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1. The Atypical Cannabinoid Abn-CBD Reduces Inflammation and Protects Liver, Pancreas, and Adipose Tissue in a Mouse Model of Prediabetes and Non-alcoholic Fatty Liver Disease

Author

Silvana Y. Romero-Zerbo, María García-Fernández, Vanesa Espinosa-Jiménez, Macarena Pozo-Morales, Alejandro Escamilla-Sánchez, Lourdes Sánchez-Salido, Estrella Lara, Nadia Cobo-Vuilleumier, Alex Rafacho, Gabriel Olveira, Gemma Rojo-Martínez, Benoit R. Gauthier, Isabel González-Mariscal, Francisco J. Bermúdez-Silva, [Romero-Zerbo,SY, Espinosa-Jiménez,V, Pozo-Morales,M, Sánchez-Salido,L, Olveira,G, Rojo-Martínez,G, González-Mariscal,I, Bermúdez-Silva, FJ] UGC Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Regional de Málaga, Universidad de Málaga, Málaga, Spain. [García-Fernández,M, Lara,E, ] Departamento de Fisiología Humana, Facultad de Medicina, Instituto de Investigación Biomédica de Málaga-IBIMA, Universidad de Málaga, Málaga, Spain. [Escamilla-Sánchez,A] Plataforma de Microscopía, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [Cobo-Vuilleumier,N, Gauthier,BR] Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain. [Rafacho,A] Laboratory of Investigation in Chronic Diseases - LIDoC, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil. [Olveira,G, Gauthier,BR, Bermúdez-Silva,FJ] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain., This work was supported by Consejería de Salud de la Junta de Andalucía Andalucía se mueve con Europa (PI-0574-2012 to SR-Z) and Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad, Gobierno de España Una manera de hacer Europa (13/00309 and 17/01004 to FB-S, co-funded by FEDER, EU). SR-Z was recipient of a postdoctoral fellowship from Consejeria de Salud de la Junta de Andalucia (RH-0070-2013). AR received a short-term stay fellowship from Banco Santander (Programa Bolsas Iberoamericanas Jovens Professores e Pesquisadores) and was funded by a CNPq research grant (Grant No. 306359/2017-0). IG-M was funded by the European Commission Research & Innovation, Horizon2020 program, call H2020-MSCA-IF-2016 (GA: 748749). FB-S belongs to the regional Nicolás Monardes research program of the Consejería de Salud (C-0070-2012 and RC0005-2016, Junta de Andalucía, Spain). BG was supported by the Ministerio de Economia y Competitividad co-funded by FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P). CIBERDEM is an initiative of the Instituto de Salud Carlos III., Junta de Andalucía, European Commission, Instituto de Salud Carlos III, Ministerio de Sanidad (España), Banco Santander, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
Male, 0301 basic medicine, obesity, Anatomy::Digestive System::Liver [Medical Subject Headings], Endocrinology, Diabetes and Metabolism, Obesidad, Mice, Obese, Adipose tissue, White adipose tissue, prediabetes, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Mice, Endocrinology, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Organisms::Eukaryota::Animals [Medical Subject Headings], Hyperinsulinemia, Medicine, Glucose homeostasis, Original Research, Anatomy::Digestive System::Pancreas [Medical Subject Headings], Hígado, Fatty liver, Islets of langerhans, Enfermedad del hígado graso no alcohólico, Anatomy::Tissues::Connective Tissue::Adipose Tissue [Medical Subject Headings], 3. Good health, medicine.anatomical_structure, surgical procedures, operative, Adipose Tissue, Liver, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Phenols::Resorcinols [Medical Subject Headings], Cannabinoides, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Pharmacological Processes::Cytoprotection [Medical Subject Headings], islets of Langerhans, medicine.symptom, Beta cell, Tejido adiposo, medicine.medical_specialty, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Obese [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Diseases::Digestive System Diseases::Liver Diseases::Fatty Liver [Medical Subject Headings], 030209 endocrinology & metabolism, Inflammation, Diet, High-Fat, liver, digestive system, Prediabetic State, 03 medical and health sciences, cannabinoids, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Diet, High-Fat [Medical Subject Headings], Internal medicine, NAFLD, Animals, Obesity, Pancreas, Diseases::Endocrine System Diseases::Diabetes Mellitus::Prediabetic State [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], lcsh:RC648-665, Inflamación, Cannabinoids, business.industry, Pancreatic islets, Resorcinols, medicine.disease, digestive system diseases, Islotes pancreáticos, Diseases::Animal Diseases::Disease Models, Animal [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Cytoprotection, inflammation, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], business, Prediabetes, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings]
Abstract

