Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo

被引：245

作者：

Kawamori, Dan ^{[1
,2
]}

Kurpad, Amarnath J. ^{[1
,2
]}

Hu, Jiang ^{[1
,2
]}

Liew, Chong Wee ^{[1
,2
]}

Shih, Judy L. ^{[1
,2
]}

Ford, Eric L. ^{[3
]}

Herrera, Pedro L. ^{[4
]}

Polonsky, Kenneth S. ^{[3
]}

McGuinness, Owen P. ^{[5
]}

Kulkarni, Rohit N. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Dept Cellular & Mol Physiol, Joslin Diabet Ctr, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA

[3] Washington Univ, Sch Med, Div Metab, Dept Internal Med, St Louis, MO 63110 USA

[4] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[5] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37240 USA

来源：

CELL METABOLISM | 2009年 / 9卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

SENSITIVE K+ CHANNELS; BETA-CELL; ENDOCRINE PANCREAS; RECEPTOR EXPRESSION; GENE-TRANSCRIPTION; DIABETES-MELLITUS; GLUCOSE; HYPOGLYCEMIA; RESPONSES; INHIBITION;

D O I：

10.1016/j.cmet.2009.02.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In, this study, we created and characterized alpha cell-specific insulin receptor knockout (alpha IRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alpha IRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alpha IRKO mice. The mutants also exhibited an age-dependent increase in 0 cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions.

引用

页码：350 / 361

页数：12

共 63 条

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