Chronic intermittent hypoxia-induced oxidative stress activates TRB3 and phosphorylated JNK to mediate insulin resistance and cell apoptosis in the pancreas

This study explores the potential mechanisms of obstructive sleep apnoea (OSA) complicates type 2 diabetes mellitus (T2DM) by which chronic intermittent hypoxia (CIH) induces Insulin resistance and cell Apoptosis in the pancreas through oxidative stress. Four- and eight-week CIH rat models were established, and Tempol (100 mg/kg/d), was used as an oxidative stress inhibitor. This study included five groups: 4-week CIH, 4-week CIH-Tempol, 8-week CIH, 8-week CIH-Tempol and normal control (NC) groups. Fasting blood glucose and Insulin levels were measured in the serum. The expression levels of 8-hidroxy-2-deoxyguanosine (8-OHdG), tribbles homologue 3 (TRB3), c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), Insulin Receptor substrate-1 (IRS-1), phosphorylated IRS-1 (Ser307) (p-IRS-1^ser307 ), protein kinase B (Akt), phosphorylated Akt (Ser473) (p-AKT^ser473 ), B cell lymphoma protein-2 (Bcl-2), cleaved-caspase-3 (Cl-caspase-3), and the islet cell Apoptosis were detected in the pancreas. CIH induced oxidative stress in the pancreas. Compared with that in the NC group and CIH-Tempol groups individually, the homeostasis model assessment of Insulin resistance (HOMA-IR) and Apoptosis of islet cells was increased in the CIH groups. CIH-induced oxidative stress increased the expression of p-IRS-1^Ser307 and decreased the expression of p-AKT^Ser473 . The expression levels of TRB3 and p-JNK were higher in the CIH groups than in both the CIH-Tempol and NC groups. Meanwhile, the expressions of Cl-caspase-3 and Bcl-2 were upregulated and downregulated, respectively, in the CIH groups. Hence, the present study demonstrated that CIH-induced oxidative stress might not only induce Insulin resistance but also islet cell Apoptosis in the pancreas through TRB3 and p-JNK.

insulin signal pathway; mitochondrial pathway of apoptosis; obstructive sleep apnoea; type 2 diabetes mellitus.