Molecular Mechanisms for Pancreatic Islet Disfunction in Development of Diabetes Mellitus-a study using WFS1 knockout mice

点击翻译按钮获取中文摘要

Establishment of WFS1-deficient insulinoma cell lines. To examine the influence of WFS1-deficiency specifically in a homogenous β-cell population, β-cell lines were established by crossing wfs1^<-/-> mice with IT6 mice expressing simian virus 40 large T antigen under the insulin promoter. We found impaired insulin secretion in response to high glucose, which was recovered by adenovirus-mediated expression of wild-type WFS 1 but not of mutant WFS1 proteins found in Wolfram-syndrome patients.Role of WFS1 protein in intracellular calcium homeostasis. We analyzed WFS1-knockdown and-overexpressing HEK293 cells, and found that WFS1 protein modulates [Ca^<2+>]_<er> by positively regulating the ER Ca^<2+> uptake, which is associated with changes in the [Ca^<2+>]_<cyt> response evoked by Ca^<2+> store depletion.Identification of the translational suppressor 4E-BP1 as a pro-survival factor in β-cells under ER stress. Expression profiling in WFS1-deficient islets revealed increased 4E-BPI expression. We found that expression of 4E-BP1 was also enhanced in islets under ER stress in mouse models of diabetes. 4E-BP1 induction was found to be mediated by the transcription factor ATF4. 4E-BP1-deficient MIN6 β-cells were more vulnerable to apoptosis triggered by ER stress, with greater induction of C/EBP homologue protein. Furthermore, Eif4ebp1 deletion exacerbated hyperglycemia, with accelerated (3-cell failure, in mouse diabetes models with ER stress. Thus, 4E-BP1 induction is a pro-survival signal for (3-cells under ER stress and a potential therapeutic target for diabetes.Increased glucagon secretion from WFS1-deficient islets. Pyruvate was previously shown to stimulate glucagon secretion. In this study, we found increased alpha cell numbers and enhanced pyruvate-stimulated glucagon secretion in WFS1-deficient islets.Multiple abnormalities are suggested to contribute development of diabetes in the mouse model of Wolfram syndrome.