TY - JOUR
T1 - FKBP12.6 disruption impairs glucose-induced insulin secretion
AU - Noguchi, Naoya
AU - Yoshikawa, Takeo
AU - Ikeda, Takayuki
AU - Takahashi, Iwao
AU - Shervani, Nausheen Jamal
AU - Uruno, Akira
AU - Yamauchi, Akiyo
AU - Nata, Koji
AU - Takasawa, Shin
AU - Okamoto, Hiroshi
AU - Sugawara, Akira
N1 - Funding Information:
We are grateful to Mr. Yuya Shichinohe for technical assistance and Mr. Brent Bell for critical reading of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. A.U. is the recipient of a fellowship from the Japan Society for Promotion of Science.
PY - 2008/7/11
Y1 - 2008/7/11
N2 - Cyclic ADP-ribose (cADPR), accumulated in pancreatic β-cells in response to elevated ATP levels after glucose stimulation, mobilizes Ca2+ from the endoplasmic reticulum through the ryanodine receptor (RyR) and thereby induces insulin secretion. We have recently demonstrated in an in vitro study that cADPR activates RyR through binding to FK506-binding protein 12.6 (FKBP12.6), an accessory protein of RyR. Here we generated FKBP12.6-deficient (FKBP12.6-/-) mice by homologous recombination. FKBP12.6-/- mice showed glucose intolerance coupled to insufficient insulin secretion upon a glucose challenge. Insulin secretion in response to glucose was markedly impaired in FKBP12.6-/- islets, while sulfonylurea- or KCl-induced insulin secretion was unaffected. No difference was found in the glucose oxidation rate between FKBP12.6-/- and wild-type islets. These results indicate that FKBP12.6 plays a role in glucose-induced insulin secretion downstream of ATP production, independently of ATP-sensitive K+ channels, in pancreatic β-cells.
AB - Cyclic ADP-ribose (cADPR), accumulated in pancreatic β-cells in response to elevated ATP levels after glucose stimulation, mobilizes Ca2+ from the endoplasmic reticulum through the ryanodine receptor (RyR) and thereby induces insulin secretion. We have recently demonstrated in an in vitro study that cADPR activates RyR through binding to FK506-binding protein 12.6 (FKBP12.6), an accessory protein of RyR. Here we generated FKBP12.6-deficient (FKBP12.6-/-) mice by homologous recombination. FKBP12.6-/- mice showed glucose intolerance coupled to insufficient insulin secretion upon a glucose challenge. Insulin secretion in response to glucose was markedly impaired in FKBP12.6-/- islets, while sulfonylurea- or KCl-induced insulin secretion was unaffected. No difference was found in the glucose oxidation rate between FKBP12.6-/- and wild-type islets. These results indicate that FKBP12.6 plays a role in glucose-induced insulin secretion downstream of ATP production, independently of ATP-sensitive K+ channels, in pancreatic β-cells.
KW - Cyclic ADP-ribose
KW - FKBP12.6
KW - Ryanodine receptor
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U2 - 10.1016/j.bbrc.2008.04.142
DO - 10.1016/j.bbrc.2008.04.142
M3 - Article
C2 - 18466757
AN - SCOPUS:44149089532
SN - 0006-291X
VL - 371
SP - 735
EP - 740
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -