PMID- 35681432 OWN - NLM STAT- MEDLINE DCOM- 20220613 LR - 20220716 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 11 IP - 11 DP - 2022 May 25 TI - Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse. LID - 10.3390/cells11111737 [doi] LID - 1737 AB - Cystathionine beta synthase (CBS) catalyzes the first step of the transsulfuration pathway from homocysteine to cystathionine, and its deficiency leads to hyperhomocysteinemia (HHcy) in humans and rodents. To date, scarce information is available about the HHcy effect on insulin secretion, and the link between CBS activity and the setting of type 2 diabetes is still unknown. We aimed to decipher the consequences of an inborn defect in CBS on glucose homeostasis in mice. We used a mouse model heterozygous for CBS (CBS+/-) that presented a mild HHcy. Other groups were supplemented with methionine in drinking water to increase the mild to intermediate HHcy, and were submitted to a high-fat diet (HFD). We measured the food intake, body weight gain, body composition, glucose homeostasis, plasma homocysteine level, and CBS activity. We evidenced a defect in the stimulated insulin secretion in CBS+/- mice with mild and intermediate HHcy, while mice with intermediate HHcy under HFD presented an improvement in insulin sensitivity that compensated for the decreased insulin secretion and permitted them to maintain a glucose tolerance similar to the CBS+/+ mice. Islets isolated from CBS+/- mice maintained their ability to respond to the elevated glucose levels, and we showed that a lower parasympathetic tone could, at least in part, be responsible for the insulin secretion defect. Our results emphasize the important role of Hcy metabolic enzymes in insulin secretion and overall glucose homeostasis. FAU - Cruciani-Guglielmacci, Celine AU - Cruciani-Guglielmacci C AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Meneyrol, Kelly AU - Meneyrol K AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Denom, Jessica AU - Denom J AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Kassis, Nadim AU - Kassis N AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Rachdi, Latif AU - Rachdi L AUID- ORCID: 0000-0002-1089-2837 AD - Institut Cochin, Universite Paris Cite, INSERM U1016, CNRS UMR 8104, 75014 Paris, France. FAU - Makaci, Fatna AU - Makaci F AD - Institut Cochin, Universite Paris Cite, INSERM U1016, CNRS UMR 8104, 75014 Paris, France. FAU - Migrenne-Li, Stephanie AU - Migrenne-Li S AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Daubigney, Fabrice AU - Daubigney F AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Georgiadou, Eleni AU - Georgiadou E AD - Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK. FAU - Denis, Raphael G AU - Denis RG AUID- ORCID: 0000-0002-7677-7460 AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. AD - Institut Cochin, Universite Paris Cite, INSERM U1016, CNRS UMR 8104, 75014 Paris, France. FAU - Rodriguez Sanchez-Archidona, Ana AU - Rodriguez Sanchez-Archidona A AD - Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Paul, Jean-Louis AU - Paul JL AD - Georges Pompidou European Hospital Department of Biochemistry, Assistance Publique-Hopitaux de Paris (AP-HP), 75013 Paris, France. FAU - Thorens, Bernard AU - Thorens B AUID- ORCID: 0000-0002-3738-0129 AD - Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. FAU - Rutter, Guy A AU - Rutter GA AD - Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK. AD - Cardiometabolic Axis, CR-CHUM, Universite de Montreal, Montreal, QC H3T 1J4, Canada. AD - Lee King Chian Medical School, Nanyang Technological University, Singapore 639798, Singapore. FAU - Magnan, Christophe AU - Magnan C AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. FAU - Le Stunff, Herve AU - Le Stunff H AD - Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Universite Paris-Saclay, 91400 Saclay, France. FAU - Janel, Nathalie AU - Janel N AD - Unite de Biologie Fonctionnelle et Adaptative, Universite Paris Cite, CNRS, 75013 Paris, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220525 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0LVT1QZ0BA (Homocysteine) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Animals MH - Cystathionine beta-Synthase/metabolism MH - *Diabetes Mellitus, Type 2 MH - Glucose MH - Homeostasis MH - Homocysteine MH - *Homocystinuria/metabolism MH - *Hyperhomocysteinemia/metabolism MH - Mice PMC - PMC9179272 OTO - NOTNLM OT - autonomic nervous system OT - hyperhomocysteinemia OT - insulin secretion OT - type 2 diabetes COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2022/06/11 06:00 MHDA- 2022/06/14 06:00 PMCR- 2022/05/25 CRDT- 2022/06/10 01:07 PHST- 2022/04/19 00:00 [received] PHST- 2022/05/16 00:00 [revised] PHST- 2022/05/20 00:00 [accepted] PHST- 2022/06/10 01:07 [entrez] PHST- 2022/06/11 06:00 [pubmed] PHST- 2022/06/14 06:00 [medline] PHST- 2022/05/25 00:00 [pmc-release] AID - cells11111737 [pii] AID - cells-11-01737 [pii] AID - 10.3390/cells11111737 [doi] PST - epublish SO - Cells. 2022 May 25;11(11):1737. doi: 10.3390/cells11111737.