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22 results on '"MESH: Insulin-Secreting Cells"'

1. SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

Author

Nancy Antoine, Lucie Ruiz, Holger Klein, Patrick Gilon, Anne Wojtusciszyn, Fiona M. Gribble, Frank Reimann, Robert Augustin, Bao-Khanh Lai, Bilal Singh, Michael P. Pieper, Eva Gatineau, Nano Rita, Mohammed Bensellam, Pedro Luis Herrera, Birgit Stierstorfer, Firas Khattab, Heeyoung Chae, Lorenzo Piemonti, Davide Brusa, Michael Mark, Eric Mayoux, Christophe Broca, Université Catholique de Louvain = Catholic University of Louvain (UCL), Boehringer Ingelheim Pharma GmbH & Co. KG, University of Geneva [Switzerland], Addenbrooke's Hospital, Cambridge University NHS Trust, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Lausanne University Hospital, IRCCS Ospedale San Raffaele [Milan, Italy], Chae, Heeyoung, Augustin, Robert, Gatineau, Eva, Mayoux, Eric, Bensellam, Mohammed, Antoine, Nancy, Khattab, Fira, Lai, Bao-Khanh, Brusa, Davide, Stierstorfer, Birgit, Klein, Holger, Singh, Bilal, Ruiz, Lucie, Pieper, Michael, Mark, Michael, Herrera, Pedro L, Gribble, Fiona M, Reimann, Frank, Wojtusciszyn, Anne, Broca, Christophe, Rita, Nano, Piemonti, Lorenzo, Gilon, Patrick, Gribble, Fiona [0000-0002-4232-2898], Reimann, Frank [0000-0001-9399-6377], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Blood Glucose, medicine.medical_treatment, IC50, half maximal inhibitory concentration, SGLT2i, sodium-glucose cotransporter 2 inhibitors, MESH: Insulin Secretion, MESH: Glucosides, MESH: Insulin-Secreting Cells, chemistry.chemical_compound, Mice, αMG, α-methyl-D-glucopyranoside, EGP, endogenous glucose production, 0302 clinical medicine, Glucosides, Glucagon-Like Peptide 1, Insulin-Secreting Cells, FACS, fluorescence-activated cell sorting, Insulin Secretion, Insulin, ddc:576.5, MESH: Animals, Dapagliflozin, geography.geographical_feature_category, Chemistry, MESH: Glucagon, BW, body weight, Diabetes, SGLT2 inhibitor, MESH: Pancreas, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Islet, 3. Good health, SGLT, sodium-glucose cotransporter, MESH: Glucose, MESH: Sodium-Glucose Transporter 2, No direct effect of SGLT2i on α- and β-cells, MESH: Sodium-Glucose Transporter 2 Inhibitors, Ketone bodies, Original Article, medicine.medical_specialty, lcsh:Internal medicine, endocrine system, MESH: Rats, 030209 endocrinology & metabolism, MESH: Insulin, Glucagon, 03 medical and health sciences, Islets of Langerhans, Gliflozins, TPM, transcripts per million, Sodium-Glucose Transporter 2, G, glucose, In vivo, Internal medicine, Empagliflozin, medicine, MESH: Benzhydryl Compounds, Animals, Humans, Benzhydryl Compounds, lcsh:RC31-1245, Molecular Biology, MESH: Mice, Pancreas, Sodium-Glucose Transporter 2 Inhibitors, geography, MESH: Humans, MESH: Islets of Langerhans, Glucose transporter, MESH: Glucagon-Like Peptide 1, Cell Biology, Rats, 030104 developmental biology, Endocrinology, Glucose, Glucagon-Secreting Cells, MESH: Blood Glucose, MESH: Glucagon-Secreting Cells, Cmax, maximum serum concentration, diabetes, glucagon, insulin
Abstract

Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches. Methods We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression. Results SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets. Conclusions The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells., Highlights • Gliflozins (SGLT2 and SGLT1/2 inhibitors) increase plasma glucagon/insulin ratio. • SGLT2 is not expressed in rodent and human pancreatic α- and β-cells. • SGLT1 is however expressed in human α-cells. • SGLT2 and SGLT1/2 inhibitors do not directly affect glucagon and insulin secretion.

Published
2020
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2. The Drosophila TNF Eiger Is an Adipokine that Acts on Insulin-Producing Cells to Mediate Nutrient Response

Author

Davide Basco, Pierre Léopold, Matthieu Pasco, Bernard Thorens, Renald Delanoue, Alessandra Mauri, Neha Agrawal, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), RUIZ, Caroline, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL)

Subjects
0301 basic medicine, medicine.medical_specialty, MESH: Drosophila Proteins, Physiology, medicine.medical_treatment, Adipose tissue, MESH: Insulin, Biology, MESH: Insulin-Secreting Cells, Cell Line, MESH: Drosophila melanogaster, MESH: Food Deprivation, Mice, 03 medical and health sciences, MESH: Adipokines, 0302 clinical medicine, Adipokines, Insulin-Secreting Cells, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, Body Size, Drosophila Proteins, Insulin, MESH: Animals, Receptor, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Molecular Biology, MESH: Body Size, Tumor Necrosis Factor-alpha, Cell Biology, MESH: Cell Line, Crosstalk (biology), Drosophila melanogaster, 030104 developmental biology, Endocrinology, Cell culture, MESH: Tumor Necrosis Factor-alpha, Tumor necrosis factor alpha, Food Deprivation, 030217 neurology & neurosurgery, Drosophila Protein, Hormone
Abstract

International audience; Adaptation of organisms to ever-changing nutritional environments relies on sensor tissues and systemic signals. Identification of these signals would help understand the physiological crosstalk between organs contributing to growth and metabolic homeostasis. Here we show that Eiger, the Drosophila TNF-α, is a metabolic hormone that mediates nutrient response by remotely acting on insulin-producing cells (IPCs). In the condition of nutrient shortage, a metalloprotease of the TNF-α converting enzyme (TACE) family is active in fat body (adipose-like) cells, allowing the cleavage and release of adipose Eiger in the hemolymph. In the brain IPCs, Eiger activates its receptor Grindelwald, leading to JNK-dependent inhibition of insulin production. Therefore, we have identified a humoral connexion between the fat body and the brain insulin-producing cells relying on TNF-α that mediates adaptive response to nutrient deprivation.

Published
2016
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3. GLP-1: What is known, new and controversial in 2010?

Author

Sylvie Dejager, Rémy Burcelin, Simon, Marie Francoise, 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), Recherche clinique et développement, Novartis Pharma SAS, and Novartis Pharma

Subjects
endocrine system, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Incretin, MESH: Insulin, Biology, Bioinformatics, Neuroprotection, MESH: Insulin-Secreting Cells, Endocrinology, Internal medicine, Diabetes mellitus, MESH: Molecular Targeted Therapy, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Endocrine system, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Endocrine System, MESH: Humans, MESH: Peptides, MESH: Glucagon, Insulin, digestive, oral, and skin physiology, MESH: Glucagon-Like Peptide 1, General Medicine, medicine.disease, Metformin, Beta cell, hormones, hormone substitutes, and hormone antagonists, Hormone, medicine.drug
Abstract

