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1. Obesity interferes with the orosensory detection of long-chain fatty acids in humans

Author

Géraldine Enderli, Déborah Ancel, Michael Chevrot, Isabelle Robin, Sylvie Issanchou, Arnaud Bernard, Bruno Vergès, Patricia Passilly-Degrace, Philippe Besnard, Marlène Gomes, Sophie Nicklaus, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) ( NUTox ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), 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 ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Supported by the Burgundy Council and Centre National Interprofessionnel de l'Economie Laitie're (HumanFATaste program, to PB). MC is a PhD fellow of the HumanFATaste program., Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), 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), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Bernard, Arnaud, and Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Blood Glucose, Male, obesity, Chemical Phenomena, MESH : Insulin, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Cholesterol, VLDL, Medicine (miscellaneous), MESH: Food Habits, Stimulation, MESH: Energy Intake, MESH : Taste, MESH : Fasting, Body Mass Index, chemistry.chemical_compound, MESH: Cholesterol, VLDL, MESH: Diet Records, Insulin, MESH: Obesity, MESH : Physicochemical Phenomena, Completely randomized design, MESH : Food Habits, Cross-Over Studies, MESH: Middle Aged, MESH : Food Preferences, Nutrition and Dietetics, Fasting, Middle Aged, Diet Records, MESH : Triglycerides, Sensory Thresholds, Taste, MESH : Obesity, MESH: Triglycerides, medicine.medical_specialty, MESH : Male, Linoleic acid, MESH: Fasting, MESH: Insulin, MESH: Cross-Over Studies, MESH: Body Mass Index, Linoleic Acid, MESH : Diet Records, Food Preferences, BMI, MESH : Linoleic Acid, Internal medicine, Autonomic reflex, medicine, Humans, MESH : Middle Aged, human, MESH: Food Preferences, Triglycerides, MESH : Cholesterol, VLDL, MESH: Linoleic Acid, MESH: Humans, Cholesterol, business.industry, MESH : Humans, MESH : Energy Intake, Feeding Behavior, MESH : Blood Glucose, MESH : Cross-Over Studies, medicine.disease, Crossover study, Obesity, MESH: Male, fat taste, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH: Physicochemical Phenomena, MESH : Body Mass Index, Endocrinology, chemistry, MESH: Blood Glucose, MESH: Taste, food preference, MESH: Sensory Thresholds, Energy Intake, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Body mass index, MESH : Sensory Thresholds
Abstract

Background: The association between the orosensory detection of lipids, preference for fatty foods, and body mass index (BMI; in kg/m 2 ) is controversial in humans. Objective: We explored the oral lipid-sensing system and the orosensory-induced autonomic reflex system in lean and obese subjects. Design: Lean (BMI: 19 to ,25; n = 30) and obese (BMI .30; n = 29) age-matched men were enrolled. Their oral threshold sensitivity to linoleic acid (LA) was determined by using a 3-alternative forced-choice ascending procedure, and their eating habits were established by the analysis of 4 consecutive 24-h food-consumption diaries. The effect of brief oral lipid stimulations on plasma triglyceride [(TG)pl] concentrations was analyzed in overnight-fasted lean and obese individuals subjected to a whole-mouth stimulation (sipand-spit procedure) with a control or 1% LA emulsions for 5 min according to a within-subject randomized design. Results: A large distribution of LA detection was shown in both groups. Mean detection thresholds were 0.053% (wt:wt) and 0.071% (wt:wt) in lean and obese subjects, respectively. No relation between the LA detection threshold and BMI was observed. The 5 subjects who detected only the higher concentration of LA (5% wt: wt) or were unable to distinguish properly between control and LA emulsions were obese. An analysis of dietary habits showed that these obese LA nontasters consumed more lipids and energy than did all other subjects. Brief whole-mouth stimulations (sip-and-spit procedure) with a control or 1% LA emulsion revealed an LAmediated rise in (TG)pl concentrations in overnight-fasted, lean subjects. The origin of this change seemed to be hepatic. This (TG)pl upregulation was not shown in obese subjects, which suggested that obesity led to disturbances in the oral-brainstem-periphery loop. Conclusion: Altogether, these data strongly suggest that obesity may interfere with the orosensory system responsible for the detection of free long-chain fatty acids in humans. This trial was registered at clinicaltrials.gov as NCT02028975. Am J Clin Nutr doi: 10. 3945/ajcn.113.077198.

Published
2014
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2. Physiological and Pharmacological Mechanisms through which the DPP-4 Inhibitor Sitagliptin Regulates Glycemia in Mice

Author

Pierre Cattan, Julien Castel, Rémy Burcelin, Aurélie Waget, Daniel J. Drucker, Mattieu Armanet, Melis Karaca, Christophe Magnan, Jens J. Holst, Céline Garret, Thierry Sulpice, Gaëlle Payros, Myriam Masseboeuf, Adriano Maida, Cendrine Cabou, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cell Therapy Unit, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Fonctionnelle et Adaptative ( BFA ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Medicine, University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital ( MSH ), Physiogenex SAS, Prologue Biotech, PHYSIOGENEX S.A.S, Department of Biomedical Sciences, The panum Institute-University of Copenhagen ( KU ), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto-Samuel Lunenfeld Research Institute-Mount Sinai Hospital [Toronto, Canada] (MSH), Physiogenex, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto-Mount Sinai Hospital [Toronto, Canada] (MSH)-Samuel Lunenfeld Research Institute, and University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)

Subjects
MESH : Insulin, medicine.medical_treatment, MESH : Vagus Nerve, MESH : Receptors, Glucagon, 0302 clinical medicine, Endocrinology, MESH: Dipeptides, MESH: Vagus Nerve, Glucose homeostasis, MESH: Animals, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Dipeptidyl-Peptidase IV Inhibitors, 0303 health sciences, Glucose tolerance test, MESH: Middle Aged, MESH: Dipeptidyl-Peptidase IV Inhibitors, medicine.diagnostic_test, MESH : Glucagon, MESH: Glucagon, digestive, oral, and skin physiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Adult, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucagon-like peptide-1, 3. Good health, MESH : Pyrazines, MESH: Pyrazines, Sitagliptin, hormones, hormone substitutes, and hormone antagonists, medicine.drug, endocrine system, medicine.medical_specialty, MESH: Glucose Tolerance Test, MESH : Male, MESH : Dipeptides, MESH : Receptors, Gastrointestinal Hormone, Incretin, 030209 endocrinology & metabolism, MESH: Insulin, MESH : Mice, Inbred C57BL, Biology, Sitagliptin Phosphate, MESH : Glucose Tolerance Test, MESH: Receptors, Glucagon, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, MESH : Triazoles, medicine, MESH : Middle Aged, MESH: Mice, Dipeptidyl peptidase-4, 030304 developmental biology, MESH: Humans, MESH: Receptors, Gastrointestinal Hormone, Insulin, MESH : Humans, MESH: Adult, MESH: Dipeptidyl Peptidase 4, MESH : Blood Glucose, MESH: Male, MESH: Triazoles, MESH : Dipeptidyl Peptidase 4, MESH: Blood Glucose, MESH : Animals
Abstract

International audience; Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.

Published
2011
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3. Efficacy and safety of an insulin infusion protocol during and after cardiac surgery

Author

C. Studer, W. Sankou, Alfred Penfornis, Marc Puyraveau, Emmanuel Samain, A. Cordier, Joseph-Philippe Etievent, Sebastien Pili-Floury, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Diabétologie - Endocrinologie [CHRU Besançon], Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), and Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon )

Subjects
Blood Glucose, Male, MESH: Hypoglycemia, MESH : Insulin, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH : Aged, Aorta, Thoracic, 030204 cardiovascular system & hematology, law.invention, Intraoperative Period, 0302 clinical medicine, Endocrinology, MESH: Postoperative Period, law, Insulin, MESH : Female, Postoperative Period, 030212 general & internal medicine, Coronary Artery Bypass, Infusions, Intravenous, Prospective cohort study, MESH: Aged, MESH: Middle Aged, MESH: Cardiac Surgical Procedures, MESH : Vascular Surgical Procedures, MESH : Infusions, Intravenous, General Medicine, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Middle Aged, Intensive care unit, 3. Good health, Cardiac surgery, MESH : Intraoperative Period, Female, Safety, Vascular Surgical Procedures, medicine.medical_specialty, MESH : Male, MESH: Aorta, Thoracic, MESH : Drug Administration Schedule, MESH: Monitoring, Intraoperative, MESH: Insulin, MESH: Drug Administration Schedule, Hypoglycemia, MESH : Cardiac Surgical Procedures, Drug Administration Schedule, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Hypoglycemic Agents, Monitoring, Intraoperative, Diabetes mellitus, Internal Medicine, medicine, Humans, Hypoglycemic Agents, MESH : Middle Aged, MESH : Safety, Cardiac Surgical Procedures, MESH: Infusions, Intravenous, MESH: Vascular Surgical Procedures, Pancreatic hormone, MESH : Aorta, Thoracic, Aged, MESH : Postoperative Period, MESH: Intraoperative Period, MESH: Humans, MESH : Hypoglycemia, business.industry, MESH: Coronary Artery Bypass, MESH : Humans, MESH: Safety, Perioperative, MESH : Blood Glucose, medicine.disease, MESH : Hypoglycemic Agents, MESH : Coronary Artery Bypass, MESH: Male, Surgery, Hyperglycemia, MESH : Hyperglycemia, MESH: Blood Glucose, MESH : Monitoring, Intraoperative, MESH: Hyperglycemia, business, MESH: Female
Abstract

International audience; AIM: Perioperative tight blood glucose (BG) control using insulin therapy after major surgery is a difficult, time-consuming task that also raises some concerns over the risk of severe hypoglycaemia. The aim of the present prospective study was to evaluate the efficacy and safety of an insulin therapy protocol in use at our institution. METHODS: A total of 230 consecutive patients (mean+/-SD age: 67+/-11 years; diabetic patients: n=62) undergoing cardiac surgery (coronary artery bypass grafting: n=137; 20% off-pump) or intrathoracic aortic (n=10) surgery were included. BG control was managed according to an insulin therapy protocol, described by Goldberg et al. (2004) [11], in use for 6 months in our intensive care unit. Insulin infusion rate and frequency of BG monitoring were both adjusted according to: (1) the current BG value; (2) the previous BG value; and (3) the current insulin infusion rate. Efficacy was assessed by the percentage of time spent at the target BG level (100-139 mg/dL) intraoperatively and during the first 2 postoperative days (POD). RESULTS: All patients received postoperative insulin therapy. Patients spent 57.3% and 69.7% of time within the BG target range on POD 1 and 2, respectively. The percentage of time was significantly higher in nondiabetics than in diabetics. Mean BG measurements per patient intraoperatively, on POD 1 and on POD 2 were 4+/-1, 10+/-2 and 7+/-2, respectively. No patient experienced any severe hypoglycaemic events (BG

Published
2010
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4. Acute activation of cannabinoid receptors by anandamide reduces gastrointestinal motility and improves postprandial glycemia in mice

Author

Stephanie Troy-Fioramonti, Laurent Demizieux, Joseph Gresti, Tania Muller, Bruno Vergès, Pascal Degrace, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), This work was supported by funds from the Regional Council ofBurgundy and European Union (FEDER)., Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and DEGRACE, Pascal

Subjects
Blood Glucose, Male, Indoles, Cannabinoid receptor, MESH : Piperidines, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH: Endocannabinoids, MESH : Pyrazoles, MESH : Receptors, Cannabinoid, Mice, chemistry.chemical_compound, Piperidines, MESH : Indoles, MESH: Receptors, Cannabinoid, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Arachidonic Acids, Glucose homeostasis, MESH: Gastrointestinal Transit, MESH: Animals, Receptors, Cannabinoid, MESH: Indoles, Reverse Transcriptase Polymerase Chain Reaction, MESH : Rats, MESH : Reverse Transcriptase Polymerase Chain Reaction, Anandamide, Postprandial Period, Endocannabinoid system, MESH : Gastrointestinal Motility, Postprandial, MESH: Piperidines, MESH: Postprandial Period, MESH: Gastrointestinal Motility, Rimonabant, MESH : Endocannabinoids, MESH : Gastrointestinal Transit, medicine.medical_specialty, MESH: Rats, Polyunsaturated Alkamides, MESH : Male, Arachidonic Acids, MESH : Mice, Inbred C57BL, MESH : Rats, Wistar, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, Internal Medicine, medicine, Animals, MESH: Arachidonic Acids, MESH : Polyunsaturated Alkamides, Rats, Wistar, Gastrointestinal Transit, MESH: Mice, Gastric emptying, MESH: Polyunsaturated Alkamides, Glucose transporter, MESH: Rats, Wistar, MESH : Blood Glucose, MESH: Male, Rats, Mice, Inbred C57BL, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, chemistry, Hyperglycemia, MESH : Hyperglycemia, MESH: Blood Glucose, Pyrazoles, MESH : Animals, Cannabinoid, MESH : Postprandial Period, Gastrointestinal Motility, MESH: Hyperglycemia, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Pyrazoles, Endocannabinoids
Abstract

International audience; The endocannabinoid system (ECS) is associated with an alteration of glucose homeostasis dependent on cannabinoid receptor-1 (CB1R) activation. However, very little information is available concerning the consequences of ECS activation on intestinal glucose absorption. Mice were injected intraperitoneally with anandamide, an endocannabinoid binding both CB1R and CB2R. We measured plasma glucose and xylose appearance after oral loading, gastrointestinal motility, and glucose transepithelial transport using the everted sac method. Anandamide improved hyperglycemia after oral glucose charge whereas glucose clearance and insulin sensitivity were impaired, pointing out some gastrointestinal events. Plasma xylose appearance was delayed in association with a strong decrease in gastrointestinal transit, while anandamide did not alter transporter-mediated glucose absorption. Interestingly, transit was nearly normalized by coinjection of SR141716 and AM630 (CB1R and CB2R antagonist, respectively), and AM630 also reduced the delay of plasma glucose appearance induced by anandamide. When gastric emptying was bypassed by direct glucose administration in the duodenum, anandamide still reduced plasma glucose appearance in wild-type but not in CB1R(-/-) mice. In conclusion, our findings demonstrated that acute activation of intestinal ECS reduced postprandial glycemia independently on intestinal glucose transport but rather inhibiting gastric emptying and small intestine motility and strongly suggest the involvement of both CB1R and CB2R.

Published
2015
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5. Effects of chronic calorie restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate, Microcebus murinus

Author

Fabien Pifferi, Julia Marchal, Fabienne Aujard, Stéphane Blanc, Jacques Epelbaum, Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Muséum national d'Histoire naturelle (MNHN), Département Ecologie, Physiologie et Ethologie (DEPE-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes adaptatifs : des organismes aux communautés ( MAOAC ), Muséum National d'Histoire Naturelle ( MNHN ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ), Département Ecologie, Physiologie et Ethologie ( DEPE-IPHC ), Institut Pluridisciplinaire Hubert Curien ( IPHC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Blood Glucose, Male, Phytochemistry, Time Factors, Anatomy and Physiology, medicine.medical_treatment, MESH : Insulin, MESH: Lemur, lcsh:Medicine, MESH: Dietary Supplements, Biochemistry, [ SDE ] Environmental Sciences, 0302 clinical medicine, MESH: Stilbenes, Stilbenes, Hyperinsulinemia, Insulin, MESH: Animals, MESH: Oxygen Consumption, MESH: Animal Feed, lcsh:Science, MESH : Oxygen Consumption, 2. Zero hunger, 0303 health sciences, Glucose tolerance test, Multidisciplinary, medicine.diagnostic_test, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Chemistry, MESH: Insulin Resistance, MESH : Animal Feed, [ SDV.BID.EVO ] Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDE]Environmental Sciences, Medicine, MESH : Insulin Resistance, MESH : Lemur, Research Article, MESH : Time Factors, medicine.medical_specialty, MESH : Caloric Restriction, MESH : Male, MESH: Glucose Tolerance Test, Calorie restriction, Endocrine System, MESH: Insulin, Carbohydrate metabolism, Biology, MESH : Stilbenes, MESH : Diet, MESH : Glucose Tolerance Test, 03 medical and health sciences, Oxygen Consumption, Insulin resistance, MESH: Diet, Internal medicine, Diabetes mellitus, medicine, Animals, MESH : Dietary Supplements, Caloric Restriction, Nutrition, 030304 developmental biology, MESH: Caloric Restriction, Endocrine Physiology, Lemur, lcsh:R, MESH: Time Factors, Glucose Tolerance Test, medicine.disease, MESH : Blood Glucose, Animal Feed, MESH: Male, Diet, Endocrinology, Resveratrol, Dietary Supplements, Basal metabolic rate, MESH: Blood Glucose, lcsh:Q, MESH : Animals, Insulin Resistance, Physiological Processes, 030217 neurology & neurosurgery
Abstract

International audience; The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg*day(-1)*kg(-1)). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes.

Published
2012
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6. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis

Author

Marc Riviere, Victor de Ledinghen, Dominique Larrey, Marianne Maynard, Claire Wartelle-Bladou, Vlad Ratziu, Jean-Philippe Bastard, Christophe Renou, Lawrence Serfaty, Jean Spénard, Dominique Bonnefont-Rousselot, Frédéric Oberti, Philippe Mathurin, Philippe Sogni, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Département d'hépato-gastroentérologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Hepatology, Hopital, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépato-gastro-enterologie, Hospices Civils de Lyon (HCL), Service d'hépatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Service d'hépatologie [Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), FRESGUN, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire HIFIH, PRES Université Nantes Angers Le Mans ( UNAM ) -IFR132-UPRES 3859, Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ) -PRES Université Nantes Angers Le Mans ( UNAM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Hospices Civils de Lyon ( HCL ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Blood Glucose, Male, Pathology, Cholagogues and Choleretics, Steatosis, MESH : Fatty Liver, MESH : Insulin, MESH : Cholagogues and Choleretics, MESH : Dose-Response Relationship, Drug, Aminotransferases, Gastroenterology, law.invention, MESH: Dose-Response Relationship, Drug, Liver disease, 0302 clinical medicine, Randomized controlled trial, law, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Insulin, MESH : Female, MESH : Hemoglobin A, Glycosylated, MESH: Cholagogues and Choleretics, MESH: Fatty Liver, MESH: Treatment Outcome, 0303 health sciences, education.field_of_study, MESH: Middle Aged, Ursodeoxycholic Acid, MESH: Follow-Up Studies, MESH : Adult, Middle Aged, Ursodeoxycholic acid, 3. Good health, MESH: Insulin Resistance, Treatment Outcome, Tolerability, MESH : Ursodeoxycholic Acid, MESH: Hemoglobin A, Glycosylated, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Female, Randomized clinical trials, MESH : Insulin Resistance, medicine.drug, Adult, medicine.medical_specialty, MESH : Male, Population, MESH : Treatment Outcome, MESH: Insulin, Placebo, 03 medical and health sciences, Internal medicine, Multicenter trial, medicine, Humans, MESH : Middle Aged, Nonalcoholic steatohepatitis, education, 030304 developmental biology, Glycated Hemoglobin, MESH: Humans, Hepatology, Dose-Response Relationship, Drug, business.industry, MESH : Humans, MESH : Follow-Up Studies, Insulin resistance, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Blood Glucose, medicine.disease, Fibrosis, MESH: Male, Fatty Liver, MESH: Blood Glucose, business, MESH: Ursodeoxycholic Acid, MESH: Female, Follow-Up Studies
Abstract

International audience; BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease associated with increased morbidity and mortality. Ursodeoxycholic acid (UDCA) may have antioxidant, anti-inflammatory, and antifibrotic properties and may reduce liver injury in NASH. To date, no studies have assessed the efficacy and safety of high-dose UDCA (HD-UDCA) in patients with NASH. METHODS: We conducted a 12-month, randomized, double-blind, placebo-controlled multicenter trial to evaluate the efficacy and safety of HD-UDCA (28-35 mg/kg per day) in 126 patients with biopsy-proven NASH and elevated alanine aminotransferase (ALT) levels. The primary study end point was reduction in ALT levels from baseline in patients treated with HD-UDCA compared with placebo. Secondary study end points were the proportion of patients with ALT normalization, relative reduction in the scores of serum markers of fibrosis and hepatic inflammation, and safety and tolerability. RESULTS: HD-UDCA significantly reduced mean ALT levels -28.3% from baseline after 12 months compared with -1.6% with placebo (p

