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
| Autor: | 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 |
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| Přispěvatelé: | 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], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Molecular Metabolism Molecular metabolism, vol. 42, pp. 101071 Molecular metabolism Molecular metabolism, Elsevier, 2020, 42, pp.101071. ⟨10.1016/j.molmet.2020.101071⟩ Molecular Metabolism (2020) P. 101071 Molecular Metabolism, Vol 42, Iss, Pp 101071-(2020) |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2020.101071⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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