TY - JOUR
T1 - Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes
AU - Zhang, Chen Yu
AU - Baffy, György
AU - Perret, Pascale
AU - Krauss, Stefan
AU - Peroni, Odile
AU - Grujic, Danica
AU - Hagen, Thilo
AU - Vidal-Puig, Antonio J.
AU - Boss, Olivier
AU - Kim, Young Bum
AU - Zheng, Xin Xiao
AU - Wheeler, Michael B.
AU - Shulman, Gerald I.
AU - Chan, Catherine B.
AU - Lowell, Bradford B.
N1 - Funding Information:
We wish to thank Barbara Kahn, Jeffrey Flier, Bruce Spiegelman, and all members of the Lowell lab for helpful discussions and for critically reading the manuscript, Keith Tornheim and Barbara Corkey for advice in assessing ATP levels and insulin release in pancreatic islets, and members of the BIDMC Transgenic Facility (Director, Joel Lawitts). This work was supported by grants from NIH (RO1 DK53477) and Eli Lilly to B.B.L., from The Canadian Diabetes Association in honor of Doris Evangeline Bradley to C.B.C. and M.B.W., a HFSP Postdoctoral Fellowship grant (LT 0020/1999) to O.B., an NIH training grant (T32 DK07533) to G.B., the Boston Area Diabetes Endocrinology Research Center Physiology Core (DK57521), and the Boston Obesity/Nutrition Research Center Transgenic Core (DK46200).
PY - 2001/6/15
Y1 - 2001/6/15
N2 - β cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of β cell glucose sensing, and as a critical link between obesity, β cell dysfunction, and type 2 diabetes.
AB - β cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of β cell glucose sensing, and as a critical link between obesity, β cell dysfunction, and type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=0035875087&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(01)00378-6
DO - 10.1016/S0092-8674(01)00378-6
M3 - Article
C2 - 11440717
AN - SCOPUS:0035875087
SN - 0092-8674
VL - 105
SP - 745
EP - 755
JO - Cell
JF - Cell
IS - 6
ER -