Published
2011
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7. 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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8. Treatment with the arginase inhibitor N(omega)-hydroxy-nor-L-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat

Author

Alain Berthelot, Céline Demougeot, Pascal Laurant, Yves Claude Guillaume, Claire André, Malika Bouhaddi, Teddy Bagnost, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), and Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon )

Subjects
Blood Glucose, Male, Arginine, Physiology, MESH: Mesenteric Arteries, MESH: Rats, Inbred SHR, Aorta, Thoracic, Blood Pressure, 030204 cardiovascular system & hematology, Kidney, Rats, Inbred WKY, MESH: Hypertension, chemistry.chemical_compound, 0302 clinical medicine, Heart Rate, MESH : Arginine, Rats, Inbred SHR, Urea, MESH: Animals, MESH: Heart Rate, MESH : Mesenteric Arteries, MESH : Body Weight, MESH : Isoenzymes, 0303 health sciences, MESH : Rats, MESH: Arginine, MESH : Hypertension, MESH : Arginase, MESH: Blood Pressure, MESH : Kidney, Mesenteric Arteries, 3. Good health, Isoenzymes, Arginase, MESH: Arginase, medicine.anatomical_structure, Liver, MESH : Nitric Oxide, Hypertension, MESH: Isoenzymes, MESH: Vasoconstriction, MESH: Endothelium, Vascular, MESH : Vasoconstriction, Cardiology and Cardiovascular Medicine, Vascular function, MESH: Rats, Inbred WKY, medicine.medical_specialty, Endothelium, MESH: Rats, MESH : Male, MESH: Aorta, Thoracic, In Vitro Techniques, MESH : Rats, Inbred WKY, Nitric Oxide, Nitric oxide, 03 medical and health sciences, Spontaneously hypertensive rat, MESH : Urea, Internal medicine, medicine.artery, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal Medicine, medicine, MESH : Blood Pressure, Animals, MESH: Urea, 030304 developmental biology, MESH : Aorta, Thoracic, Aorta, MESH : Rats, Inbred SHR, business.industry, MESH : Heart Rate, Body Weight, MESH : Liver, MESH: Kidney, MESH : Blood Glucose, MESH: Male, Rats, MESH: Body Weight, Endocrinology, Blood pressure, chemistry, Vasoconstriction, MESH : Endothelium, Vascular, MESH: Nitric Oxide, MESH: Blood Glucose, Endothelium, Vascular, MESH : Animals, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Liver
Abstract

International audience; OBJECTIVE: High vascular arginase activity and subsequent reduction in vascular nitric oxide production were recently reported in animal models of hypertension. The present study investigated the effects of in-vivo arginase inhibition on blood pressure and vascular function in adult spontaneously hypertensive rats. METHODS: Ten-week-old spontaneously hypertensive rats and normotensive age-matched Wistar-Kyoto rats were treated with or without the selective arginase inhibitor N-hydroxy-nor-L-arginine for 3 weeks (10 or 40 mg/kg per day, intraperitoneally). Systolic blood pressure and cardiac rate were measured before and during treatment. Flow and pressure-dependent reactivity as well as remodeling of mesenteric arteries, acetylcholine-dependent vasodilation of aortic rings, cardiac hypertrophy, arginase activity and nitric oxide production were investigated in 13-week-old spontaneously hypertensive rats. RESULTS: In spontaneously hypertensive rats, N-hydroxy-nor-L-arginine treatment decreased arginase activity (30-40%), reduced blood pressure ( approximately 35 mmHg) and improved the reactivity of mesenteric vessels. However, vascular and cardiac remodeling was not different between treated and untreated spontaneously hypertensive rats. In Wistar-Kyoto rats, N-hydroxy-nor-L-arginine did not affect blood pressure. Finally, arginase inhibition was associated with increased nitric oxide production. Consistent with this, the response of aortic rings to acetylcholine was fully restored by N-hydroxy-nor-L-arginine, and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the effect of N-hydroxy-nor-L-arginine on flow-dependent vasodilation. CONCLUSION: Pharmacological inhibition of arginase in adult spontaneously hypertensive rats decreases blood pressure and improves the reactivity of resistance vessels. These data represent in-vivo argument in favor of selective arginase inhibition as a new therapeutic strategy against hypertension.

Published
2008
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9. Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes

Author

Hervé Dubouchaud, Karine Couturier, Luc Demaison, Martine Lanson, Xavier Leverve, Guillaume Vial, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Géophysique Interne et Tectonophysique (LGIT), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Central des Ponts et Chaussées (LCPC)-Centre National de la Recherche Scientifique (CNRS), FLAveur, VIsion et Comportement du consommateur (FLAVIC), Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Hamant, Sarah, Bioenergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Géophysique Interne et Tectonophysique ( LGIT ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Laboratoire Central des Ponts et Chaussées ( LCPC ) -Institut des Sciences de la Terre ( ISTerre ), Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers ( INSU - CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ), FLAveur, VIsion et Comportement du consommateur ( FLAVIC ), Etablissement National d'Enseignement Supérieur Agronomique de Dijon ( ENESAD ) -Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Laboratoire Central des Ponts et Chaussées (LCPC)-Institut des Sciences de la Terre (ISTerre), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers (INSU - CNRS)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), and Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-Etablissement National d'Enseignement Supérieur Agronomique de Dijon (ENESAD)

