title: FKBP12.6 disruption impairs glucose-induced insulin secretion.
abstract: 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.
authors.affiliation: Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Noguchi
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Iwao
authors.initials: I
authors.lastname: Takahashi
authors.forename: Nausheen Jamal
authors.initials: NJ
authors.lastname: Shervani
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Akiyo
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Koji
authors.initials: K
authors.lastname: Nata
authors.forename: Shin
authors.initials: S
authors.lastname: Takasawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
mesh_terms: 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*
chemical_list: D005947:Glucose; D007328:Insulin; D054086:KATP Channels; D011189:Potassium Chloride; D012333:RNA, Messenger; D013453:Sulfonylurea Compounds; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse