2. Academic Validation
  3. Chronic d-serine supplementation impairs insulin secretion

Chronic d-serine supplementation impairs insulin secretion

  • Mol Metab. 2018 Oct;16:191-202. doi: 10.1016/j.molmet.2018.07.002.
Lisa Suwandhi 1,  Simone Hausmann 1,  Alexander Braun 2,  Tim Gruber 3,  Silke S Heinzmann 4,  Eric J C Gálvez 5,  Achim Buck 6,  Beata Legutko 7,  Andreas Israel 1,  Annette Feuchtinger 6,  Elizabeth Haythorne 8,  Harald Staiger 9,  Martin Heni 10,  Hans-Ulrich Häring 10,  Philippe Schmitt-Kopplin 4,  Axel Walch 6,  Cristina García Cáceres 7,  Matthias H Tschöp 3,  Guy A Rutter 8,  Till Strowig 5,  Martin Elsner 11,  Siegfried Ussar 12
Affiliations

Affiliations

  • 1 RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  • 2 Institute of Groundwater Ecology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
  • 3 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Germany.
  • 4 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Research Unit Analytical BioGeoChemistry, Department of Environmental Sciences, Helmholtz Center Munich, 85764 Neuherberg, Germany.
  • 5 Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • 6 Research Unit Analytical Pathology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
  • 7 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany.
  • 8 Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, UK.
  • 9 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
  • 10 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, 72076 Tübingen, Germany.
  • 11 Institute of Groundwater Ecology, Helmholtz Center Munich, 85764 Neuherberg, Germany; Analytical Chemistry and Water Chemistry, Technical University of Munich, 81377 Munich, Germany.
  • 12 RG Adipocytes & Metabolism, Institute for Diabetes & Obesity, Helmholtz Center Munich, 85748 Garching, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address: siegfried.ussar@helmholtz-muenchen.de.
PMID: 30093356 DOI: 10.1016/j.molmet.2018.07.002
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.

Keywords

Diabetes; Insulin secretion; Obesity; d-serine.

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