[Background and Aims]: The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD)., [Materials and Methods]: Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis., [Results]: Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice., [Conclusions]: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders., This work was supported by Consejería de Salud de la Junta de Andalucía Andalucía se mueve con Europa (PI-0574-2012 to SR-Z) and Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad, Gobierno de España Una manera de hacer Europa (13/00309 and 17/01004 to FB-S, co-funded by FEDER, EU). SR-Z was recipient of a postdoctoral fellowship from Consejeria de Salud de la Junta de Andalucia (RH-0070-2013). AR received a short-term stay fellowship from Banco Santander (Programa Bolsas Iberoamericanas Jovens Professores e Pesquisadores) and was funded by a CNPq research grant (Grant No. 306359/2017-0). IG-M was funded by the European Commission Research & Innovation, Horizon2020 program, call H2020-MSCA-IF-2016 (GA: 748749). FB-S belongs to the regional Nicolás Monardes research program of the Consejería de Salud (C-0070-2012 and RC0005-2016; Junta de Andalucía, Spain). BG was supported by the Ministerio de Economia y Competitividad co-funded by FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

Published
2020
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2. LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus

Author

Francisco-Javier Bermúdez-Silva, Reinhold Schirmbeck, Piero Marchetti, Livia López-Noriega, Paolo Meda, Nadia Cobo-Vuilleumier, Christian Claude Lachaud, Petra I. Lorenzo, Noelia García Rodríguez, Abdelkrim Hmadcha, Bernat Soria, Marco Bugliani, Esther Fuente-Martin, Katja Stifter, Peter de Haan, Alejandro Martin-Montalvo, Miguel G. Toscano, Luc St-Onge, Géraldine Parnaud, Vincenzo De Tata, Germán Perdomo, Silvana-Yanina Romero-Zerbo, Luis Sánchez Palazón, David Pozo, Benoit R. Gauthier, Kristina Schoonjans, Javier Florido, Irene de Gracia Herrera Gómez, José Manuel Mellado-Gil, Domenico Bosco, Mathurin Baquié, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Juvenile Diabetes Research Foundation, Junta de Andalucía, Ministerio de Economía y Competitividad (España), European Commission, German Research Foundation, Instituto de Salud Carlos III, Amarna Therapeutics, Centro Andaluz de Investigaciones en Biología Molecular y Medina Regenerativa (CABIMER), [Cobo-Vuilleumier,N, Lorenzo,PI, García Rodríguez,N, Herrera Gómez,IG, Fuente-Martin,E, López-Noriega,L, Mellado-Gil,JM, Claude Lachaud,C, Hmadcha,A, Martín-Montalvo,A, Soria,B, Gauthier, BR] Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, 41092, Spain. [Romero-Zerbo,SY, Bermúdez-Silva,FJ] Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA) Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, 29010, Spain. [Romero-Zerbo,SY, Bermúdez-Silva,FJ] Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, 28029, Spain. [Baquié,M] Neurix SA, Geneva, 1228, Switzerland. [Stifter,K, Schirmbeck,R] Ulm University Hospital, Ulm, 89081, Germany. [Perdomo,G] Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, 09001, Spain. [Bugliani,M, Marchetti,P] Department Clinical and Experimental Medicine, University of Pisa—AOUP University Hospital, Pisa, 56126, Italy. [De Tata,V] Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, 56126, Italy. [Bosco,D, Parnaud,G] Cell Isolation and Transplantation Centre, University Hospital, Geneva, 1211, Switzerland. [Pozo,D] Department of Cell Dynamics and Signalling, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain. [Florido,JP] Clinical Bioinformatics Area, Fundación Progreso y Salud, Consejería de Salud, Seville, 41013, Spain. [Toscano,MG, and de Haan,P] Amarna Therapeutics, Seville, 41092, Spain. [Schoonjans,K] Laboratory of Metabolic Signaling, EPFL, Lausanne, 1015, Switzerland. [Sánchez Palazón,L] Biological Resources, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, 41092, Spain. [Meda,P] Department of Cell Physiology and Metabolism, University of Geneva, Geneva, 1211, Switzerland. [St-Onge,L] Neuried Munich, 82061, Germany.

