| First Author | Ladiges WC | Year | 2005 |
| Journal | Diabetes | Volume | 54 |
| Issue | 4 | Pages | 1074-81 |
| PubMed ID | 15793246 | Mgi Jnum | J:98194 |
| Mgi Id | MGI:3577591 | Doi | 10.2337/diabetes.54.4.1074 |
| Citation | Ladiges WC, et al. (2005) Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54(4):1074-81 |
| abstractText | The endoplasmic reticulum (ER) transmits apoptotic signals in the pancreas during ER stress, implicating ER stress-mediated apoptosis in the development of diabetes. P58(IPK) (DNAJC3) is induced during ER stress and functions as a negative feedback component to inhibit eIF-2alpha signaling and attenuate the later phases of the ER stress response. To gain insight into a more comprehensive role of P58(IPK) function, we generated deletion mutant mice that showed a gradual onset of glucosuria and hyperglycemia associated with increasing apoptosis of pancreatic islet cells. Lack of P58(IPK) had no apparent effect on the functional integrity of viable beta-cells. A set of genes associated with apoptosis showed altered expression in pancreatic islets from P58(IPK)-null mice, further substantiating the apoptosis phenotype. The data provide in vivo evidence to support the concept that P58(IPK) functions as a signal for the downregulation of ER-associated proteins involved in the initial ER stress response, thus preventing excessive cell loss by degradation pathways. Insulin deficiency associated with the absence of P58(IPK) mimics beta-cell failure associated with type 1 and late-stage type 2 diabetes. P58(IPK) function and activity may therefore provide a novel area of investigation into ER-mediated mechanistic and therapeutic approaches for diabetes. |