International audience; Over the past 2 years, more than 1300 manuscripts have been published on glucagon-like peptide-1 (GLP-1) and yet, what do we know about it for sure? The European Club for the Study of GLP-1 (EuCSGLP-1) has debated the latest controversies concerning GLP-1, including both fundamental and clinical aspects, and concluded that the control of glucose metabolism by GLP-1 requires paracrine activation of the enteric nervous system to regulate numerous physiological functions. This involves-but is not limited to-the endocrine pancreas, liver, cardiovascular system, gastric-emptying and the brain. For this reason, the role of GLP-1 as an endocrine hormone has come under question. As systemic concentration of the peptide was not thought to be relevant to its physiological action, it was proposed that dipeptidyl peptidase-4 (DPP4) inhibitors would involve the control of enteric, rather than circulating, DPP4 activity to effectively regulate glycaemia. In any case, the concomitant insulinotropic and glucagonostatic roles of GLP-1 were believed to be of equal importance to glucose control. Another important question was related to the role of GLP-1 on beta cell apoptosis, regeneration and differentiation in type 2 diabetic patients. Although evidence in vitro showed that GLP-1 controls these functions, such effects remain elusive in humans in vivo. Nevertheless, the consensus was that GLP-1 could control glucose responsiveness, one of the first impaired physiological functions at the onset of diabetes. The therapeutic efficiency of GLP-1 would be related to the initial restoration of glucose competence, while an increase of beta cell mass has not yet been demonstrated. From a clinical and fundamental point of view, it was concluded that, at the onset of diabetes, an initial triggering of GLP-1 secretion-by metformin coupled with a DPP4 inhibitor-would help to activate the gut-peripheral axis and, hence, restore adequate regulation of glycaemia. GLP-1 analogues would certainly be helpful in association with long-acting insulin (albeit off-label) in patients with impaired beta cells and GLP-1 secretory potential. However, a reliable and routine feasible test to systematically assess dynamic insulin secretion is essential. More important, factors that influence therapeutic response, such as compliance and lifestyle, as well as pharmacokinetics and dosing, disease duration, age, gender, ethnicity, patients' clinical characteristics, autonomic nervous system integrity and genotype characteristics also need to be considered. A few innovative perspectives have been debated, such as the recently discovered cardiovascular protective effects of the native GLP-1 peptide and its degradation product GLP-1(9-36), as well as the neuroprotection offered by GLP-1. Although still considered speculative, these perspectives remain hopeful and promising.

Published
2010
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4. Neurotensin is a regulator of insulin secretion in pancreatic beta-cells

Author

Gérard Waeber, Thierry Coppola, Amar Abderrahmani, Jacques Noël, Jean Mazella, Frédéric Brau, Sophie Béraud-Dufour, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Département de Médecine Interne, Université de Lausanne (UNIL), and Département de Biologie Cellulaire et de Morphologie

Subjects
medicine.medical_treatment, MESH: Neurotensin, Biochemistry, MESH: Insulin-Secreting Cells, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, Insulin-Secreting Cells, Insulin Secretion, Insulin, Receptors, Neurotensin, MESH: Animals, PKC, Neurotensin, Calcium signaling, 0303 health sciences, MESH: Protein Kinase C-epsilon, Insulin oscillation, MESH: Piperidines, medicine.anatomical_structure, Quinolines, MESH: Protein Kinase C-alpha, Beta cell, MESH: Quinolines, MESH: Enzyme Activation, medicine.medical_specialty, Protein Kinase C-alpha, MESH: Rats, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Cyclic AMP-Dependent Protein Kinases, MESH: Insulin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein Kinase C-epsilon, Biology, Calcium, MESH: Calcium Signaling, Cell Line, Pancreatic islet, MESH: Receptors, Neurotensin, 03 medical and health sciences, Internal medicine, medicine, Animals, Calcium Signaling, 030304 developmental biology, Calcium metabolism, Pancreatic islets, Cell Biology, Cyclic AMP-Dependent Protein Kinases, MESH: Cell Line, Rats, Enzyme Activation, MESH: Cytoprotection, Endocrinology, chemistry, Cytoprotection, Pyrazoles, MESH: Pyrazoles, 030217 neurology & neurosurgery
Abstract

International audience; Neurotensin (NT) is secreted from neurons and gastrointestinal endocrine cells. We previously reported that the three NT receptors (NTSRs) are expressed in pancreatic islets and beta cell lines on which we observed a protective effect of NT against cytotoxic agents. In this study, we explored the role of NT on insulin secretion in the endocrine pancreatic beta cells. We observed that NT stimulates insulin secretion at low glucose level and has a small inhibiting effect on stimulated insulin secretion from isolated islets or INS-1E cells. We studied the mechanisms by which NT elicited calcium concentration changes using fura-2 loaded islets or INS-1E cells. NT increases calcium influx through the opening of cationic channels. Similar calcium influxes were observed after treatment with NTSR selective ligands. NT-evoked calcium regulation involves PKC and the translocation of PKCalpha and PKCepsilon to the plasma membrane. Part of NT effects appears to be also mediated by PKA but not via the Erk pathway. Taken together, these data provide evidence for an important endocrine role of NT in the regulation of the secretory function of beta cells.

Published
2010
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5. [Reprogramming pancreatic cells to β cells]

Author

Andhira, Vieira, Noémie, Druelle, Monica, Courtney, Fabio, Avolio, Nouha, Ben-Othman, Anja, Pfeifer, Elisabet, Gjernes, Biljana, Faurite, Patrick, Collombat, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
MESH: Cell Differentiation, MESH: Tissue Donors, MESH: Humans, Islets of Langerhans Transplantation, Pancreatic Ducts, MESH: Regeneration, Cell Differentiation, MESH: Acinar Cells, Acinar Cells, MESH: Pancreas, Tissue Donors, MESH: Insulin-Secreting Cells, Diabetes Mellitus, Type 1, MESH: Islets of Langerhans Transplantation, MESH: Pancreatic Ducts, Insulin-Secreting Cells, Humans, Regeneration, MESH: Diabetes Mellitus, Type 1, Pancreas, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract

International audience; Type 1 diabetes (T1DM) is a common metabolic disorder affecting an ever-increasing number of patients worldwide. T1DM is caused by the selective destruction of pancreatic insulin-producing β-cells by the immune system. Such loss results in chronic hyperglycemia and could induce a number of cardio-vascular complications. Despite the classical insulin-based therapy, compared to healthy people, patients with T1DM display a shortened life expectancy due to the treatment's inability to strictly regulate glycemic levels. An alternative therapy involves pancreatic islet transplantation but the shortage of donors and the required immuno-suppressive treatments limit the widespread use of this approach. Therefore, the search of new approaches to generate functional β-cells is of growing interest. In this review, we describe several novel strategies aiming at the conversion of diverse pancreatic cells into β-cells, such as acinar, ductal, and endocrine cells. Clearly, such promising results could open new research avenues in the context of type 1 diabetes research.

Published
2013
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6. Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

Author

Aurélie Waget, Miriam Cnop, Lutgart Overbergh, Decio L. Eizirik, João Paulo Monteiro Carvalho Mori da Cunha, Alessandra K Cardozo, Chantal Mathieu, Michael Maris, E Verdrengh, Conny Gysemans, Tomomi Gotoh, Rémy Burcelin, Laboratory for Experimental Medicine and Endocrinology, Catholic University of Leuven (LEGENDO), Université Catholique de Louvain = Catholic University of Louvain (UCL), 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), Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Université libre de Bruxelles (ULB), Department of School Health, Faculty of Education & Department of Molecular Genetics, Kumamoto University, Kumamoto, Kumamoto University, Simon, Marie Francoise, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles (ULB)

Subjects
MESH: Inflammation, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, CHOP, MESH: Mice, Knockout, MESH: Insulin-Secreting Cells, Mice, 0302 clinical medicine, Insulin-Secreting Cells, Insulin, MESH: Obesity, MESH: Animals, MESH: Fatty Liver, Mice, Knockout, 0303 health sciences, Sciences bio-médicales et agricoles, MESH: Insulin Resistance, Adipose Tissue, Liver, MESH: Transcription Factor CHOP, medicine.symptom, Beta cell, MESH: Adipose Tissue, medicine.medical_specialty, Inflammation, MESH: Insulin, 03 medical and health sciences, Insulin resistance, Internal medicine, Glucose Intolerance, Internal Medicine, medicine, Animals, Obesity, MESH: Mice, MESH: Glucose Intolerance, 030304 developmental biology, business.industry, Endoplasmic reticulum, CHOP. Endoplasmic reticulum-Inflammation-Obesity. Steatosis-Type 2 diabetes, medicine.disease, Fatty Liver, Endocrinology, Apoptosis, Unfolded protein response, Médecine clinique [biologie clinique], Insulin Resistance, business, Transcription Factor CHOP, 030217 neurology & neurosurgery, MESH: Liver
Abstract