Subjects
Male, Wistar, Guanidines, 0302 clinical medicine, MESH : 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Medicine, MESH: Animals, Acidosis, 0303 health sciences, Symporters, Heart, General Medicine, 3. Good health, MESH: Guanidines, Sodium nitroprusside, MESH : Diabetes Mellitus, Experimental, MESH: Endothelium, Vascular, Nitroprusside, medicine.medical_specialty, MESH: Dilatation, Streptozocin, 03 medical and health sciences, Heart rate, Diabetes Mellitus, Endothelium, Lactic Acid, Rats, Wistar, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Sulfones, MESH: Sodium-Hydrogen Antiporter, Cariporide, MESH : Glucose, MESH : Nitroprusside, MESH: Streptozocin, Streptozotocin, medicine.disease, MESH: Heart, 15-Hydroxy-11 alpha, MESH: Carbachol, Endocrinology, Glucose, chemistry, MESH : Endothelium, Vascular, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, MESH : Lactic Acid, MESH: Blood Glucose, Endothelium, Vascular, MESH : Monocarboxylic Acid Transporters, Blood Glucose, Clinical Biochemistry, MESH : Dilatation, 030204 cardiovascular system & hematology, chemistry.chemical_compound, Thromboxane A2, MESH: Diabetes Mellitus, Experimental, Sulfones, MESH: Monocarboxylic Acid Transporters, Sodium-Hydrogen Exchanger 1, MESH : Rats, MESH: Sulfones, MESH : Sodium-Hydrogen Antiporter, MESH : Guanidines, 9 alpha-(epoxymethano)prosta-5, MESH: Glucose, medicine.anatomical_structure, MESH : Symporters, Heart Function Tests, MESH : Heart Function Tests, medicine.symptom, medicine.drug, Monocarboxylic Acid Transporters, MESH: Symporters, Sodium-Hydrogen Exchangers, MESH: Rats, MESH : Male, Sodium-Hydrogen Antiporter, In Vitro Techniques, MESH : Rats, Wistar, Diabetes Mellitus, Experimental, Experimental, MESH : Heart, Internal medicine, Diabetes mellitus, Vascular, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Streptozocin, 030304 developmental biology, business.industry, Cell Biology, MESH: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, MESH: Rats, Wistar, MESH : Blood Glucose, Dilatation, MESH: Male, MESH: Nitroprusside, Rats, Ventricle, MESH : Carbachol, 13-dienoic Acid, Carbachol, MESH: Lactic Acid, MESH : Animals, business, MESH: Heart Function Tests
Abstract

International audience; Hyperglycemia encountered during diabetes triggers abnormalities of vascular function associated with cell acidosis and calcium overload. The purpose of this study was to determine, whether Na+/H+ exchanger (NHE-1) inhibition by cariporide protects coronary cells against the deleterious effect of hyperglycemia in the rat. In vivo hyperglycemia was triggered by streptozotocin injection. One week after, the glycemia was checked and the control and diabetic animals were treated or not with cariporide (2.5 mg/kg/day) for two weeks. Glycemia was again estimated and the hearts were perfused according to the Langendorff mode at forced flow. The left ventricle developed pressure (LVDP) and heart rate (HR) were determined with a latex balloon inserted into the left ventricle. Coronary pressure was artificially increased to 130 mmHg by infusing a thromboxane A2 analogue (U46619). This allowed the evaluation of endothelium-dependent (EDD) and endothelium-independent (EID) dilatation through bolus injections of carbamoylcholin and sodium nitroprusside, respectively. Releases of lactate and pyruvate in the coronary effluents were also determined. Diabetes did not modified LVDP, but reduced HR (-15%). This was associated with a marked decrease in EDD (-56%) and EID (-30%), while the cytosolic redox potential (estimated as the lactate/pyruvate ratio) was reduced. NHE-1 inhibition restored EDD and the lactate/pyruvate ratio without improving EID and HR. The present findings indicate that NHE-1 exchanger inhibition by cariporide protects the coronary endothelium against the deleterious effects of hyperglycemia.

Published
2008
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10. Predictive value of admission hyperglycaemia on mortality in patients with acute myocardial infarction

Author

Schiele , F., Descotes-Genon , V., Seronde , M. F., Blonde , M. C., Legalery , P., Meneveau , N., Ecarnot , F., Mercier , Mariette, Penfornis , A., Thebault , L., Boumal , D., Bassand , J.-P., Renseigné , Non, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Diabétologie - Endocrinologie [CHRU Besançon], and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)

