DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DOCUMENT
DATASET
DATASET
1/1
Excitotoxicity and overnutrition additively impair metabolic function and identity of pancreatic β-cells
figure
posted on 2020-05-29, 20:11 authored by Ada AdminAda Admin, Anna B. Osipovich, Jennifer S. Stancill, Jean-Philippe Cartailler, Karrie D.Dudek, Mark A. MagnusonA 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.