AIMS/HYPOTHESIS: Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance. METHODS: Metabolic studies were performed in Chop ( -/- ) and wild-type C57Bl/6 mice, and included euglycaemic-hyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. RESULTS: Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop ( -/- ) mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. CONCLUSIONS/INTERPRETATION: These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2012
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7. A role for glutamate transporters in the regulation of insulin secretion

Author

Runhild Gammelsaeter, Romano Regazzi, David Attwell, Païkan Marcaggi, Thierry Coppola, Jon Storm-Mathisen, Farrukh A. Chaudhry, Vidar Gundersen, Division of Anatomy [Oslo], Department of Molecular Medicine [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Institute of Basic Medical Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, University College of London [London] (UCL), Biotechnology center of Oslo, University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Département de Biologie Cellulaire et de Morphologie, Université de Lausanne (UNIL), Department of Neurology, and Rikshospitalet

Subjects
MESH: Hydrogen-Ion Concentration, Anatomy and Physiology, MESH: Secretory Vesicles, lcsh:Medicine, Gene Expression, MESH: Vesicular Glutamate Transport Proteins, MESH: Insulin-Secreting Cells, Membrane Potentials, Mice, 0302 clinical medicine, Insulin-Secreting Cells, Insulin Secretion, Vesicular Glutamate Transport Proteins, Molecular Cell Biology, Insulin, MESH: Animals, lcsh:Science, 0303 health sciences, Multidisciplinary, MESH: Amino Acid Transport Systems, Acidic, biology, Granule (cell biology), Glutamate receptor, Metabotropic glutamate receptor 6, MESH: Glutamic Acid, Animal Models, Hydrogen-Ion Concentration, Cell biology, Protein Transport, Glutamate dehydrogenase 1, Biochemistry, Excitatory Amino Acid Transporter 2, Medicine, Research Article, Signal Transduction, MESH: Protein Transport, MESH: Rats, Amino Acid Transport Systems, Acidic, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endocrine System, MESH: Insulin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Signaling Pathways, Exocytosis, 03 medical and health sciences, Model Organisms, MESH: Membrane Potentials, Animals, Rats, Wistar, MESH: Mice, Biology, 030304 developmental biology, Endocrine Physiology, Secretory Vesicles, lcsh:R, Cell Membrane, Glutamic acid, MESH: Rats, Wistar, Neuroendocrinology, Rats, MESH: Excitatory Amino Acid Transporter 2, Metabotropic glutamate receptor, biology.protein, Rat, lcsh:Q, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract

International audience; In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from β-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in β-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from β-cells is modulated by the flux of glutamate through the secretory granules.

Published
2011
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8. Balancing mitochondrial redox signaling: a key point in metabolic regulation

Author

Audrey Carrière, Corinne Leloup, Lionel Carneiro, Luc Pénicaud, Louis Casteilla, Anne Galinier, Alexandre Benani, Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie, plasticité tissulaire et métabolisme énergétique ( NPTME ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Blood Glucose, MESH: Oxidation-Reduction, MESH: Signal Transduction, Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Cell, MESH: Neurons, Adipose tissue, MESH : Reactive Oxygen Species, Biochemistry, Ion Channels, MESH: Insulin-Secreting Cells, 0302 clinical medicine, Insulin-Secreting Cells, Uncoupling Protein 2, MESH: Animals, General Environmental Science, Neurons, chemistry.chemical_classification, 0303 health sciences, Adipogenesis, MESH : Adipogenesis, MESH: Reactive Oxygen Species, MESH: Mitochondrial Proteins, Mitochondria, Cell biology, medicine.anatomical_structure, MESH : Mitochondria, Oxidation-Reduction, MESH : Ion Channels, Signal Transduction, Cell type, medicine.medical_specialty, Cell signaling, MESH : Hypothalamus, MESH: Mitochondria, Hypothalamus, Context (language use), Biology, MESH : Neurons, Mitochondrial Proteins, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Molecular Biology, MESH : Mitochondrial Proteins, 030304 developmental biology, MESH : Oxidation-Reduction, MESH : Signal Transduction, Reactive oxygen species, MESH: Humans, [ SDV ] Life Sciences [q-bio], Mechanism (biology), MESH : Humans, MESH : Insulin-Secreting Cells, Cell Biology, MESH : Blood Glucose, MESH: Hypothalamus, Endocrinology, Metabolic regulation, chemistry, MESH: Ion Channels, MESH: Blood Glucose, General Earth and Planetary Sciences, MESH : Animals, Reactive Oxygen Species, MESH: Adipogenesis, 030217 neurology & neurosurgery
Abstract

WOS: 000285876900015; International audience; Mitochondrial reactive oxygen species (mROS) have emerged as signaling molecules in physiology primarily as a result of studies of uncoupling mechanisms in mitochondrial respiration. The discovery that this mechanism negatively regulates mROS generation in many cell types has drawn the attention of the scientific community to the pathological consequences of excess mROS production. From reports of the energetic fluxes in cells grown under normal conditions, the hypothesis that mROS are an integrated physiological signal of the metabolic status of the cell has emerged. Here, we consider recent studies that support this point of view in two key nutrient sensors of the body, beta cells and the hypothalamus, which are the main coordinators of endocrine and nervous controls of energy metabolism and adipose tissue, which is of paramount importance in controlling body weight and, therefore, the development of obesity and type 2 diabetes. In this context, finely balanced mROS production may be at the core of proper metabolic maintenance, and unbalanced mROS production, which is largely documented, might be an important trigger of metabolic disorders.

Published
2011
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9. Lipid-induced ER stress in yeast and β cells: parallel trails to a common fate

Author

Pineau, Ludovic, Ferreira, Thierry, Department of Biochemistry, University of Geneva [Switzerland], Institut de physiologie et biologie cellulaires (IPBC), and Université de Poitiers-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Humans, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Saccharomyces cerevisiae, MESH: Unfolded Protein Response, Endoplasmic Reticulum, MESH: Lipids, MESH: Saccharomyces cerevisiae, Lipids, MESH: Insulin-Secreting Cells, MESH: Endoplasmic Reticulum, Stress, Physiological, Insulin-Secreting Cells, Unfolded Protein Response, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Stress, Physiological
Abstract

IF : 2,622; International audience; Exposure to long-chain saturated fatty acids (SFAs; e.g. palmitate) induces apoptosis in pancreatic β cells, a process that may contribute to the development of type 2 diabetes. Under palmitate treatment, β cells undergo a so-called endoplasmic reticulum (ER) stress that can be counteracted by the unfolded protein response (UPR). The UPR is a coordinated response, which is primarily devoted to helping the ER to cope with the accumulation of misfolded proteins. Sustained SFA exposure may ultimately overwhelm the UPR, resulting in cell death. By contrast, unsaturated fatty acids (e.g. oleate) are much less harmful to the cells and can even alleviate palmitate toxicity. Surprisingly, recent evidences indicate that a simple unicellular eukaryote, the budding yeast Saccharomyces cerevisiae, which is not routinely exposed to high-fat diets, also undergoes ER stress under lipotoxic conditions. This suggests that the mechanisms of SFA toxicity are largely conserved throughout eukaryotes and are not specific of a given cell type. The present review discusses the mechanisms of SFA toxicity in yeast and β cells, with a main emphasis on their potential impacts on ER-membrane organization/function and ER-based processes.

