Abstract
Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.
Highlights
D-serine is a non-proteinogenic amino acid with a critical role in the central nervous system (CNS) as a regulator of neural development, plasticity, excitability, and viability but its potential role in peripheral tissues has received less attention
We found that D-serine potentiated in vitro glucosestimulated insulin secretion (GSIS) of mouse islets and depolarized the membranes of individual β-cells, but this was dependent on the expression of β-cell N-methyl Daspartate receptors (NMDARs) and the inclusion of a receptor-specific glutamate analog (NMDA)
This was surprising based on previous studies showing improved glucose tolerance and insulin secretion in mice with a loss of D-serine synthetic capacity [1] or D-serine-targeted NMDARs in the pancreas [6]
Summary
D-serine is a non-proteinogenic amino acid with a critical role in the central nervous system (CNS) as a regulator of neural development, plasticity, excitability, and viability but its potential role in peripheral tissues has received less attention. Our work and other recent studies have demonstrated changes in glucose homeostasis and insulin secretion in association with Srr loss [1], chronic D-serine supplementation [5], and the inhibition or tissue-specific loss of the D-serine targeted. N-methyl D-aspartate receptors (NMDARs) [6] These changes appear to be unusually context-specific with, for example, both hyperinsulinemic and hypoinsulinemic effects of D-serine drinking in male mice, dependent on dose [5]. While excellent work in genetically-static and chronic administration models has converged on a novel role for D-serine in the regulation of glucose homeostasis, the absence of a thorough characterization of D-serine’s acute effects, on glucose-stimulated β-cell insulin secretion, remains a significant barrier to understanding that role
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