Subjects
Genetics and Molecular Biology (all), Male, endocrine system diseases, Trans-Differentiation, Cell Communication/drug effects, Islets of Langerhans Transplantation, Receptors, Cytoplasmic and Nuclear, Apoptosis, Cell Communication, T-Lymphocytes, Regulatory, Biochemistry, Mice, Endocrinology, Islet Regeneration, Organisms::Eukaryota::Animals [Medical Subject Headings], Insulin, Macrophages/drug effects/immunology/pathology, lcsh:Science, geography.geographical_feature_category, Islets of Langerhans/drug effects/immunology/pathology, ddc:617, Type 1 diabetes, Phenalenes/pharmacology, Pancreas, Regulatory/drug effects/immunology/pathology, Islotes Pancreáticos, Science, General Biochemistry, Genetics and Molecular Biology, Streptozocin, 03 medical and health sciences, Physics and Astronomy (all), Islets of Langerhans, Cytoplasmic and Nuclear/agonists/genetics/immunology, Diabetes Mellitus, Humans, Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 1 [Medical Subject Headings], Macrophages, Apoptosis/drug effects, Immunity, Diseases::Endocrine System Diseases::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], nutritional and metabolic diseases, Insulin-Secreting Cells/drug effects/immunology/pathology, medicine.disease, Immunity, Innate, Lrh-1, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 2, Nr5a2, lcsh:Q, Chemistry (all), Biochemistry, Genetics and Molecular Biology (all), 0301 basic medicine, T-Lymphocytes, General Physics and Astronomy, Diabetes Mellitus Tipo 2, Type 2 diabetes, Diabetes Mellitus Tipo 1, Inbred C57BL, Insulin-Secreting Cells, Receptors, Endocrinología, Innate, Heterologous, Multidisciplinary, Diabetes, Type 2/genetics/immunology/pathology, Phenalenes, Islet, medicine.anatomical_structure, Female, medicine.symptom, Beta cell, Cell Survival/drug effects, Insulin/metabolism, Cell Survival, Transplantation, Heterologous, Inflammation, Diabetes Mellitus, Experimental, Hypoglycemic Agents/pharmacology, Immune system, Anatomy::Endocrine System::Endocrine Glands::Islets of Langerhans [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae [Medical Subject Headings], Immune Tolerance, medicine, Hypoglycemic Agents, Animals, ddc:612, geography, Transplantation, Diseases::Endocrine System Diseases::Diabetes Mellitus [Medical Subject Headings], business.industry, Pancreatic islets, General Chemistry, Microreview, Experimental/chemically induced/genetics/immunology/therapy, Gene Expression Regulation, Cancer research, Therapy, business
Abstract

