N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking β Cell Dysfunction in Type 2 Diabetes

  • Cell Metab. 2017 Jun 6;25(6):1334-1347.e4. doi: 10.1016/j.cmet.2017.04.012.
Michaela Aichler  1 ,  Daniela Borgmann  2 ,  Jan Krumsiek  3 ,  Achim Buck  2 ,  Patrick E MacDonald  4 ,  Jocelyn E Manning Fox  4 ,  James Lyon  5 ,  Peter E Light  4 ,  Susanne Keipert  6 ,  Martin Jastroch  6 ,  Annette Feuchtinger  2 ,  Nikola S Mueller  7 ,  Na Sun  2 ,  Andrew Palmer  8 ,  Theodore Alexandrov  9 ,  Martin Hrabe de Angelis  10 ,  Susanne Neschen  11 ,  Matthias H Tschöp  12 ,  Axel Walch  13
Affiliations
  • 1. Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg 85764, Germany. Electronic address: [email protected].
  • 2. Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  • 3. Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg 85764, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, Neuherberg 85764, Germany.
  • 4. Alberta Diabetes Institute, University of Alberta, Edmonton T6G 2E1, Canada; Department of Pharmacology, University of Alberta, Edmonton T6G 2E1, Canada.
  • 5. Alberta Diabetes Institute, University of Alberta, Edmonton T6G 2E1, Canada.
  • 6. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, Neuherberg 85764, Germany; Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  • 7. Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg 85764, Germany.
  • 8. Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany.
  • 9. Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA; SCiLS GmbH, 28359 Bremen, Germany.
  • 10. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, Neuherberg 85764, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, Neuherberg 85764, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354 Freising, Germany.
  • 11. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, Neuherberg 85764, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, Neuherberg 85764, Germany.
  • 12. German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, Neuherberg 85764, Germany; Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg 85764, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
  • 13. Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg 85764, Germany. Electronic address: [email protected].
PMID: 28591636 DOI: 10.1016/j.cmet.2017.04.012
Abstract

The processes contributing to β cell dysfunction in type 2 diabetes (T2D) are uncertain, largely because it is difficult to access β cells in their intact immediate environment. We examined the pathophysiology of β cells under T2D progression directly in pancreatic tissues. We used MALDI imaging of Langerhans islets (LHIs) within mouse tissues or from human tissues to generate in situ-omics data, which we supported with in vitro experiments. Molecular interaction networks provided information on functional pathways and molecules. We found that stearoylcarnitine accumulated in β cells, leading to arrest of Insulin synthesis and energy deficiency via excessive β-oxidation and depletion of TCA cycle and Oxidative Phosphorylation metabolites. Acetylcarnitine and an accumulation of N-acyl taurines, a group not previously detected in β cells, provoked Insulin secretion. Thus, β cell dysfunction results from enhanced Insulin secretion combined with an arrest of Insulin synthesis.

Keywords
Langerhans islets; MALDI imaging mass spectrometry; MALDI-FT-ICR; N-acyl taurines; acylcarnitines; diabetes type 2; pathophysiology; β cells.
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