ABSTRACT
[This corrects the article DOI: 10.1155/2018/7653904.].
ABSTRACT
Islet ß cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet ß cell apoptosis is induced by high-glucose/fatty acid levels. In the present study, we show that Par-4, which is induced by high-glucose/fatty acid levels, interacts with and inhibits TERT in the cytoplasm and then translocates to the nucleus. Par-4 also inhibited Akt phosphorylation, leading to islet ß cell apoptosis. We inhibited Par-4 in islet ß cells under high-glucose/fatty acid conditions and knocked out Par-4 in diabetic mice, which led to the up-regulation of TERT and an improvement in the apoptosis rate. We inhibited Akt phosphorylation in islet ß cells and diabetic mice, which led to aggressive apoptosis. In addition, the biological film interference technique revealed that Par-4 bound to TERT via its NLS and leucine zipper domains. Our research suggests that Par-4 activation and binding to TERT are key steps required for inducing the apoptosis of islet ß cells under high-glucose/fatty acid conditions. Inhibiting Akt phosphorylation aggravated apoptosis by activating Par-4 and inhibiting TERT, and Par-4 inhibition may be an attractive target for the treatment of islet ß cell apoptosis.
Subject(s)
Apoptosis , Diabetes Mellitus, Experimental/enzymology , Diabetes Mellitus, Type 2/enzymology , Insulin-Secreting Cells/enzymology , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Thrombin/metabolism , Telomerase/metabolism , Active Transport, Cell Nucleus , Animals , Blood Glucose/metabolism , Case-Control Studies , Cell Line, Tumor , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Humans , Insulin-Secreting Cells/pathology , Leucine Zippers , Male , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Protein Binding , Protein Interaction Domains and Motifs , Receptors, Thrombin/deficiency , Receptors, Thrombin/genetics , Signal Transduction , Telomerase/blood , Telomerase/geneticsABSTRACT
Apoptosis of islet ß cells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces islet ß cell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in islet ß cell apoptosis and type 2 diabetes.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , Diabetes Mellitus, Type 2/genetics , Endoplasmic Reticulum Stress/genetics , Insulin-Secreting Cells/metabolism , NF-kappa B/genetics , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/drug effects , Apoptosis Regulatory Proteins/metabolism , Cell Line , Diabetes Mellitus, Type 2/metabolism , Endoplasmic Reticulum Stress/drug effects , Glucose/pharmacology , In Vitro Techniques , Insulin-Secreting Cells/drug effects , Mice , Mitochondria/drug effects , Mitochondria/metabolism , NF-kappa B/drug effects , NF-kappa B/metabolism , Palmitates/pharmacologyABSTRACT
OBJECTIVE: To investigate the effect and mechanism of the exenatide on diabetic cardiomyopathy. METHODS: Rats were divided into control group, diabetes group (D), diabetes treated with insulin (DI) group, and diabetes treat with exenatide (DE) group. We detected apoptosis rate by TUNEL, the adiponectin and high molecular weight adiponectin (HMW-adiponectin) by ELISA, and the expression of APPL1, p-AMPK/T-AMPK, PPARα, and NF-κB by immunohistochemistry and western blotting. RESULTS: Compared with the D group, the apoptosis in the Control and DE groups was decreased (P < 0.05); the adiponectin and HMW-adiponectin were increased (P < 0.05); the APPL1, p-AMPK/T-AMPK, PPARα, and LV -dP/dt were increased (P < 0.05); and the NF-κB, GRP78, and LVEDP were decreased (P < 0.05). Compared with DE group, the glucose levels in the DI group were similar (P < 0.05); the apoptosis and LVEDP were increased; the APPL1, p-AMPK/T-AMPK, PPARα, and LV -dP/dt were decreased (P < 0.05); the NF-κB and GRP78 were increased (P < 0.05); the adiponectin and HMW-adiponectin were significantly decreased (P < 0.05). CONCLUSION: Our model of diabetic cardiomyopathy was constructed successfully. After being treated with exenatide, the adiponectin and HMW-adiponectin and the APPL1-AMPK-PPARα axis were increased, the NF-κB and the apoptosis were decreased, the cardiac function of the diabetic rats was improved, and these effects were independent of glucose control.
