Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK.

Publication Type:

Journal Article


Diabetes, Volume 54, Issue 4, p.1074-81 (2005)


Animals, APOPTOSIS, Diabetes Mellitus, Endoplasmic Reticulum, Female, Glycosuria, HSP40 Heat-Shock Proteins, Hyperglycemia, Insulin, Islets of Langerhans, Male, MICE, Mice, Knockout, MOLECULAR CHAPERONES, Mutation, Repressor Proteins, Up-Regulation


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.