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

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

Affiliations

  • 1 Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg 85764, Germany. Electronic address: michaela.aichler@helmholtz-muenchen.de.
  • 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: axel.walch@helmholtz-muenchen.de.
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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