Subjects
Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, MESH: Diabetic Angiopathies, Myocardial Infarction, MESH : Aged, MESH: Hospitalization, 030204 cardiovascular system & hematology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH : Diabetes Mellitus, Type 2, ST segment, MESH : Female, 030212 general & internal medicine, Myocardial infarction, MESH: Cohort Studies, MESH: Aged, Framingham Risk Score, Mortality rate, MESH : Diagnostic Tests, Routine, MESH: Predictive Value of Tests, 3. Good health, Hospitalization, MESH: Myocardial Infarction, Predictive value of tests, MESH : Hospitalization, Female, Cohort study, MESH: Diabetes Mellitus, Type 2, medicine.medical_specialty, MESH : Male, MESH : Cohort Studies, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, MESH : Predictive Value of Tests, Risk factor, MESH: Diagnostic Tests, Routine, Aged, MESH: Humans, business.industry, Diagnostic Tests, Routine, MESH : Diabetic Angiopathies, MESH : Humans, medicine.disease, MESH : Blood Glucose, MESH: Male, Surgery, Diabetes Mellitus, Type 2, Hyperglycemia, MESH: Blood Glucose, MESH : Hyperglycemia, MESH : Myocardial Infarction, business, MESH: Hyperglycemia, MESH: Female, Diabetic Angiopathies
Abstract

International audience; RATIONALE AND AIM: In patients with an acute myocardial infarction, admission hyperglycaemia (AH) is a major risk factor for mortality. However, the predictive value of AH, when the risk score and use of guidelines-recommended treatments are considered, is poorly documented. METHODS: The first fasting plasma glucose levels after admission, risk level, guidelines-recommended treatment use and 1-year mortality were recorded. Patients with first fasting glucose level after admission > 7.7 mmo/l were considered to have AH. RESULTS: Three hundred and twenty patients with ST segment elevation myocardial infarction (STEMI) and 404 with non-ST segment elevation myocardial infarction (NSTEMI) were included. One hundred and seventy-five (24%) patients had pre-existing diabetes (diabetes group), 154 (21%) had AH (AH+ group) and the remainding 395 (55%) had neither diabetes nor AH (AH- group). The Global Registry of Acute Coronary Events (GRACE) risk score was lower in the AH- group, but the use of guidelines-recommended treatment was comparable in all groups. At 1 year, the mortality rate was higher in the AH+ group compared with the AH- group (18.8 vs. 6.1%, P < 0.01) and similar to that in the diabetes group (18.8 vs. 16.6%, P = NS). The relation between glycaemic status and mortality remained strong [AH+ vs. AH-, OR = 3.0 (1.5, 6.0) and diabetes vs. AH-, OR = 3.6 (1.7, 6.6)] after adjustment for the GRACE risk score [OR = 2.4 (1.8, 3.1) per 10% increase] and for treatment score [OR = 0.7 (0.6, 0.8) per 10% increase]. CONCLUSIONS: In patients without a history of diabetes, the presence of AH indicates an increased risk of 1-year mortality, similar to that of patients with diabetes, even when the risk score and use of guidelines-recommended treatment are controlled for.

Published
2006
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11. Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene, insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects

Author

Reis, A. F., Hani, E. H., Beressi, N., Robert, J. J., Bresson, J. L., Froguel, P., Gilberto Velho, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Laboratoire de Dynamique des Fluides Complexes ( LDFC ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire Louis Néel ( LLN ), Centre National de la Recherche Scientifique ( CNRS ), CENTRE DE RECHERCHE SUR LES CIVILISATIONS CHINOISE, JAPONAISE ET TIBETAINE ( CRCAO ), École pratique des hautes études ( EPHE ) -Collège de France ( CdF ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales ( CSIC ), Instituto de Ciencia de Materiales, Laboratoire de pharmacologie des agents anticancéreux ( LPAA ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Centre National de la Recherche Scientifique ( CNRS ), Département d'Informatique et de Mathématiques ( DIM ), Université du Québec [Chicoutimi] ( UQAC ), Laboratoire de Physique des Lasers ( LPL ), Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut Galilée-Centre National de la Recherche Scientifique ( CNRS ), Service de chirurgie dentaire pédiatrique et physiologie, Hôpital Pontchaillou, Service : maladies du métabolisme, pédiatrie, neurologie, diabétologie, endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], École Polytechnique de Montréal ( EPM ), Maison des technologies de formation et d apprentissage Roland-Giguère ( MAISON DES TECHNOLOGIES DE FORMATION ET D APPRENTISSAGE ROLAND-GIGUèRE ), Maison des technologies de formation et d apprentissage Roland-Giguère, Laboratoire Environnement et Minéralurgie ( LEM ), Institut National Polytechnique de Lorraine ( INPL ) -Centre National de la Recherche Scientifique ( CNRS ), Institut universitaire de formation des maîtres - Champagne-Ardenne ( IUFM Champagne-Ardenne ), Université de Reims Champagne-Ardenne ( URCA ), CIC Necker Enfants Malades ( CIC 9303 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Dynamique des Fluides Complexes (LDFC), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Laboratoire Louis Néel (LLN), Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur les civilisations chinoise, japonaise et tibétaine (UMR 8155), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Instituto de Ciencia de Materiales de Aragón [Saragoza, España] (ICMA-CSIC), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Laboratoire de pharmacologie des agents anticancéreux (LPAA), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Centre National de la Recherche Scientifique (CNRS), Département d'Informatique et de Mathématiques (DIM), Université du Québec à Chicoutimi (UQAC), Laboratoire de Physique des Lasers (LPL), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École Polytechnique de Montréal (EPM), Maison des technologies de formation et d apprentissage Roland-Giguère (MAISON DES TECHNOLOGIES DE FORMATION ET D APPRENTISSAGE ROLAND-GIGUèRE), Laboratoire Environnement et Minéralurgie (LEM), Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Institut universitaire de formation des maîtres - Champagne-Ardenne (IUFM Champagne-Ardenne), Université de Reims Champagne-Ardenne (URCA), CIC Necker Enfants Malades (CIC 9303), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre de recherche sur les civilisations chinoise, japonaise et tibétaine (CRCAO), École pratique des hautes études (EPHE)-Collège de France (CdF)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Instituto de Ciencia de Materiales (CSIC), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC)-Institut Galilée-Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Blood Glucose, Potassium Channels, Receptors, Drug, MESH : Insulin, MESH : Genotype, Sulfonylurea Receptors, Polymerase Chain Reaction, MESH: Variation (Genetics), MESH: Genotype, MESH : Exons, MESH : Diabetes Mellitus, Type 2, Reference Values, Insulin Secretion, Insulin, MESH: C-Peptide, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, MESH : Polymerase Chain Reaction, C-Peptide, MESH: Kinetics, MESH : Variation (Genetics), MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Reference Values, MESH: Potassium Channels, Inwardly Rectifying, Exons, MESH: Potassium Channels, MESH: Amino Acid Substitution, MESH : C-Peptide, MESH: ATP-Binding Cassette Transporters, MESH : Kinetics, Polymorphism, Restriction Fragment Length, MESH: Diabetes Mellitus, Type 2, Genotype, MESH: Insulin, MESH : Reference Values, Polymorphism, Single Nucleotide, MESH : Potassium Channels, MESH : Amino Acid Substitution, MESH: Receptors, Drug, Humans, Family, MESH : ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, MESH: Family, MESH : Polymorphism, Restriction Fragment Length, MESH: Humans, MESH : Receptors, Drug, MESH: Polymorphism, Restriction Fragment Length, MESH : Humans, Genetic Variation, MESH: Polymerase Chain Reaction, MESH : Blood Glucose, Kinetics, Amino Acid Substitution, Diabetes Mellitus, Type 2, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH : Potassium Channels, Inwardly Rectifying, MESH: Blood Glucose, ATP-Binding Cassette Transporters, MESH : Family, MESH: Exons
Abstract

BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families.

Published
2002

12. beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations

Author

Phillipe Froguel, Andrew T. Hattersley, P. M. Clark, Ewan R. Pearson, Michael P. Bulman, Amanda Stride, Maggie Shepherd, Gilberto Velho, Sian Ellard, Timothy M. Frayling, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Génétique des maladies multifactorielles ( GMM ), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Section of Genomic Medicine, Imperial College London, Genome Centre, Imperial College London-Hammersmith campus, Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Génétique des maladies multifactorielles (GMM), and Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS)

Subjects
Blood Glucose, Male, MESH : Transcription Factors, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, MESH : Insulin, MESH : Fasting, MESH : Diabetes Mellitus, Type 2, Glucokinase, Insulin, Glycolysis, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, MESH : Proinsulin, Glucose tolerance test, medicine.diagnostic_test, MESH : Glucokinase, MESH: Hepatocyte Nuclear Factor 1, Age Factors, Nuclear Proteins, MESH: Transcription Factors, MESH: Glucokinase, Fasting, MESH : Adult, MESH: Genes, DNA-Binding Proteins, Hepatocyte nuclear factors, MESH: Insulin Resistance, MESH: Proinsulin, Hepatocyte Nuclear Factor 1, MESH : Genes, MESH : Hepatocyte Nuclear Factor 1-alpha, Female, MESH : DNA-Binding Proteins, Beta cell, MESH : Mutation, MESH : Insulin Resistance, MESH : Hepatocyte Nuclear Factor 1-beta, MESH: Diabetes Mellitus, Type 2, Proinsulin, Adult, medicine.medical_specialty, MESH: Mutation, MESH: Glucose Tolerance Test, MESH : Male, MESH: Fasting, MESH: Insulin, Biology, MESH : Family Health, MESH : Glucose Tolerance Test, MESH : Hepatocyte Nuclear Factor 1, Islets of Langerhans, Insulin resistance, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, MESH : Islets of Langerhans, MESH: Hepatocyte Nuclear Factor 1-beta, MESH: Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, MESH: Age Factors, Family Health, MESH: Humans, MESH: Islets of Langerhans, MESH : Humans, MESH : Nuclear Proteins, MESH: Adult, Glucose Tolerance Test, medicine.disease, MESH : Blood Glucose, MESH: Male, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Diabetes Mellitus, Type 2, Genes, Mutation, MESH: Blood Glucose, MESH: Family Health, MESH : Age Factors, Insulin Resistance, MESH: Nuclear Proteins, MESH: Female, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

Mutations in the beta-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the most common causes of maturity-onset diabetes of the young (MODY). Studying patients with mutations in these genes gives insights into the functions of these two critical beta-cell genes in humans. We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers and 40 HNF-1alpha mutation carriers. Homeostasis model assessment of fasting insulin and glucose showed reduced beta-cell function in both GCK (48% controls, P

Published
2001

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