Published
2010
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10. Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: new therapeutic strategies and consequences for drug screening

Author

Gyslaine Bertrand, Stéphane Dalle, Magalie A. Ravier, Equipe 14, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)

Subjects
MESH: Signal Transduction, Arrestins, medicine.medical_treatment, Drug Evaluation, Preclinical, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Receptors, G-Protein-Coupled, MESH: Insulin-Secreting Cells, Receptors, G-Protein-Coupled, Insulin-Secreting Cells, Receptors, Glucagon, MESH: Animals, Receptor, ComputingMilieux_MISCELLANEOUS, beta-Arrestins, 0303 health sciences, 030302 biochemistry & molecular biology, 3. Good health, Cell biology, MESH: Glucose, beta-Arrestin 1, MESH: Drug Evaluation, Preclinical, MESH: Receptor Protein-Tyrosine Kinases, MESH: Arrestins, Signal transduction, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction, medicine.medical_specialty, MESH: Diabetes Mellitus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, MESH: Receptors, Glucagon, Internal medicine, medicine, Diabetes Mellitus, Animals, Humans, Protein kinase B, 030304 developmental biology, G protein-coupled receptor, MESH: Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, MESH: Humans, Beta-Arrestins, Insulin, Receptor Protein-Tyrosine Kinases, Cell Biology, Endocrinology, Glucose
Abstract

Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.

Published
2010
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11. Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha

Author

Jacques Pouysségur, Mylène Heinis, Nathalie M. Mazure, Bertrand Duvillié, Karine Ilc, M. Simon, Raphael Scharfmann, Institute of Developmental Biology and Cancer ( IBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institute of Developmental Biology and Cancer (IBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, MESH : Oxygen, MESH : Basic Helix-Loop-Helix Transcription Factors, Endocrinology, Diabetes and Metabolism, Cellular differentiation, MESH: Anoxia, MESH: Insulin-Secreting Cells, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, Insulin-Secreting Cells, MESH: Basic Helix-Loop-Helix Transcription Factors, MESH: Gene Expression Regulation, Developmental, Basic Helix-Loop-Helix Transcription Factors, MESH: Animals, MESH : Female, MESH: Nerve Tissue Proteins, MESH : Homeodomain Proteins, Hypoxia, MESH: Embryonic Stem Cells, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH : Nerve Tissue Proteins, MESH : Organ Culture Techniques, 0303 health sciences, MESH : Rats, Gene Expression Regulation, Developmental, Cell Differentiation, respiratory system, Cell biology, Oxygen tension, Hypoxia-inducible factors, cardiovascular system, Original Article, Female, medicine.symptom, Signal transduction, MESH : Cell Differentiation, MESH: Oxygen, Signal Transduction, circulatory and respiratory physiology, MESH: Cell Differentiation, inorganic chemicals, medicine.medical_specialty, Cell type, MESH : Hypoxia-Inducible Factor 1, alpha Subunit, MESH: Rats, MESH : Anoxia, Nerve Tissue Proteins, Biology, MESH : Rats, Wistar, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, Islets of Langerhans, 03 medical and health sciences, Organ Culture Techniques, Internal medicine, MESH: Homeodomain Proteins, Internal Medicine, medicine, Animals, MESH : Embryonic Stem Cells, MESH : Islets of Langerhans, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Rats, Wistar, Progenitor cell, Embryonic Stem Cells, 030304 developmental biology, Homeodomain Proteins, MESH : Signal Transduction, MESH: Islets of Langerhans, MESH : Insulin-Secreting Cells, MESH: Rats, Wistar, Hypoxia (medical), Hypoxia-Inducible Factor 1, alpha Subunit, Embryonic stem cell, MESH: Organ Culture Techniques, Rats, respiratory tract diseases, Oxygen, MESH : Pregnancy, Endocrinology, Islet Studies, Transcription Factor HES-1, MESH : Animals, MESH : Gene Expression Regulation, Developmental, MESH: Female, 030217 neurology & neurosurgery
Abstract

OBJECTIVE Recent evidence indicates that low oxygen tension (pO2) or hypoxia controls the differentiation of several cell types during development. Variations of pO2 are mediated through the hypoxia-inducible factor (HIF), a crucial mediator of the adaptative response of cells to hypoxia. The aim of this study was to investigate the role of pO2 in β-cell differentiation. RESEARCH DESIGN AND METHODS We analyzed the capacity of β-cell differentiation in the rat embryonic pancreas using two in vitro assays. Pancreata were cultured either in collagen or on a filter at the air/liquid interface with various pO2. An inhibitor of the prolyl hydroxylases, dimethyloxaloylglycine (DMOG), was used to stabilize HIF1α protein in normoxia. RESULTS When cultured in collagen, embryonic pancreatic cells were hypoxic and expressed HIF1α and rare β-cells differentiated. In pancreata cultured on filter (normoxia), HIF1α expression decreased and numerous β-cells developed. During pancreas development, HIF1α levels were elevated at early stages and decreased with time. To determine the effect of pO2 on β-cell differentiation, pancreata were cultured in collagen at increasing concentrations of O2. Such conditions repressed HIF1α expression, fostered development of Ngn3-positive endocrine progenitors, and induced β-cell differentiation by O2 in a dose-dependent manner. By contrast, forced expression of HIF1α in normoxia using DMOG repressed Ngn3 expression and blocked β-cell development. Finally, hypoxia requires hairy and enhancer of split (HES)1 expression to repress β-cell differentiation. CONCLUSIONS These data demonstrate that β-cell differentiation is controlled by pO2 through HIF1α. Modifying pO2 should now be tested in protocols aiming to differentiate β-cells from embryonic stem cells.

Published
2010
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12. Clinical and metabolic characteristics of patients with latent autoimmune diabetes in adults (LADA): absence of rapid beta-cell loss in patients with tight metabolic control

Author

Richard Marechaud, E. Mathieu, Béatrice Bouhanick, P. Saï, M Delamaire, E. Sonnet, Pierre-Henri Ducluzeau, Véronique Kerlan, P. Lecomte, B. Charbonnel, Lucy Chaillous, V. Rohmer, D. Maugendre, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'immuno-endocrinologie (ENVN), ONIRIS, Service de médecine interne et gérontologie clinique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Service d'Endocrinologie (CHRU - Endocrino), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Biochimie Médicale (ANGERS - Biochimie Médicale), Université d'Angers (UA), Médecine Interne, Maladies Vasculaires, Endocrinologie (ANGERS - Endocrino), Centre Hospitalier Universitaire d'Angers (CHU Angers), RENNES - Centre de Transfusion Sanguine (RENNES - CTS), Centre de Transfusion Sanguine - RENNES, Service d'endocrinologie diabétologie et nutrition [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, POITIERS (POITIERS - Médecine Interne, Endocrinologie), Centre hospitalier universitaire de Poitiers (CHU Poitiers), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Hôpital Anne-de-Bretagne, and Unité de recherche de l'institut du thorax (ITX-lab)

Subjects
Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Type 2 diabetes, 030204 cardiovascular system & hematology, MESH: Insulin-Secreting Cells, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Insulin-Secreting Cells, Insulin, Prospective Studies, MESH: C-Peptide, Age of Onset, PEPTIDE C, MESH: Aged, MESH: Middle Aged, C-Peptide, C-peptide, General Medicine, Middle Aged, 3. Good health, Disease Progression, Female, MESH: Disease Progression, Beta cell, MESH: Diabetes Mellitus, Type 1, Adult, medicine.medical_specialty, MESH: Age of Onset, 030209 endocrinology & metabolism, MESH: Insulin, MESH: Body Mass Index, 03 medical and health sciences, MESH: Cross-Sectional Studies, Internal medicine, Diabetes mellitus, MESH: Hypoglycemic Agents, Internal Medicine, medicine, Humans, Hypoglycemic Agents, DIABÈTE DE TYPE 1 LENT, Aged, Autoimmune disease, Type 1 diabetes, MESH: Humans, business.industry, MESH: Biological Markers, INSULINOSECRETION, MESH: Adult, medicine.disease, MESH: Male, MESH: Prospective Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 1, chemistry, Metabolic control analysis, MESH: Blood Glucose, business, MESH: Female, Biomarkers
Abstract

International audience; AIM AND METHODS: The present study compared the clinical and metabolic characteristics of latent autoimmune diabetes in adults (LADA) with type 2 diabetes, as well as the residual beta-cell function and progression to insulin treatment, over a 2-year follow-up period, of antibody (Ab)-positive and Ab-negative patients who achieved tight glycaemic control (HbA(1c) 7.0+/-0.8% and 6.5+/-0.9%, respectively, at the time of entry into the study). RESULTS: Glutamic acid decarboxylase antibodies (GADA) and/or islet cell antibodies (ICA) were detected in 10% of patients presenting with non-insulin-dependent diabetes. Around half of Ab-positive patients required insulin treatment during the follow-up. Ab-positive patients displayed lower stimulated C-peptide levels both at entry and during the follow-up compared with Ab-negative patients, although no significant decline in C-peptide levels was observed in either subgroup over two years. Nevertheless, Ab-positive patients progressed more frequently to insulin treatment, and stimulated C-peptide tended to decrease in LADA patients who subsequently required insulin, whereas it remained stable in those who were non-insulin-dependent. In those who progressed, the trend towards C-peptide decline persisted even after starting insulin treatment. CONCLUSION: LADA patients demonstrate lower residual beta-cell function than do type 2 diabetes patients. However, those who achieve tight metabolic control do not present with a rapid decline in beta-cell function. Further studies are needed to determine the optimal treatment strategy in such patients.

