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Chronic d-serine supplementation impairs insulin secretion.
Suwandhi, Lisa Hausmann, Simone Braun, Alexander Gruber, Tim Heinzmann, Silke S Gálvez, Eric J C Buck, Achim Legutko, Beata Israel, Andreas Feuchtinger, Annette
Suwandhi, Lisa
Hausmann, Simone
Braun, Alexander
Gruber, Tim
Heinzmann, Silke S
Gálvez, Eric J C
Buck, Achim
Legutko, Beata
Israel, Andreas
Feuchtinger, Annette
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2018-07-25
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The 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. We 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. We 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. Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.
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2212-8778
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Attribution-NonCommercial-ShareAlike 3.0 United States