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

Publication date: 6 June 2017
Source:Cell Metabolism, Volume 25, Issue 6
Author(s): Michaela Aichler, Daniela Borgmann, Jan Krumsiek, Achim Buck, Patrick E. MacDonald, Jocelyn E. Manning Fox, James Lyon, Peter E. Light, Susanne Keipert, Martin Jastroch, Annette Feuchtinger, Nikola S. Mueller, Na Sun, Andrew Palmer, Theodore Alexandrov, Martin Hrabe de Angelis, Susanne Neschen, Matthias H. Tschöp, Axel Walch
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.

Graphical abstract

Teaser

Aichler et al. used a MALDI mass spectrometry-based systems approach to characterize molecular interaction networks of functional pathways in mouse and human pancreatic tissues. They identify classes of metabolites involved in insulin synthesis and secretion, which are disrupted in diabetes.


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