title: FKBP12.6-knockout mice display hyperinsulinemia and resistance to high-fat diet-induced hyperglycemia.
abstract: FK506 binding protein 12.6 kDa (FKBP12.6), a protein that regulates ryanodine Ca(2+) release channels, may act as an important regulator of insulin secretion. In this study, the role of FKBP12.6 in the control of insulin secretion and blood glucose is clarified using FKBP12.6(-/-) mice. FKBP12.6(-/-) mice showed significant fed hyperinsulinemia but exhibited normoglycemia, fasting normoinsulinemia, and normal body weight compared with wild-type (WT) littermate control mice. Deletion of FKBP12.6 resulted in enhanced glucose-stimulated insulin secretion (GSIS) both in vivo and in vitro, a result that is due to enhanced glucose-induced islet Ca(2+) elevation. After a high-fat dietary challenge (HF diet) for 3 mo, FKBP12.6(-/-) mice displayed higher body weight, hyperinsulinemia, and lower fed blood glucose concentrations compared with WT mice. FKBP12.6(-/-) mice displayed hyperinsulinemia, and resistance to HF diet-induced hyperglycemia, suggesting that FKBP12.6 plays an important role in insulin secretion and blood glucose control, and raising the possibility that it may be a potential therapeutic target for the treatment of type 2 diabetes.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhengzheng
authors.initials: Z
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Yin
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Michael I
authors.initials: MI
authors.lastname: Kotlikoff
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects*; D006943:Hyperglycemia / Q000378:metabolism* / Q000517:prevention & control; D006946:Hyperinsulinism / Q000209:etiology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D022061:Tacrolimus Binding Protein 1A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D022061:Tacrolimus Binding Protein 1A