Objective To investigate the role and mechanism of nuclear factor-κB (NF-κB)/cyclophilin D (CypD)-mediated mitochondrial stress signaling pathway in islet β-cell dysfunction in type 2diabetic (T2DM)mice.

Methods Six-week-old CypD gene knockout (CypD^-/-) mice and their wild-type (WT) littermates were randomly divided into normal control groups (CypD^-/- group and WT group) and diabetic model groupsCypD^-/-+high-fat diet (HFD)+streptozotocin (STZ) group and WT+HFD+STZ group, with six mice in each group. The fasting blood glucose, serum insulin, pancreatic insulin levels, glucose-stimulated insulin secretion (GSIS), NF-κB levels, pancreatic and duodenal homeobox-1 (PDX-1) expression levels, and mitochondrial respiratory oxygen consumption rate (OCR) of islet cells were measured in each group. The CypD level in islet β-cells (INS-1 cells) overexpressing NF-κB was detected using recombinant adenovirus infection technology.

Results Compared with the WT+HFD+STZ group, the CypD^-/-+HFD+STZ group showed significant decrease in fasting blood glucose levels, significant increase in serum insulin and pancreatic insulin levels (P < 0.001), and PDX-1 expression levels (P < 0.001). The CypD^-/-+HFD+STZ group also exhibited significantly elevated GSIS levels (P < 0.001), and enhanced basal respiration, ATP production, maximal respiration, and reserve respiratory capacity of islet cells compared with the WT+HFD+STZ group (P < 0.001 or P < 0.05). The relative expression level of CypD protein in islet β-cells overexpressing NF-κB was significantly higher than that in control cells (P < 0.05).

Conclusion CypD^-/- can improve fasting blood glucose and insulin levels in T2DM mice, regulate the downregulation of PDX-1expression, enhance GSIS and mitochondrial respiratory function, and protect islet β-cells. Overexpression of NF-κB can induce the upregulation of CypD expression and play an upstream regulatory role in the NF-κB/CypD-mediated mitochondrial stress signaling pathway.