Research ArticleAUTOIMMUNE DIABETES

Restoration of the Unfolded Protein Response in Pancreatic β Cells Protects Mice Against Type 1 Diabetes

Science Translational Medicine  13 Nov 2013:
Vol. 5, Issue 211, pp. 211ra156
DOI: 10.1126/scitranslmed.3006534

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Performance Enhancement

The stress response can help raise a person’s performance level at crucial times—when meeting a cougar on a hike, dancing Swan Lake for the first time, or teaching your teen to drive. But chronic stress strains the body and mind in unhealthy ways. This principle holds true at the molecular level. When organs place a high demand on the cell’s endoplasmic reticulum (ER) for proper synthesis, folding, and trafficking of large amounts of protein, misfolded or unfolded proteins can accumulate in the ER and trigger the unfolded protein response (UPR). The UPR is a complex program that drives either proper folding of misfolded proteins via chaperones or degradation of these proteins to restore ER homeostasis. This adaptation to ER stress is beneficial in acute situations but detrimental under chronic pathological conditions. Indeed, recent research illustrates the importance of restoring ER homeostasis in type 2 diabetes (T2D) and neurodegenerative disorders. Now, Engin et al. investigate ER stress in the context of autoimmune (type 1) diabetes (T1D).

Tweaks in ER homeostasis are known to spur stress responses that modify glucose and lipid metabolism. But little is known about the role of the UPR in the natural history of T1D or in the disease’s characteristic dysfunction and death of pancreatic β cells. These cells play a central role in initiating carbohydrate metabolism by secreting insulin in response to glucose intake.

The authors uncovered defects in the expression of two UPR mediators, ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1), in pancreatic β cells from T1D patients and two distinct mouse models of T1D. When the mice were treated at the prediabetic stage with tauroursodeoxycholic acid (TUDCA)—a bile acid produced by the liver and known to quell ER stress—diabetes incidence was significantly reduced in an ATF6-dependent manner. The treated mice also displayed decreased infiltration of autoimmune-associated lymphocytes in the pancreas and increased survival, insulin secretion, and UPR-mediator expression in pancreatic β cells.

The data show that, in mouse models of T1D, a functional UPR participates in the preservation of pancreatic β cells and that UPR dysfunction can be prevented with TUDCA therapy. Currently, autoantibody testing permits the identification of human T1D patients one to two years before they develop symptoms. Therefore, this study suggests a strategy for preventing aberrant ER function in prediabetic autoantibody-positive patients. Further, a clinical (safety) trial for the TUDCA precursor UDCA was initiated for patients with Huntington’s disease (NCT00514774), a neurological disorder that is associated with protein misfolding and aggregation and might involve a dysfunctional UPR. Thus reversing stressful conditions in the ER might have wide-ranging therapeutic consequences.