Published
2010
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13. Neurotensin receptor-2 and -3 are crucial for the anti-apoptotic effect of neurotensin on pancreatic beta-TC3 cells

Author

Sophie Béraud-Dufour, Jean Mazella, Fabienne Massa, Thierry Coppola, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Receptor complex, [SDV]Life Sciences [q-bio], MESH: Neurotensin, Apoptosis, Biochemistry, MESH: Insulin-Secreting Cells, Mice, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Insulin-Secreting Cells, MESH: RNA, Small Interfering, MESH: Caspase 3, Receptors, Neurotensin, MESH: Animals, RNA, Small Interfering, Receptor, Neurotensin, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Caspase 3, Kinase, 3. Good health, Cell biology, Protein Transport, Beta cell, Protein Binding, Signal Transduction, medicine.medical_specialty, MESH: Protein Transport, Neurotensin receptor 2, Neuropeptide, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, MESH: Receptors, Neurotensin, Internal medicine, medicine, Animals, MESH: Protein Binding, MESH: Mice, 030304 developmental biology, MESH: Apoptosis, Cell Biology, MESH: 1-Phosphatidylinositol 3-Kinase, Staurosporine, MESH: Cell Line, MESH: Cytoprotection, Endocrinology, chemistry, Cytoprotection, MESH: Staurosporine, 030217 neurology & neurosurgery
Abstract

International audience; The neuropeptide neurotensin (NT) has been recently shown to protect pancreatic beta cells from toxic agents-induced apoptosis through interaction with the NT receptor-2 (NTSR2) and activation of the phosphatidylinositol-3 kinase pathway. However, expression of the NT receptor-3/sortilin (NTSR3) in the mouse pancreatic beta cell line -TC3 led us to investigate its possible functional role in these cells. By using siRNA, immunoprecipitation, co-localization and caspase-3 assays,we provide evidence for a functional endogenous interaction between NTSR2 and NTSR3. Expression of both receptors is necessary for the protective action of NT on staurosporine-induced caspase-3 activity in -TC3 cells. Moreover, NTSR2 and NTSR3 co-immunoprecipitate and are co-localized at the plasma membrane. Thus, the NT response in beta cells is controlled by the formation of a functional complex between NTSR2 and NTSR3.

Published
2009
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14. A role for the gut-to-brain GLP-1-dependent axis in the control of metabolism

Author

Matteo Serino, Cendrine Cabou, Rémy Burcelin, 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), and Simon, Marie Francoise

Subjects
medicine.medical_specialty, medicine.medical_treatment, Molecular Sequence Data, MESH: Amino Acid Sequence, MESH: Insulin, Type 2 diabetes, Biology, Carbohydrate metabolism, MESH: Incretins, Incretins, Models, Biological, MESH: Insulin-Secreting Cells, MESH: Brain, Intestinal mucosa, Glucagon-Like Peptide 1, Internal medicine, Insulin-Secreting Cells, Drug Discovery, Insulin Secretion, medicine, Animals, Humans, Insulin, MESH: Animals, Secretion, Amino Acid Sequence, Intestinal Mucosa, Receptor, Pharmacology, MESH: Molecular Sequence Data, MESH: Humans, digestive, oral, and skin physiology, MESH: Models, Biological, MESH: Glucagon-Like Peptide 1, Brain, Metabolism, medicine.disease, Glucagon-like peptide-1, Cell biology, MESH: Glucose, Intestines, Endocrinology, Glucose, hormones, hormone substitutes, and hormone antagonists, MESH: Intestines
Abstract

International audience; Over the past years tremendous amounts of clinical and fundamental data have been generated about GLP-1 and related therapeutic strategies for the treatment of type 2 diabetes. However, the cellular and physiological mechanisms through which GLP-1 is secreted, controls glycemia, and behaves as a therapeutic agent are certainly unclear. This is due to the dogma that proposes that upon glucose absorption GLP-1 is secreted into the hepatoportal blood flow, binds to its receptor at the surface of the insulin secreting beta cells, and triggers the secretion of insulin to control glycemia. However, these events have never been demonstrated sequentially for the control of glycemia. This conclusion is supported by a growing number of evidences that point out that the enteric and the central nervous systems are main actors in the control of GLP-1 action. This involves the triggering of the gut-to-brain and to periphery axis where nutrients regulate the release of GLP-1 and activate the tightly regulated enteric and cerebral neuronal circuits. These integrate and redistribute the GLP-1-dependent signals toward numerous targeted tissues. We will review some of them.

Published
2009
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15. A potent, non-toxic insulin-releasing peptide isolated from an extract of the skin of the Asian frog, Hylarana guntheri (Anura:Ranidae)

Author

Conlon, J Michael, Power, Gavin, Abdel-Wahab, Yasser, Flatt, Peter, Jiansheng, Hu, Coquet, Laurent, Leprince, Jérôme, Jouenne, Thierry, Vaudry, Hubert, Conlon, J. Michael, Abdel-Wahab, Yasser H.A., Vaudry, Hu, Faculty of Medicine and Health Science, UAE University, Polymères, biopolymères, membranes (PBM), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Différenciation et communication neuronale et neuroendocrine (DC2N)

Subjects
Blood Glucose, Male, Ranidae, Physiology, medicine.medical_treatment, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, MESH: Insulin Secretion, Biochemistry, MESH: Insulin-Secreting Cells, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, Insulin-Secreting Cells, MESH: Amphibian Proteins, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin Secretion, Insulin, MESH: Animals, Peptide sequence, Antibacterial agent, Skin, chemistry.chemical_classification, 0303 health sciences, MESH: Ranidae, MESH: Antimicrobial Cationic Peptides, 3. Good health, medicine.medical_specialty, Basal rate, MESH: Rats, Molecular Sequence Data, 030209 endocrinology & metabolism, MESH: Insulin, Biology, Amphibian Proteins, Cell Line, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Skin, Internal medicine, Lactate dehydrogenase, medicine, Animals, Amino Acid Sequence, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, Temporin, MESH: Male, MESH: Cell Line, Rats, chemistry, MESH: Blood Glucose, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Frog Skin, Antimicrobial Cationic Peptides
Abstract

Peptides in extract of the skin of the Asian frog Hylarana guntheri Boulenger,1882 were purified by reversed-phase HPLC and individual components analysed for their ability to release insulin from the rat BRIN-BD11 clonal beta cell line. The most potent peptide identified in the extract belonged to the brevinin-2 family (brevinin-2GUb; GVIIDTLKGAAKTVAAELLRKAHCKLTNSC). Other peptides with weaker insulin-releasing activity belonged to the brevinin-1 (2 peptides), brevinin-2 (2 peptides) and temporin (3 peptides) families. Only the brevinin-1 peptides showed cytolytic activity against the BRIN-BD11 cells, as demonstrated by an increased rate of release of the cytosolic enzyme, lactate dehydrogenase. A synthetic replicate of brevinin-2GUb produced a significant stimulation of insulin release (139% of basal rate; P

