UCP2 Regulates the Glucagon Response to Fasting and Starvation

被引：57

作者：

Allister, Emma M. ^{[1
]}

Robson-Doucette, Christine A. ^{[1
]}

Prentice, Kacey J. ^{[1
]}

Hardy, Alexandre B. ^{[1
]}

Sultan, Sobia ^{[1
]}

Gaisano, Herbert Y. ^{[1
]}

Kong, Dong ^{[2
,3
]}

Gilon, Patrick ^{[4
]}

Herrera, Pedro L. ^{[5
]}

Lowell, Bradford B. ^{[2
,3
]}

Wheeler, Michael B. ^{[1
]}

机构：

[1] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[2] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Catholic Univ Louvain, Inst Rech Expt & Clin, B-1200 Brussels, Belgium

[5] Univ Geneva, Fac Med, Dept Genet Med & Dev, Geneva, Switzerland

来源：

DIABETES | 2013年 / 62卷 / 05期

基金：

加拿大健康研究院;

关键词：

K-ATP-CHANNELS; KNOCKOUT MICE; ALPHA-CELLS; GLUCOSE; SECRETION; INSULIN; MOUSE; DYSFUNCTION; MECHANISMS; EXPRESSION;

D O I：

10.2337/db12-0981

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2(-/-)) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created alpha-cell-specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted alpha-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, alpha-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal alpha-cell glucose sensing and the maintenance of euglycemia. Diabetes 62:1623-1633, 2013

引用

页码：1623 / 1633

页数：11

共 46 条

[1] Uncoupling protein-2 attenuates glucose-stimulated insulin, secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species [J].