Journal
DIABETES
Volume 54, Issue 4, Pages 1074-1081Publisher
AMER DIABETES ASSOC
DOI: 10.2337/diabetes.54.4.1074
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Funding
- NHLBI NIH HHS [HL52848] Funding Source: Medline
- NIAID NIH HHS [R01AI22646] Funding Source: Medline
- NIDDK NIH HHS [P30DK17047] Funding Source: Medline
- NIEHS NIH HHS [P30ES0703, U01ES11045] Funding Source: Medline
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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-2 alpha 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 P58IPK 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.
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