Abstract
ObjectiveThe metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. MethodsWe apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding. Moreover, we identify SNPs in SRR, the enzyme converting L-to d-serine and two subunits of the NMDA receptor to associate with insulin secretion in humans, based on the analysis of 2760 non-diabetic Caucasian individuals. ResultsWe show that chronic elevation of d-serine results in reduced high fat diet intake. In addition, d-serine leads to diet-independent hyperglycemia due to blunted insulin secretion from pancreatic beta cells. Inhibition of alpha 2-adrenergic receptors rapidly restores glycemia and glucose tolerance in d-serine supplemented mice. Moreover, we show that single nucleotide polymorphisms (SNPs) in SRR as well as in individual NMDAR subunits are associated with insulin secretion in humans. ConclusionThus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
Highlights
Type 2 diabetes (T2D) is a multifactorial metabolic disease, which, as shown by a large number of studies including genome-wide association studies (GWAS) [1e3] as well as numerous large scale metabolite screens [4,5] depends on complex gene and environment interactions
D-serine supplementation ameliorates diet induced obesity and preference to high fat diet (HFD) Following oral gavage, D-serine rapidly appeared in plasma and perigonadal fat (PGF) with peak concentrations after 15 min followed by appearance in kidneys at 30 min and liver after 60 min (Figure 1A)
To test if changes in specific bacterial species not captured by 16S rRNA analysis or their activity contribute to the altered weight gain, germfree C57Bl/6 mice were fed a HFD with or without D-serine supplementation
Summary
Type 2 diabetes (T2D) is a multifactorial metabolic disease, which, as shown by a large number of studies including genome-wide association studies (GWAS) [1e3] as well as numerous large scale metabolite screens [4,5] depends on complex gene and environment interactions. Many of the identified SNPs and metabolites associate with alterations in beta cell function and insulin secretion [9e11]. Some of these proteins and metabolites are associated with the development of other diseases not directly linked to beta cell function [12]. 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. Dysfunction of SRR, the D-serine degrading D-amino acid oxidase
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