Cells.: co-auth.: group B.Thorens

Cells. 2022 May 25;11(11):1737. doi: 10.3390/cells11111737.

Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse

Céline Cruciani-Guglielmacci 1Kelly Meneyrol 1Jessica Denom 1Nadim Kassis 1Latif Rachdi 2Fatna Makaci 2Stéphanie Migrenne-Li 1Fabrice Daubigney 1Eleni Georgiadou 3Raphaël G Denis 1 2Ana Rodriguez Sanchez-Archidona 4Jean-Louis Paul 5Bernard Thorens 4Guy A Rutter 3 6 7Christophe Magnan 1Hervé Le Stunff 8Nathalie Janel 1


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.

Keywords: autonomic nervous system; hyperhomocysteinemia; insulin secretion; type 2 diabetes.