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Suwandhi, L. ; Hausmann, S. ; Braun, A. ; Gruber, T. ; Heinzmann, S.S. ; Gálvez, E.J.C.* ; Buck, A. ; Legutko, B. ; Israel, A. ; Feuchtinger, A. ; Haythorne, E.* ; Staiger, H. ; Heni, M. ; Häring, H.-U. ; Schmitt-Kopplin, P. ; Walch, A.K. ; Cáceres, C.G.* ; Tschöp, M.H. ; Rutter, G.A.* ; Strowig, T.* ; Elsner, M. ; Ussar, S.

Chronic d-serine supplementation impairs insulin secretion.

Mol. Metab., DOI: 10.1016/j.molmet.2018.07.002 (2018)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Diabetes ; Insulin Secretion ; Obesity ; D-serine
Language english
Publication Year 2018
HGF-reported in Year 2018
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Research Unit BioGeoChemistry and Analytics (BGC)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes Research and Metabolic Diseases (IDM)
CF Pathology & Tissue Analytics (CF-PTA)
POF-Topic(s) 30502 - Diabetes: Pathophysiology, Prevention and Therapy
30201 - Metabolic Health
30202 - Environmental Health
30205 - Bioengineering and Digital Health
90000 - German Center for Diabetes Research
30505 - New Technologies for Biomedical Discoveries
Research field(s) Helmholtz Diabetes Center
Environmental Sciences
Enabling and Novel Technologies
PSP Element(s) G-508600-009
G-502200-001
G-504800-001
G-500390-001
G-501900-221
G-502400-001
G-502400-002
A-630600-001
DOI 10.1016/j.molmet.2018.07.002
Scopus ID 85050982928
PubMed ID 30093356
Erfassungsdatum 2018-09-12
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