Serine racemase is expressed in islets and contributes to the regulation of glucose homeostasis

Abstract

NMDA receptors (NMDARs) have recently been discovered as functional regulators of pancreatic β-cell insulin secretion. While these excitatory receptor channels have been extensively studied in the brain for their role in synaptic plasticity and development, little is known about how they work in β-cells. In neuronal cells, NMDAR activation requires the simultaneous binding of glutamate and a rate-limiting co-agonist, such as D-serine. D-serine levels and availability in most of the brain rely on endogenous synthesis by the enzyme serine racemase (Srr). Srr transcripts have been reported in human and mouse islets but it is not clear whether Srr is functionally expressed in β-cells or what its role in the pancreas might be. In this investigation, we reveal that Srr protein is highly expressed in primary human and mouse β-cells. Mice with whole body deletion of Srr (Srr KO) show improved glucose tolerance through enhanced insulin secretory capacity, possibly through Srr-mediated alterations in islet NMDAR expression and function. We observed elevated insulin sensitivity in some animals, suggesting Srr metabolic regulation in other peripheral organs as well. Srr expression in neonatal and embryonic islets, and adult deficits in Srr KO pancreas weight and islet insulin content, point toward a potential role for Srr in pancreatic development. These data reveal the first evidence that Srr may regulate glucose homeostasis in peripheral tissues and provide circumstantial evidence that D-serine may be an endogenous islet NMDAR co-agonist in β-cells.

Chiral micellar electrokinetic chromatographic separation for determination ofl- andd-primary amines released from murine islets of Langerhans

“…21 While either Gly or D-Ser can be a ligand for the receptor, 19,20 ser racemase (Srr), the enzyme responsible for conversion of L-Ser to D-Ser, was found in both human and murine islets. 24 Together, the presence of both Srr and NMDAR in murine and human islets raises the possibility that release of D-Ser from islets may play a role in autocrine or paracrine signaling through NMDAR within the islet or to nearby synaptic terminals, similar to other small molecules released from in islets. [4][5][6][7][8][9][10][11] Direct drug targeting of these receptors could be part of a step forward in better managing diabetes for people worldwide.…”

Chronic d-serine supplementation impairs insulin secretion

“…One of those genes is serine racemase (SRR) [13] , which catalyzes the conversion from l -serine to d -serine, an important co-agonist of N-methyl- d -aspartate (NMDA) receptors. SRR function was recently suggested to regulate insulin secretion from pancreatic beta cells [3] , [14] , and chronic as well as acute supplementation of the SRR product d -serine reduced food intake and weight gain upon high fat diet (HFD) feeding in mice [15] , [16] . However, dysfunction of SRR, the d -serine degrading d -amino acid oxidase (DAO), and the main d -serine transporter alanine-serine-cysteine transporter 1 (Asc-1) are implicated in the development of schizophrenia, Alzheimer's disease, and depression [17] , [18] , [19] , [20] , [21] .…”

Revealing the action mechanisms of dexamethasone on the birth weight of infant using RNA-sequencing data of trophoblast cells

“…KCNJ2 gene is reported to have expression in human placenta and in all development and differentiation stages of cytotrophoblast cells. [ 33 ] Lockridge et al [ 34 ] demonstrated that SRR in peripheral tissues may be critical for glucose homeostasis, and D-serine in β-cells may act as an endogenous islet NMDA receptor ( NMDAR ) co-agonist. SRR mRNA is detected in placenta, and D-serine transported by amino acid transport system B 0 (ATB 0 ) has a higher circulating concentration in the fetus compared with the mother.…”