Chronic d-serine supplementation impairs insulin secretion

Authors:

Suwandhi L, Hausmann S, Braun A, Gruber T,  Heinzmann SS, Gálvez EJC, Buck A, Legutko B, Israel A, Feuchtinger A, Haythorne E, Staiger H, Heni M, Häring HU, Schmitt-Kopplin P,  Walch AK,  Cáceres CG, Tschöp MH, Rutter GA, Strowig, T, Elsner M, Ussar S

Year of publication:

2018

Volume:

16

Issue:

ISSN:

2212-8778

Journal (long):

Molecular Metabolism

Journal (short):

Mol. Metab.

Impact factor:

6.448

Abstract:

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: Thus, we identify a novel role of d-serine in regulating systemic glucose metabolism through modulating insulin secretion.

Participating Institutes