Background:
Pancreatic -cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in -cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of -cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in -cell compensatory response to insulin resistance in obesity is unclear.
Methods:
In this study, using obese (ob/ob) mice with an absence of NF-Y subunit A (NF-YA) in -cells (ob, Nf-ya KO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to -cell compensation upon metabolic stress.
Results:
Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of -cell Nf-ya in obese mice worsened glucose intolerance and resulted in -cell dysfunction, which was attributable to augmented -cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya KO mice were sensitive to palmitate-induced -cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 -cell line could rescue palmitate-induced -cell apoptosis, dysfunction, and mitochondrial impairment.
Conclusion:
Pancreatic NF-Y might be an essential regulator of -cell compensation under metabolic stress.
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