Bidirectional modulation of TCA cycle metabolites and anaplerosis by metformin and its combination with SGLT2i.

Metformin / pharmacology Animals Citric Acid Cycle / drug effects Sodium-Glucose Transporter 2 Inhibitors / pharmacology Humans Hypoglycemic Agents / pharmacology Diabetes Mellitus, Type 2 / drug therapy Male Liver / metabolism Kidney / metabolism Female Drug Therapy, Combination Mice, Inbred C57BL Metabolomics Biomarkers / blood Middle Aged Blood Glucose / metabolism Longitudinal Studies Mice Aged Treatment Outcome
Anaplerosis Anti-inflammatory effects Metabolic dysfunction-associated steatotic liver disease (MASLD) Metformin Pharmacometabolomics SGLT2 inhibitors TCA cycle Type 2 diabetes

Journal

Cardiovascular diabetology
ISSN: 1475-2840
Titre abrégé: Cardiovasc Diabetol
Pays: England
ID NLM: 101147637

Informations de publication

Date de publication:
12 Jun 2024
Historique:
received: 05 02 2024
accepted: 28 05 2024
medline: 13 6 2024
pubmed: 13 6 2024
entrez: 12 6 2024
Statut: epublish

Résumé

Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Sections du résumé

BACKGROUND BACKGROUND
Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans.
METHODS METHODS
Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications.
RESULTS RESULTS
Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses.
CONCLUSION CONCLUSIONS
This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.

Identifiants

DOI: 10.1186/s12933-024-02288-x PMID: 38867314
pubmed: 38867314
doi: 10.1186/s12933-024-02288-x
pii: 10.1186/s12933-024-02288-x
doi:

Substances chimiques

Metformin 9100L32L2N
Sodium-Glucose Transporter 2 Inhibitors 0
Hypoglycemic Agents 0
Biomarkers 0
Blood Glucose 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

199

Informations de copyright

© 2024. The Author(s).

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Auteurs

Makoto Harada (M)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.

Jonathan Adam (J)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Marcela Covic (M)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Jianhong Ge (J)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.

Stefan Brandmaier (S)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Caroline Muschet (C)

Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Jialing Huang (J)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Siyu Han (S)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.

Martina Rommel (M)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Markus Rotter (M)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Margit Heier (M)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
KORA Study Centre, University Hospital of Augsburg, Augsburg, Germany.

Robert P Mohney (RP)

Metabolon, Inc., Durham, NC, USA.

Jan Krumsiek (J)

Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Gabi Kastenmüller (G)

Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Wolfgang Rathmann (W)

German Center for Diabetes Research (DZD), Neuherberg, Germany.
Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.

Zhongmei Zou (Z)

Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Sven Zukunft (S)

Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Markus F Scheerer (MF)

Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Susanne Neschen (S)

Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Jerzy Adamski (J)

Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

Christian Gieger (C)

Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Annette Peters (A)

German Center for Diabetes Research (DZD), Neuherberg, Germany.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Institute for Medical Information Processing, Biometry, and Epidemiology, Pettenkofer School of Public Health, Ludwig Maximilian University of Munich (LMU), Munich, Germany.

Donna P Ankerst (DP)

Departments of Mathematics and Life Science Systems, Technical University of Munich (TUM), Garching, Germany.

Thomas Meitinger (T)

Institute of Human Genetics, Klinikum Rechts der Isar, TUM, Munich, Germany.

Tanya L Alderete (TL)

Department of Integrative Physiology, University of Colorado Boulder, Boulder, USA.

Martin Hrabe de Angelis (MH)

German Center for Diabetes Research (DZD), Neuherberg, Germany.
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Chair of Experimental Genetics, TUM School of Life Sciences, TUM, Freising, Germany.

Karsten Suhre (K)

Department of Physiology and Biophysics, Weill Cornell Medicine - Qatar, Education City - Qatar Foundation, Doha, Qatar.

Rui Wang-Sattler (R)

Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de.
German Center for Diabetes Research (DZD), Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de.
Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. rui.wang-sattler@helmholtz-muenchen.de.

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Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Amidines › Guanidines › Biguanides › Metformine › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Eucaryotes › Animaux › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Cycle citrique › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › Inhibiteurs du cotransporteur sodium-glucose de type 2 › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Maladies endocriniennes › Diabète › Diabète de type 2 › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Système digestif › Foie › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Métabolomique › Bidirectional modulation of TCA cycle...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Bidirectional modulation of TCA cycle...
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