Cobo-Vuilleumier, Nadia et al., Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus., This work was funded by grants from the Juvenile Diabetes Research Foundation (17-2013-372 to B.R.G.), the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and P10CTS6505 to B.S.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competidividad co-funded by Fondos FEDER (PI10/00871, PI13/00593, and BFU2017-83588-P to B.R.G.; PI14/01015, RD12/0019/0028, and RD16/0011/0034 to B.S.; PI16/00259 to A.H.) and Deutsche Forschungsgemeinschaft (GRK-1789 ´CEMMA´ and DFG SCHI-505/6-1 to R.S.). Special thanks to the families of the DiabetesCero Foundation that graciously supported this work (to B.R.G.). A.M.M. is a recipient of a Miguel Servet grant (CP14/00105) from the Instituto de Salud Carlos III co-funded by Fondos FEDER whereas E.F.M. is a recipient of a Juan de la Cierva Fellowship. I.G.H.G. is supported by a fellowship from Amarna Therapeutics. In some instances, human islets were procured through the European Consortium for Islet Transplantation funded by Juvenile Diabetes Research Foundation (3-RSC-2016-162-I-X).

Published
2018

3. PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet

Author

Alejandro Martin-Montalvo, Petra I. Lorenzo, Nadia Cobo-Vuilleumier, Benoit R. Gauthier, Esther Fuente-Martín, Bernat Soria, José Manuel Mellado-Gil, Carmen Maria Jimenez-Moreno, Irene de Gracia Herrera Gómez, Livia López Noriega, Thierry Brun, [Lorenzo,PI, Fuente-Martín,E, Cobo-Vuilleumier,N, Jimenez-Moreno,CM, Herrera Gomez,IG, López Noriega,L, Mellado-Gil, JM, Martin-Montalvo,A, Gauthier,BR] Pancreatic Islet Development and Regeneration Unit, and [Soria,B] Cellular Therapy of Diabetes Mellitus and its Complications, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain. [Brun,T] Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. [Soria,B] CIBERDEM, Instituto Carlos III, Madrid, Spain, and This work was funded by grants from the Consejeria de Salud, Fundacion Publica Andaluza Progreso y Salud, Junta de Andalucia (PI-0727-2010 to B.R.G. and PI-0085-2013 to P.I.L.), Consejeria de Economia, Innovacion y Ciencia (P10.CTS.6359 to B.R.G.), the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III co-funded by Fondos FEDER (PI10/00871 and PI13/00593 to B.R.G.) and the Fundacion Vencer el Cancer (to B.R.G.).

Subjects
Aumento de la célula, Apoptosis, Green fluorescent protein, Cell growth, Mice, Insulin-Secreting Cells, Insulin Secretion, Insulin, Paired Box Transcription Factors, Promoter Regions, Genetic, Regulation of gene expression, education.field_of_study, Multidisciplinary, geography.geographical_feature_category, ndocrine system and metabolic diseases, Islet, Enfermedades del sistema endocrino, Cell biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings], Enfermedades metabólicas, medicine.medical_specialty, Green Fluorescent Proteins, Population, Cre recombinase, Mice, Transgenic, Biology, Article, Internal medicine, Diabetes Mellitus, medicine, Animals, Cell Lineage, Progenitor cell, education, Cell Proliferation, Homeodomain Proteins, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Dedifferentiation [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], geography, Anatomy::Digestive System::Pancreas::Islets of Langerhans [Medical Subject Headings], Anatomy::Cells::Endocrine Cells::Enteroendocrine Cells::Insulin-Secreting Cells [Medical Subject Headings], Cell Dedifferentiation, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Mice, Inbred C57BL, Endocrinology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Luminescent Proteins::Green Fluorescent Proteins [Medical Subject Headings], Gene Expression Regulation, Hyperglycemia, PAX4
Abstract

PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4+ progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP+ subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP+ cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP+ cells were more resistant to apoptosis than their GFP- counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets.

