D-amino acids are being recognized in mammals as important molecules with function. This is a first identification of endogenous D-cysteine in mammalian pancreas. 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 studies 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 (STZ and 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 followed by reduced phosphorylation of CREB (S133), lower DNA methyltransferase enzymatic and promoter activities 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. Our data show that endogenous D-cysteine in the mammalian pancreas is a regulator of insulin secretion. Highlights 1. Serine Racemase also functions as a cysteine racemase. 2. Lack of Serine Racemase results in significantly high levels of insulin in the pancreas, plasma and larger islets. 3. D-cysteine shows greater inhibition of insulin secretion compared to D-serine. 4. Endogenous D-cysteine signals via cyclic AMP that mediates downstream CREB-DNMT1 interaction. 5. CREB-DNMT1 interaction results in hypomethylation of Ins1 promoter that can be rescued by high methyl donor dietary supplementation rescuing high insulin levels. ### Competing Interest Statement The authors have declared no competing interest.
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