Abstract
Islet β cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet β 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 β cell apoptosis. We inhibited Par-4 in islet β 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 β 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 β 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 β cell apoptosis.
Highlights
Previous studies have shown that β cell apoptosis and dysfunction are significantly increased in patients and animals with type 2 diabetes [1,2,3]
telomerase reverse transcriptase (TERT) mediates DNA synthesis of the template of the telomerase RNA gene to increase the length of telomeres, which is regulated by telomerase
Many studies have shown that TERT can interact with other signalling factors to relieve its antiapoptotic effect, which is independent of the typical telomere-telomerase system pathway
Summary
Previous studies have shown that β cell apoptosis and dysfunction are significantly increased in patients and animals with type 2 diabetes [1,2,3]. Islet β cell apoptosis has been found to be the main cause of islet β cell dysfunction and plays an important role in type 2 diabetes in humans [2, 4]. These results suggest that apoptosis is a major cause of type 2 diabetes. The mechanism of islet β cell apoptosis in type 2 diabetes has attracted substantial attention from diabetes researchers, who believe that hyperglycaemia and hyperlipidaemia in type 2 diabetes can induce endoplasmic reticulum (ER) stress, thereby inducing islet β cell apoptosis and dysfunction [4].
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