FKBP12.6 disruption impairs glucose-induced insulin secretion.
Cyclic ADP-ribose (cADPR), accumulated in pancreatic beta-cells in response to elevated ATP levels after glucose stimulation, mobilizes Ca(2+) 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 beta-cells.
Noguchi
Naoya
N
Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan.
Yoshikawa
Takeo
T
Ikeda
Takayuki
T
Takahashi
Iwao
I
Shervani
Nausheen Jamal
NJ
Uruno
Akira
A
Yamauchi
Akiyo
A
Nata
Koji
K
Takasawa
Shin
S
Okamoto
Hiroshi
H
Sugawara
Akira
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015870:Gene Expression / Q000235:genetics; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*
D005947:Glucose; D007328:Insulin; D054086:KATP Channels; D011189:Potassium Chloride; D012333:RNA, Messenger; D013453:Sulfonylurea Compounds; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse