| First Author | Osipovich AB | Year | 2020 |
| Journal | Diabetes | Volume | 69 |
| Issue | 7 | Pages | 1476-1491 |
| PubMed ID | 32332159 | Mgi Jnum | J:293253 |
| Mgi Id | MGI:6445733 | Doi | 10.2337/db19-1145 |
| Citation | Osipovich AB, et al. (2020) Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic beta-Cells. Diabetes 69(7):1476-1491 |
| abstractText | A sustained increase in intracellular Ca(2+) concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic beta-cell failure. To determine the additive effects of excitotoxicity and overnutrition on beta-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on Abcc8 knockout mice. Excitotoxicity caused beta-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca(2+) channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the beta-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid beta-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 beta-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of beta-cell epigenetic and transcriptional program. Sex had an impact on all beta-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca(2+), by altering mitochondrial function and impairing beta-cell identity, augments overnutrition-induced beta-cell failure. |
