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

Abstract

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.

The link between theANPEPgene and type 2 diabetes mellitus may be mediated by the disruption of glutathione metabolism and redox homeostasis

“…Interestingly, the livers of streptozotocin-induced diabetic rats exhibit a marked increase in CBS mRNA levels [107]. A recent experimental study in mice showed that knockout of the CBS gene impairs stimulated insulin secretion and sensitivity [108], suggesting the importance of the transsulfuration pathway in insulin secretion and overall glucose homeostasis. Cystathionine gamma-lyase (CTH) is an enzyme that catalyzes the last step in the transsulfuration pathway by cleaving the L,L-cystathionine molecule into L-cysteine, part of which is utilized for the biosynthesis of glutathione [109].…”

Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus

“…The second is an impaired synthesis of cystathionine from L-serine and homocysteine by cystathionine β-synthase and a subsequent decrease in the drain of homocysteine from the methionine cycle to the transsulfuration pathway ( Figure 2 ). The possibility is supported by the presence of hyperhomocysteinemia in humans and rodents with cystathionine β-synthase deficiency [ 49 ].…”

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas

“…tabolism pathways were identified in our insulinoma analysis due to mutations in APOB -the main apolipoprotein of chylomicrons and LDL, and genes involved in the metabolism of homocysteine, CTH (converts cystathionine derived from methionine into cysteine) and MTHFR (homocysteine remethylation to methionine). The proper homeostasis of homocysteine has been shown to be significant for controlling insulin secretion and action [68,69].…”