Restoration of the unfolded protein response in pancreatic β cells protects mice against type 1 diabetes.
Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA's actions were dependent on ATF6 and were lost in mice with β cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Feyza
F
Engin
Alena
A
Yermalovich
Truc
T
Nguyen
Truc
T
Ngyuen
Sarah
S
Hummasti
Wenxian
W
Fu
Decio L
DL
Eizirik
Diane
D
Mathis
Gökhan S
GS
Hotamisligil
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D056811:Unfolded Protein Response