Published
2008
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16. MafB is required for islet beta cell maturation

Author

Bruno Blanchi, Jeffrey C. Raum, Min Guo, Isabella Artner, Roland Stein, Sabine Cordes, Michael H. Sieweke, Tomomi Kaneko, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Time Factors, Transcription, Genetic, medicine.medical_treatment, Cellular differentiation, MESH: Insulin-Secreting Cells, Mice, 0302 clinical medicine, Maf Transcription Factors, Insulin-Secreting Cells, Insulin, MESH: Animals, Glucose Transporter Type 2, 0303 health sciences, MafB Transcription Factor, Multidisciplinary, MESH: Glucagon, Cell Differentiation, MESH: MafB Transcription Factor, Biological Sciences, Cell biology, MAFB, PDX1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Beta cell, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Mutation, MESH: Trans-Activators, MESH: Mice, Transgenic, Mice, Transgenic, MESH: Insulin, Biology, Models, Biological, 03 medical and health sciences, Internal medicine, MESH: Homeodomain Proteins, medicine, Animals, Transcription factor, MESH: Mice, 030304 developmental biology, Homeodomain Proteins, MESH: Transcription, Genetic, MESH: Time Factors, MESH: Models, Biological, Glucagon, Endocrinology, Mutation, Trans-Activators, MESH: Glucose Transporter Type 2, 030217 neurology & neurosurgery
Abstract

Pancreatic endocrine cell differentiation depends on transcription factors that also contribute in adult insulin and glucagon gene expression. Islet cell development was examined in mice lacking MafB, a transcription factor expressed in immature α (glucagon + ) and β (insulin + ) cells and capable of activating insulin and glucagon expression in vitro . We observed that MafB −/− embryos had reduced numbers of insulin + and glucagon + cells throughout development, whereas the total number of endocrine cells was unchanged. Moreover, production of insulin + cells was delayed until embryonic day (E) 13.5 in mutant mice and coincided with the onset of MafA expression, a MafB-related activator of insulin transcription. MafA expression was only detected in the insulin + cell population in MafB mutants, whereas many important regulatory proteins continued to be expressed in insulin − β cells. However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these insulin-deficient cells between E15.5 and E18.5. MafB appears to directly regulate transcription of these genes, because binding was observed within endogenous control region sequences. These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature α and β cells.

Published
2007
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17. Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway

Author

Luc Baeyens, Stefan Bonné, Philippe Ravassard, Michael S. German, Harry Heimberg, Luc Bouwens, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Pathology/molecular and cellular medicine, Cell Differentiation, Beta Cell Neogenesis, Pathologic Biochemistry and Physiology, and Medical Biochemistry

Subjects
Male, MESH: Signal Transduction, transdifferentiation, neurogenin3, Neogenesis, MESH: Animals, Newborn, MESH: Janus Kinase 2, MESH: Growth Substances, MESH: Insulin-Secreting Cells, MESH: Lipase, 0302 clinical medicine, Epidermal growth factor, Hepatocyte Nuclear Factor 6, Insulin-Secreting Cells, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, MESH: Up-Regulation, MESH: Animals, MESH: Gene Silencing, MESH: Nerve Tissue Proteins, STAT3, Growth Substances, Cells, Cultured, 0303 health sciences, Gene knockdown, diabetes, Transdifferentiation, JAK-STAT signaling pathway, MESH: STAT3 Transcription Factor, 3. Good health, Cell biology, Up-Regulation, MESH: Models, Animal, Models, Animal, MESH: Hepatocyte Nuclear Factor 6, Beta cell, Signal Transduction, MESH: Cells, Cultured, Niacinamide, STAT3 Transcription Factor, medicine.medical_specialty, endocrine system, MESH: Rats, 030209 endocrinology & metabolism, Nerve Tissue Proteins, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, Internal medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, RNA, Messenger, Rats, Wistar, Molecular Biology, Pancreas, 030304 developmental biology, MESH: RNA, Messenger, MESH: Humans, Gene Expression Profiling, Cell Biology, Lipase, MESH: Rats, Wistar, Janus Kinase 2, biology.organism_classification, beta cell, MESH: Male, Rats, Endocrinology, Animals, Newborn, biology.protein, MESH: Niacinamide
Abstract

The basic helix-loop-helix protein Neurogenin3 specifies precursor cells of the endocrine pancreas during embryonic development, and is thought to be absent postnatally. We have studied Ngn3 expression during in vitro generation of beta-cells from adult rat exocrine pancreas tissue treated with epidermal growth factor and leukaemia inhibitory factor. This treatment induced a transient expression of both Ngn3 and its upstream activator hepatocyte nuclear factor 6. Inhibition of EGF and LIF signalling by pharmacological antagonists of the JAK2/STAT3 pathway, or knockdown of Ngn3 by RNA interference prevented the generation of new insulin-positive cells. This study demonstrates that in vitro growth factor stimulation can induce recapitulation of an embryonic endocrine differentiation pathway in adult dedifferentiated exocrine cells. This could prove to be important for understanding the mechanism of beta-cell regeneration and for therapeutic ex vivo neogenesis of beta cells.

Published
2006
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18. In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion

Author

Alain Favier, Fabrice Chimienti, François Pattou, Séverine Devergnas, Rachel Garcia-Cuenca, Michel Seve, Didier Grunwald, Julie Kerr-Conte, Brigitte Vandewalle, Frans Schuit, Leentje Van Lommel, MELLITECH SAS, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Therapie Cellulaire du Diabete, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Gene Expression Unit, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), ANTE-INSERM U836, équipe 4, Muscles et pathologies, Laboratoire Canaux Ioniques et Signalisation, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Département Réponse et Dynamique Cellulaire (DRDC)-Laboratoire des composants imprimés (LCI)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Département Réponse et Dynamique Cellulaire (DRDC)-Laboratoire des composants imprimés (LCI), This work was supported by a grant from the Programme de Toxicologie Nucléaire Environnementale (www.toxnuc-e.org) to M.S. and a grant from Centre Evian pour l'Eau to F.C., and Salas, Danielle

Subjects
Male, MESH: Secretory Vesicles, medicine.medical_treatment, Gene Expression, MESH: Microscopy, Fluorescence, MESH: Zinc, MESH: Insulin-Secreting Cells, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, Insulin receptor substrate, Insulin-Secreting Cells, Insulin, MESH: Microscopy, Confocal, MESH: Animals, Cation Transport Proteins, 0303 health sciences, Microscopy, Confocal, SLC30A8, biology, Insulin secretion, MESH: Glucagon, Zinc transport, Beta cell, MESH: Glucose, Zinc, MESH: Cell Survival, Zinc Transporter 8, Langerhans islets, medicine.medical_specialty, MESH: Gene Expression, Cell Survival, Recombinant Fusion Proteins, MESH: Biological Transport, Green Fluorescent Proteins, chemistry.chemical_element, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Insulin, Glucagon, Models, Biological, Cell Line, 03 medical and health sciences, Islets of Langerhans, MESH: Cation Transport Proteins, MESH: Green Fluorescent Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Humans, Dose-Response Relationship, Drug, Secretory Vesicles, MESH: Islets of Langerhans, Cell Membrane, MESH: Models, Biological, Biological Transport, Cell Biology, MESH: Male, MESH: Cell Line, MESH: Hela Cells, Endocrinology, Glucose, chemistry, Microscopy, Fluorescence, Cell culture, biology.protein, HeLa Cells, MESH: Cell Membrane
Abstract

