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Cell Metab. 2017 Jun 6;25(6):1334-1347.e4. doi: 10.1016/j.cmet.2017.04.012.

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

Author information

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.

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

PMID:
28591636
DOI:
10.1016/j.cmet.2017.04.012
[Indexed for MEDLINE]
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