Targeting uncoupling protein-2 improves islet graft function.
Preserving and enhancing the primary function of transplanted islets is not only crucial for improving the outcome of the islet transplantation, but is also important for reducing the islet mass required to achieve insulin independence. Uncoupling protein 2 (UCP2) is a member of the uncoupling protein family, which is localized to the inner mitochondrial membrane and negatively regulates insulin secretion in the pancreatic β-cells. In this study, we assessed the importance of UCP2 in improving islet graft primary function by using UCP2 gene-knockout (UCP2-KO) mice in a syngeneic islet transplantation model. Islets were isolated from UCP2-KO or wild-type (WT) C57BL/6J mice. The effects of deficiency of UCP2 on islet transplantation and islet function were determined. Two hundred islets from UCP2-KO, but not from WT, donors were capable of completely restoring normoglycemia in 1 week in all syngeneic diabetic recipients. Islets harvested from UCP2-KO mice secreted onefold more insulin in GSIS assay than that from WT mice, and maintained normal GSIS after 72-h exposure to high glucose challenge. In addition, UCP2-KO islets expressed twofold higher Bcl-2 mRNA than that from WT islets, and were resistant to high glucose and proinflammatory cytokine induced death. Our study explored a potential mechanism that may explain the benefit of UCP2-KO islets in islet transplantation. Targeting UCP2 may provide a novel strategy to improve primary function of transplanted islets and reduce the number of islets required in transplantation.
Zhang
Dong
D
Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Shen
Miaoda
M
Mikita
Allison
A
Zhang
Wensheng
W
Liu
Yun
Y
Liu
Quan
Q
Dai
Yifan
Y
Zhang
Chenyu
C
Zheng
Shusen
S
Zheng
Xin Xiao
XX
D000818:Animals; D002470:Cell Survival; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014185:Transplantation, Isogeneic; D000071246:Uncoupling Protein 2
D016207:Cytokines; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D005947:Glucose