Published
2015
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4. Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene

Author

Pablo Rodriguez-Bada, Maria Adelaida Garcia-Gimeno, Lorenzo Lenzi, Elena Baixeras, Paolo Ciampalini, Pascual Sanz, Carlo Dionisi-Vici, Nadia Cobo-Vuilleumier, Patrizia Banin, Ornella Massa, Fernando Rodríguez de Fonseca, Juan Carlos Aledo, Carlo Colombo, Fabrizio Barbetti, Francisco Javier Bermúdez-Silva, Sonia Toni, A. Cuesta-MuNoz, [Barbetti,F, Dionisi-Vici,C, Ciampalini,P, Massa,O, Colombo,C] Bambino Gesú Pediatric Hospital Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. [Barbetti,F] Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. Laboratory of Molecular Endocrinology and Metabolism, S Raffaele Biomedical Park Foundation, Rome, Italy. [Cobo-Vuilleumier,N, Rodriguez-Bada,P, Bermudez-Silva,FJ, Rodriguez de Fonseca,F, Aledo,JC, Baixeras,E, Cuesta-Muñoz,AL] Center for the Study of Pancreatic-Cell Diseases. Instituto Mediterráneo para el Avance de la Biotecnología y la Investigación Sanitaria Foundation and Carlos Haya Hospital, Málaga, Spain. [Toni,S, Lenzi,L] Regional Center for Juvenile Diabetes, Meyer Pediatric Hospital, Florence, Italy. [Garcia-Gimeno,MA, Sanz,P] Institute of Biomedicine of Valencia (CSIC). CIBERER-ISCIII, Valencia, Spain. [Banin,P] Pediatric and Adolescent Unit, S. Anna Hospital, Ferrara, Italy. [Aledo,JC] Molecular Biology and Biochemistry Department University of Málaga, Spain., This work was supported by grants (to A.L.C.-M. and N.C.-V.) from Ministerio de Ciencia e Innovación, Dirección General de Investigación Científica y Técnica (SAF2005-08014, SAF2006-12863) and Junta de Andalucía (SAS/PI-024/2007, and SAS/PI-0236/2009).

Subjects
Male, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Phenomena and Processes::Physical Phenomena::Mechanical Phenomena::Kinetics [Medical Subject Headings], medicine.medical_treatment, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings], Mutagénesis Sitio-Dirigida, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hypoglycemia [Medical Subject Headings], medicine.disease_cause, Settore MED/13 - Endocrinologia, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical [Medical Subject Headings], Endocrinology, Glucokinase structural analysis, Recién Nacido, Monogenic Diabetes, Glucokinase, Masculino, Original Research, Genetics, Glucokinase mutations, Mutation, Femenino, Modelos Teóricos, General Medicine, Phenotype, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Pedigree, Humanos, Monogenic Hyperinsulinism, Glucokinase Disease, Female, Hipoglucemia, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Engineering::Protein Engineering::Mutagenesis, Site-Directed [Medical Subject Headings], Fenotipo, medicine.medical_specialty, Familiar Hyperinsulinism, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Predisposición Genética a la Enfermedad, Check Tags::Male [Medical Subject Headings], Biology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Glucokinase [Medical Subject Headings], Named Groups::Persons::Age Groups::Infant::Infant, Newborn [Medical Subject Headings], Cinética, Internal medicine, Diabetes mellitus, Linaje, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Mutación, Insulin, Neonatal hypoglycemia, Infant, Newborn, Models, Theoretical, medicine.disease, Glucoquinasa, Hypoglycemia, Kinetics, Check Tags::Female [Medical Subject Headings], Congenital hyperinsulinism, Mutagenesis, Site-Directed
Abstract

7 páginas, 3 figuras, 2 tablas., Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported, This work was supported by grants (to A.L.C.-M. and N.C.-V.) from Ministerio de Ciencia e Innovación, Dirección General de Investigación Científica y Técnica (SAF2005-08014; SAF2006-12863) and Junta de Andalucía (SAS/PI-024/2007; SAS/PI-0236/2009)

Published
2009

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