Insulin-secreting pancreatic beta cells are exceptionally rich in zinc. In these cells, zinc is required for zinc-insulin crystallization within secretory vesicles. Secreted zinc has also been proposed to be a paracrine and autocrine modulator of glucagon and insulin secretion in pancreatic alpha and beta cells, respectively. However, little is known about the molecular mechanisms underlying zinc accumulation in insulin-containing vesicles. We previously identified a pancreas-specific zinc transporter, ZnT-8, which colocalized with insulin in cultured beta cells. In this paper we studied its localization in human pancreatic islet cells, and its effect on cellular zinc content and insulin secretion. In human pancreatic islet cells, ZnT-8 was exclusively expressed in insulin-producing beta cells, and colocalized with insulin in these cells. ZnT-8 overexpression stimulated zinc accumulation and increased total intracellular zinc in insulin-secreting INS-1E cells. Furthermore, ZnT-8-overexpressing cells display enhanced glucose-stimulated insulin secretion compared with control cells, only for a high glucose challenge, i.e. >10 mM glucose. Altogether, these data strongly suggest that the zinc transporter ZnT-8 is a key protein for both zinc accumulation and regulation of insulin secretion in pancreatic beta cells. ispartof: Journal of Cell Science vol:119 issue:20 pages:4199-4206 ispartof: location:England status: published

Published
2006
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19. Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes

Author

Stéphane, Cauchi, David, Meyre, Christian, Dina, Hélène, Choquet, Chantal, Samson, Sophie, Gallina, Beverley, Balkau, Guillaume, Charpentier, François, Pattou, Volodymyr, Stetsyuk, Raphaël, Scharfmann, Bart, Staels, Gema, Frühbeck, Philippe, Froguel, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Université Laval [Québec] (ULaval), Centre national d'études et de formation pour l'enfance inadaptée (CNEFEI), Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie cardiovasculaire et métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de diabétologie, Centre Hospitalier Sud Francilien, Service d'endocrinologie et diabetologie, Hôpital de Corbeil-ESsonnes, Développement normal et pathologique des organes endocrines (EMI 363), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pancréas endocrine et diabète de l'enfant, Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, lipoprotéines et athérosclérose, 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, Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, CH Evry-Corbeil-CH Evry-Corbeil, Université Laval, Institut de Biologie de Lille (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Faculté de Droit -Université Laval ( FAC. DROIT ), Université de Lille, Sciences Humaines et Sociales, Centre national d'études et de formation pour l'enfance inadaptée ( CNEFEI ), Institut de Biologie de Lille ( IBL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Développement normal et pathologique des organes endocrines ( EMI 363 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs ( LGMNPN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), and 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

Subjects
Adult, Male, MESH : Case-Control Studies, endocrine system diseases, MESH: Rats, MESH : Male, MESH : Aged, MESH : Adipose Tissue, MESH: Insulin-Secreting Cells, MESH : TCF Transcription Factors, MESH : Diabetes Mellitus, Type 2, Insulin-Secreting Cells, Animals, Humans, Genetic Predisposition to Disease, MESH : Middle Aged, MESH : Female, MESH: Animals, MESH : France, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Aged, MESH: Aged, MESH: Middle Aged, MESH: Humans, MESH : Rats, MESH : Humans, MESH : Insulin-Secreting Cells, MESH: Genetic Predisposition to Disease, MESH: Adult, Middle Aged, MESH : Adult, MESH: Case-Control Studies, MESH: Male, Rats, MESH: France, Adipose Tissue, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Female, MESH : Genetic Predisposition to Disease, France, MESH : Animals, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, MESH: Female, MESH: Adipose Tissue, MESH: TCF Transcription Factors, MESH: Diabetes Mellitus, Type 2
Abstract

Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P = 6.0 x 10(-35)) and 1.60 (1.47-1.74) (P = 7.6 x 10(-28)), respectively. In nonobese type 2 diabetic subjects (BMI

Published
2006
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20. Genetic polymorphisms and weight loss in obesity:a randomised trial of hypo-energetic high- versus low-fat diets

Author

Dominique Langin, Martin Nordal Petersen, Christian Dina, Oluf Pedersen, Thorkild I. A. Sørensen, Camilla Verdich, Philippe Boutin, J. Alfredo Martínez, Moira A. Taylor, Lesli H. Larsen, Claus Holst, Karine Clément, Vladimir Stich, Søren Toubro, Arne Astrup, Jean-Michel Oppert, Philippe Froguel, Peter Arner, Liselotte Petersen, Søren M. Echwald, Ian A. Macdonald, Wim H. M. Saris, Jan Polak, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-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 - Jean Jaurès (UT2J), Université de Toulouse (UT)-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)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mécanique de Lille - FRE 3723 (LML), Université de Lille, Sciences et Technologies-Centrale Lille-Centre National de la Recherche Scientifique (CNRS), Déterminants Biologiques et Comportementaux des Obésités, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-EA3502, Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Nutrition et obésité : approches génétique et transcriptomique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Laboratoire des Amino-acides Peptides et Protéines (LAPP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre d'études spatiales de la biosphère (CESBIO), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Gestion environnementale et traitement biologique des déchets (UR GERE), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Systèmes Macromoléculaires et Physiopathologie Humaine (SMPH), BIOMERIEUX-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche sur les obésités, IFR 31 Louis Bugnard (IFR 31), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-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 de Toulouse (UT)-Université de Toulouse (UT)-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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Hôtel-Dieu, Department of Sport Medicine, Charles University [Prague] (CU), Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, Froguel, Philippe, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Université de Lille, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-EA3502, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital de l'Hôtel-Dieu, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu, Techniques of Informatics and Microelectronics for integrated systems Architecture (TIMA), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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]-Institut National de la Santé et de la Recherche Médicale (INSERM), Charles University [Prague], Humane Biologie, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Lille, Sciences et Technologies-Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), 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 - Jean Jaurès (UT2J)-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)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), and 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)

Subjects
Candidate gene, MESH: Diabetes Mellitus, MESH: Pedigree, media_common.quotation_subject, Adipokine, Physiology, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Insulin-Secreting Cells, 03 medical and health sciences, 0302 clinical medicine, Weight loss, MESH: Receptors, Drug, MESH: Hypoglycemic Agents, Medicine, MESH: Tolbutamide, Pharmacology (medical), Gene–environment interaction, MESH: Birth Weight, Nutrition, 030304 developmental biology, media_common, MESH: Heterozygote, 2. Zero hunger, Genetics, 0303 health sciences, MESH: Mutation, Missense, MESH: Humans, business.industry, Haplotype, MESH: Infant, Newborn, MESH: Potassium Channels, Inwardly Rectifying, Appetite, General Medicine, MESH: Potassium Channels, medicine.disease, Obesity, MESH: Male, 3. Good health, MESH: Diabetes Complications, MESH: Developmental Disabilities, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: ATP-Binding Cassette Transporters, medicine.symptom, business, MESH: Female, MESH: Sulfonylurea Compounds, Research Article
Abstract

Objectives: To study if genes with common single nucleotide polymorphisms (SNPs) associated with obesity-related phenotypes influence weight loss (WL) in obese individuals treated by a hypo-energetic low-fat or high-fat diet. Design: Randomised, parallel, two-arm, open-label multi-centre trial. Setting: Eight clinical centres in seven European countries. Participants: 771 obese adult individuals. Interventions: 10-wk dietary intervention to hypo-energetic (−600 kcal/d) diets with a targeted fat energy of 20%–25% or 40%–45%, completed in 648 participants. Outcome Measures: WL during the 10 wk in relation to genotypes of 42 SNPs in 26 candidate genes, probably associated with hypothalamic regulation of appetite, efficiency of energy expenditure, regulation of adipocyte differentiation and function, lipid and glucose metabolism, or production of adipocytokines, determined in 642 participants. Results: Compared with the noncarriers of each of the SNPs, and after adjusting for gender, age, baseline weight and centre, heterozygotes showed WL differences that ranged from −0.6 to 0.8 kg, and homozygotes, from −0.7 to 3.1 kg. Genotype-dependent additional WL on low-fat diet ranged from 1.9 to −1.6 kg in heterozygotes, and from 3.8 kg to −2.1 kg in homozygotes relative to the noncarriers. Considering the multiple testing conducted, none of the associations was statistically significant. Conclusions: Polymorphisms in a panel of obesity-related candidate genes play a minor role, if any, in modulating weight changes induced by a moderate hypo-energetic low-fat or high-fat diet., Editorial Commentary Background: Obesity is an important cause of death and disease, particularly in the developed world. It is understood that both environmental and genetic factors contribute towards obesity. Numerous studies have associated particular gene variants with a tendency towards obesity, but it is not known whether such gene variants affect the degree to which obese individuals will lose weight when dieting. What this trial shows: As part of a randomised trial, 771 participants were assigned to one of two different low-energy diets for 10 weeks: one low in fat or one high in fat. The researchers then did a genetic analysis of 642 participants completing the intervention, to find out whether any of 42 distinct genetic variations in 26 genes were associated with weight loss in the trial. The genetic variants were chosen for study as they were known or already thought to be associated with appetite regulation or various aspects of metabolism and fat tissue development and function. The investigators found that none of the genetic variants studied had a significant association with weight loss in the trial. It was also seen that the majority of genetic variants were not associated with efficacy of one dietary intervention over another. Strengths and limitations: Although a large number of participants was recruited into the trial, the genetic analysis involved multiple comparisons—168 tests of 42 genetic variants. This increases the likelihood that any significant associations found could have resulted from chance alone. Significant associations from this study will require additional confirmation in larger studies. Contribution to the evidence: This study adds data indicating that variation in the genes studied did not have an important influence on weight loss.

