Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells

Abstract

A sustained increase in intracellular Ca 2+ concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on Abcc8 knockout mice. Excitotoxicity caused β-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 β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-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 β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-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 β-cell identity, augments overnutrition-induced β-cell failure.

Lipid droplets protect human β cells from lipotoxic-induced stress and cell identity changes

“…These differences were also verified upon qPCR analysis of various regulatory candidates ( Fig. 2E ), including EXOC5 (27) that is involved in vesicle docking and fusion, KCNJ11 (28) encoding the ATP-sensitive inward rectifier potassium channel 11, SNAP 25 (29) of the SNARE complex, and STX1A (14) which is important in vesicle membrane docking. Taken together, our data suggest that LD accumulation affects the insulin secretory machinery and GSIS in human β cells.…”

Lipid Droplets Protect Human β-Cells From Lipotoxicity-Induced Stress and Cell Identity Changes

“…These differences were also verified upon quantitative PCR analysis of various regulatory candidates ( Fig. 2 E ), including EXOC5 ( 27 ), which is involved in vesicle docking and fusion; KCNJ11 ( 28 ) encoding the ATP-sensitive inward rectifier potassium channel 11; SNAP 25 ( 29 ) of the SNARE complex; and STX1A ( 14 ), which is important in vesicle membrane docking. Taken together, our data suggest that LD accumulation affects the insulin secretory machinery and GSIS in human β-cells.…”

Impaired Glucose Homeostasis in a Tau Knock-In Mouse Model

“…Conversely, male rodents exhibit a greater propensity for β cell failure (Gannon et al, 2018 ). Increased estrogen receptor signaling, differences in islet DNA methylation status, expression differences of antioxidant genes and of islet-enriched genes transcription factors have all been suggested as causes for these differences allowing females to tolerate HFD better than males (Liu and Mauvais-Jarvis, 2010 ; Osipovich et al, 2020 and references herein). In accordance, another important point that has not been addressed in the present study is the potential sexual-dimorphism of insulin secretion by isolated islets in response to glucose.…”