboratoire de Neuroendocrinologie Expérimentale, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Protein Precursors, Aging, endocrine system diseases, MESH: Piperazines, Pregnancy in Diabetics, Thyrotropin-releasing hormone, MESH: Animals, Newborn, Piperazines, MESH: Pregnancy, Pregnancy, MESH: Diabetes Mellitus, Experimental, Insulin, MESH: Aging, MESH: Animals, General Pharmacology, Toxicology and Pharmaceutics, Thyrotropin-Releasing Hormone, Radioimmunoassay, General Medicine, MESH: Pancreas, MESH: Rats, Inbred Strains, medicine.anatomical_structure, MESH: Pregnancy in Diabetics, Gestation, Female, Pancreas, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, endocrine system, MESH: Rats, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Insulin, Biology, Peptide hormone, Peptides, Cyclic, General Biochemistry, Genetics and Molecular Biology, Diabetes Mellitus, Experimental, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Thyrotropin-Releasing Hormone, Diabetes mellitus, Internal medicine, medicine, Animals, Protein Precursors, MESH: Peptides, Cyclic, Rats, Inbred Strains, medicine.disease, Streptozotocin, Rats, Endocrinology, Animals, Newborn, MESH: Female
Abstract: International audience; The effect of maternal diabetes (induced by i.p. injections of 40-50 mg/kg BW Streptozotocin on the day of mating) on TRH in the pancreas of newborn rats was studied. Determination of peptide alpha amidation activity and TRH precursor level on the day of birth revealed decreased biosynthesis of TRH resulting in profoundly (10 times) lower pancreatic TRH and TRH-OH concentrations in pups of diabetic rats. Pancreatic His-Pro-diketopiperazine (His-Pro-DKP) remained unaffected by maternal diabetes. The depression of pancreatic TRH was less profound 24 h later, and even elevated TRH was measured in the pancreas of pups of diabetic mothers on postnatal day 5. Short term postnatal starvation or nursing of intact pups by the diabetic foster mother did not affect pancreatic TRH. It could be postulated that postnatal TRH development in the rat pancreas is retarded by maternal diabetes, while His-Pro-DKP remains unaltered.
Published: 1989

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33 results on '"MESH: Diabetes Mellitus, Experimental"'

1. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations

2. Inflammation-linked adaptations in dermal microvascular reactivity accompany the development of obesity and type 2 diabetes

3. Erythropoietin Restores C-Fiber Function and Prevents Pressure Ulcer Formation in Diabetic Mice

4. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice.: LEPROTs decrease growth hormone signaling

5. Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

6. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

7. Interferon-α as a Mediator of Polyinosinic:Polycytidylic Acid–Induced Type 1 Diabetes

8. Early pre-diabetic state alters adaptation of myocardial glucose metabolism during ischemia in rats

9. Insulinotropic agent ID-1101 (4-hydroxyisoleucine) activates insulin signaling in rat

10. Effect of Chronic Severe Diabetes on Myocardial Stunning in the Dog

11. Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats

12. Intravenous infusion of donor apoptotic leukocytes before transplantation delays allogeneic islet graft rejection through regulatory T cells

13. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota

14. Combined insulin treatment and intense exercise training improved basal cardiac function and Ca(2+)-cycling proteins expression in type 1 diabetic rats

15. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production

16. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice.: xanthine oxidase-induced muscle oxidative stress

17. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

18. Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice

19. PPARβ/δ activation induces enteroendocrine L cell GLP-1 production

20. Effects of exercise training combined with insulin treatment on cardiac NOS1 signaling pathways in type 1 diabetic rats

21. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice

22. LEPROT and LEPROTL1 cooperatively decrease hepatic growth hormone action in mice

23. Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes

24. Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-beta: implications for diabetic atherosclerosis

25. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions

26. Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications

27. 5-lipoxygenase expression and activity in aorta from streptozotocin-induced diabetic rats

28. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

29. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice

30. Improved myocardial tolerance to ischaemia in the diabetic rabbit

31. Acute myocardial infarction in dogs with experimental diabetes

32. Acute myocardial infarction in dogs with experimental diabetes

33. Thyrotropin releasing hormone in the pancreas of newborn rats from streptozotocin-treated mothers

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33 results on '"MESH: Diabetes Mellitus, Experimental"'

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