Published
2006
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21. GAD2 on chromosome 10p12 is a candidate gene for human obesity

Author

Karine Clément, Séverine Dubois, Lynn M. Bekris, Laetitia Corset, Philippe Boutin, Philippe Froguel, Mohamed Chikri, M. Aline Charles, Bernadette Neve, Christian Dina, Francis Vasseur, Åke Lernmark, Janice Cabellon, Karin Séron, Valérie Vasseur-Delannoy, Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medicine, University of Washington [Seattle], Epidémiologie cardiovasculaire et métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital de l'Hôtel-Dieu, Section of Genomic Medicine, Imperial College London, and Froguel, Philippe

Subjects
Candidate gene, medicine.medical_treatment, Glutamate decarboxylase, MESH: gamma-Aminobutyric Acid, MESH: Eating, MESH: Insulin-Secreting Cells, MESH: Genotype, 0302 clinical medicine, MESH: Obesity, MESH: Autoantibodies, Biology (General), 2. Zero hunger, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Risk, General Neuroscience, MESH: Polymorphism, Single Nucleotide, Neuropeptide Y receptor, MESH: Case-Control Studies, MESH: Hunger, 3. Good health, MESH: Promoter Regions (Genetics), MESH: Feeding Behavior, MESH: Isoenzymes, General Agricultural and Biological Sciences, MESH: Glutamate Decarboxylase, medicine.medical_specialty, QH301-705.5, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, MESH: Insulin, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, General Biochemistry, Genetics and Molecular Biology, GAD2, 03 medical and health sciences, MESH: Plasmids, Internal medicine, medicine, SNP, MESH: Neuropeptide Y, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, General Immunology and Microbiology, Insulin, MESH: Alleles, MESH: Questionnaires, Haplotype, MESH: Adult, MESH: Haplotypes, MESH: Obesity, Morbid, MESH: Catalysis, MESH: Male, MESH: Odds Ratio, MESH: Cell Line, Endocrinology, MESH: Lod Score, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Chromosomes, Human, Pair 10, MESH: Family Health, MESH: Luciferases, MESH: Chromosome Mapping, MESH: Female, MESH: Linkage (Genetics), MESH: Paraventricular Hypothalamic Nucleus
Abstract

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11-12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of gamma-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681-0.972], p = 0.0049) and an at-risk SNP (-243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053-1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (chi(2) = 7.637, p = 0.02). In the murine insulinoma cell line betaTC3, the G at-risk allele of SNP -243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The -243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic beta cells, we analyzed GAD65 antibody level as a marker of beta-cell activity and of insulin secretion. In the control group, -243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of beta-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Published
2003
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22. RFamide peptides 43RFa and 26RFa both promote survival of pancreatic β-cells and human pancreatic islets but exert opposite effects on insulin secretion

Author

Loredana Bergandi, Rita Nano, Giuseppe Alloatti, Mauro Papotti, Lorenzo Piemonti, Letizia Trovato, Hubert Vaudry, Riccarda Granata, Ezio Ghigo, Iacopo Gesmundo, Jérôme Leprince, Marco Volante, Huy Ong, Davide Gallo, Fabio Settanni, Maria Pia Gallo, Pathology/molecular and cellular medicine, Department of Medical Sciences [Turin, Italy] (DMS), University of Turin, IRCCS San Raffaele Scientific Institute [Milan, Italie], Department of Life Sciences and Systems Biology [University of Turin], Department of Oncology [University of Turin], Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Faculty of Pharmacy [Montréal, QC, Canada], Université de Montréal (UdeM), Granata, Riccarda, Settanni, Fabio, Trovato, Letizia, Gallo, Davide, Gesmundo, Iacopo, Nano, Rita, Gallo, Maria Pia, Bergandi, Loredana, Volante, Marco, Alloatti, Giuseppe, Piemonti, Lorenzo, Leprince, Jã©rã´me, Papotti, Mauro, Vaudry, Hubert, Ong, Huy, and Ghigo, Ezio

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Glucose uptake, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Insulin Secretion, MESH: Neuropeptides, MESH: Insulin-Secreting Cells, Receptors, G-Protein-Coupled, 0302 clinical medicine, Insulin-Secreting Cells, Insulin Secretion, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin, MESH: Animals, Cells, Cultured, 0303 health sciences, MESH: Peptides, Kinase, Research Support, Non-U.S. Gov't, apoptosis, medicine.anatomical_structure, MESH: Cell Survival, Peptide, Intercellular Signaling Peptides and Proteins, islets of Langerhans, Human, MESH: Cells, Cultured, medicine.medical_specialty, Gs alpha subunit, MESH: Rats, Cell Survival, MESH: Insulin, Biology, RATS, 03 medical and health sciences, MESH: Cell Proliferation, Internal medicine, Internal Medicine, medicine, Journal Article, Animals, Humans, Secretion, Protein kinase B, Cell Proliferation, 030304 developmental biology, MESH: Humans, Animal, MESH: Apoptosis, MESH: Islets of Langerhans, Pancreatic islets, Neuropeptides, QRFP, Apoptosi, Islets of Langerhan, Neuropeptide, Endocrinology, cell proliferation, Insulin-Secreting Cell, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, peptides, Rat, 030217 neurology & neurosurgery
Abstract

RFamide peptides 43RFa and 26RFa have been shown to promote food intake and to exert different peripheral actions through G-protein-coupled receptor 103 (GPR103) binding. Moreover, 26RFa was found to inhibit pancreatic insulin secretion, whereas the role of 43RFa on β-cell function is unknown, as well as the effects of both peptides on β-cell survival. Herein, we investigated the effects of 43RFa and 26RFa on survival and apoptosis of pancreatic β-cells and human pancreatic islets. In addition, we explored the role of these peptides on insulin secretion and the underlying signaling mechanisms. Our results show that in INS-1E β-cells and human pancreatic islets both 43RFa and 26RFa prevented cell death and apoptosis induced by serum starvation, cytokine synergism, and glucolipotoxicity, through phosphatidylinositol 3-kinase/Akt- and extracellular signal-related kinase 1/2-mediated signaling. Moreover, 43RFa promoted, whereas 26RFa inhibited, glucose- and exendin-4-induced insulin secretion, through Gαs and Gαi/o proteins, respectively. Inhibition of GPR103 expression by small interfering RNA blocked 43RFa insulinotropic effect, but not the insulinostatic action of 26RFa. Finally, 43RFa, but not 26RFa, induced cAMP increase and glucose uptake. In conclusion, because of their survival effects along with the effects on insulin secretion, these findings suggest potential for 43RFa and 26RFa as therapeutic targets in the treatment of diabetes. © 2014 by the American Diabetes Association.

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