AI Article Synopsis
- - D-amino acids, particularly D-cysteine, are gaining recognition for their role in the mammalian pancreas, with D-cysteine synthesized by the enzyme serine racemase (SR), leading to significantly higher insulin levels in SR mice.
- - In diabetic mouse models, D-cysteine levels increase compared to D-serine, along with higher expression of SR, which affects insulin secretion regulation and DNA methylation patterns in pancreatic cells.
- - Dietary methyl donor supplementation can restore normal insulin levels and decrease certain enzymatic activities in SR mice, indicating that D-cysteine is a crucial regulator of insulin secretion in the pancreas.
Article Abstract
Background: D-amino acids are being recognized as important molecules in mammals with function. This is a first identification of endogenous D-cysteine in mammalian pancreas.
Methods: Using a novel stereospecific bioluminescent assay, chiral chromatography, enzyme kinetics and a transgenic mouse model we identify endogenous D-cysteine. We elucidate its function in two mice models of type 1 diabetes (STZ and NOD), and in tests of Glucose Stimulated Insulin Secretion in isolated mouse and human islets and INS-1 832/13 cell line.
Results And Discussion: D-cysteine is synthesized by serine racemase (SR) and SR mice produce 6-10 fold higher levels of insulin in the pancreas and plasma including higher glycogen and ketone bodies in the liver. The excess insulin is stored as amyloid in secretory vesicles and exosomes. In glucose stimulated insulin secretion in mouse and human islets, equimolar amount of D-cysteine showed higher inhibition of insulin secretion compared to D-serine, another closely related stereoisomer synthesized by SR. In mouse models of diabetes (Streptozotocin (STZ) and Non Obese Diabetes (NOD) and human pancreas, the diabetic state showed increased expression of D-cysteine compared to D-serine followed by increased expression of SR. SR mice show decreased cAMP in the pancreas, lower DNA methyltransferase enzymatic and promoter activities followed by reduced phosphorylation of CREB (S133), resulting in decreased methylation of the Ins1 promoter. D-cysteine is efficiently metabolized by D-amino acid oxidase and transported by ASCT2 and Asc1. Dietary supplementation with methyl donors restored the high insulin levels and low DNMT enzymatic activity in SR mice.
Conclusions: Our data show that endogenous D-cysteine in the mammalian pancreas is a regulator of insulin secretion.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536007 | PMC |
| http://dx.doi.org/10.1016/j.molmet.2024.102043 | DOI Listing |
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