Search

Pancreatic β-cells secrete insulin in response to high blood glucose levels. Type I diabetes occurs when the body fails to produce insulin and the people must take artificial insulin. Type 2 diabetes is the most common type of diabetes and in this case the cells in the body do not respond to insulin and insulin resistance takes place gradually. The present study examined the role of Endoplasmic-reticulum-associated protein degradation (ERAD) on insulin secretion in pancreatic beta cells and diabetic rat model. We demonstrate that overexpression of some ER-stress induced proteins that targets misfolded glycoproteins for ER-associated degradation in INS-1 cells increased preproinsulin mRNA, facilitates proinsulin transport to the secretory vesicles, conversion and secretion of mature insulin. Such effects were also observed in human pancreatic islets and streptozotocin diabetic rats. Our findings identify a role of ERAD pathway as potential target for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Pancreatic beta cells produce and secrete insulin as a response to rises in blood glucose. Despite the advances in understanding glucose-regulated insulin transcription and translation the mechanisms triggering the synthesis of new insulin molecules are still incompletely described. In this report, we identify EDEM1 as a new modulator of insulin synthesis and secretion. In the presence of EDEM1, INS-1E cells secrete significantly more insulin upon glucose stimulation compared to control cells. We found that overexpression of EDEM1 inhibited the IRE1/JNK/c-Jun pathway, leading to an increase in the insulin mRNA level. Similarly, EDEM1 transduced human islets secreted significantly more insulin upon stimulation. Furthermore, EDEM1 improved insulin secretion restoring normoglycemia and glucose tolerance in diabetic rats. We propose EDEM1 as a regulator of the UPR via IRE1/XBP1s and IRE1/JNK/c-Jun signaling cascades and insulin transcription in pancreatic β-cells, supporting EDEM1 as a potential target for the treatment of diabetes., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)