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Excitotoxicity and overnutrition additively impair metabolic function and identity of pancreatic β-cells

posted on 29.05.2020 by Ada Admin, Anna B. Osipovich, Jennifer S. Stancill, Jean-Philippe Cartailler, Karrie D.Dudek, Mark A. Magnuson
A sustained increase in intracellular Ca2+ concentration (referred to herein as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic b-cell failure. To determine the additive effects of excitotoxicity and overnutrition on b-cell function and gene expression, we analyzed the impact of a high fat diet (HFD) on Abcc8 knock-out mice. Excitotoxicity caused b-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca2+ channel blocker. Excitotoxicity, overnutrition and the combination of both stresses caused similar but distinct alterations in the b-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid b-oxidation and mitochondrial biogenesis, and their key regulator Ppargc1a. Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both b-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of b-cell epigenetic and transcriptional program. Sex had an impact on all b-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca2+, by altering mitochondrial function and impairing b-cell identity, augments overnutrition-induced b-cell failure.


This research was supported by institutional and philanthropic funds provided by Vanderbilt University. The Vanderbilt Islet Procurement Core is supported by DK020593. VANTAGE is supported by P30 CA68485, P30 EY08126 and G20 RR030956. VMC Flow Cytometry Shared Resource is supported by P30 CA68485 and DK058404.