title: Osteocalcin Effect on Human β-Cells Mass and Function.
abstract: The osteoblast-specific hormone osteocalcin (OC) was found to regulate glucose metabolism, fat mass, and β-cell proliferation in mice. Here, we investigate the effect of decarboxylated OC (D-OC) on human β-cell function and mass in culture and in vivo using a Nonobese diabetic-severe combined immunodeficiency mouse model. We found that D-OC at dose ranges from 1.0 to 15 ng/mL significantly augmented insulin content and enhanced human β-cell proliferation of cultured human islets. This was paralleled by increased expression of sulfonylurea receptor protein; a marker of β-cell differentiation and a component of the insulin-secretory apparatus. Moreover, in a Nonobese diabetic-severe combined immunodeficiency mouse model, systemic administration of D-OC at 4.5-ng/h significantly augmented production of human insulin and C-peptide from the grafted human islets. Finally, histological staining of the human islet grafts showed that the improvement in the β-cell function was attributable to an increase in β-cell mass as a result of β-cell proliferation indicated by MKI67 staining together with the increased β-cell number and decreased α-cell number data obtained using laser scanning cytometry. Our data for the first time show D-OC-enhanced β-cell function in human islets and support future exploitation of D-OC-mediated β-cell regulation for developing useful clinical treatments for patients with diabetes.
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: Omaima M
authors.initials: OM
authors.lastname: Sabek
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: Satoru Ken
authors.initials: SK
authors.lastname: Nishimoto
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fraga
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: Neelam
authors.initials: N
authors.lastname: Tejpal
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.affiliation: Department of Surgery (O.M.S., D.F., N.T., A.O.G.), The Methodist Hospital, Houston, Texas 77030; Weill Cornell Medical College (O.M.S., A.O.G.), New York, New York 10065; Department of Microbiology Immunology Biochemistry (S.K.N.), University of Tennessee, Memphis, Tennessee 38163; and Departments of Surgery, Microbiology, and Immunology (C.R.), Diabetes Research Institute, University of Miami, Miami, Florida 33021.
authors.forename: A O
authors.initials: AO
authors.lastname: Gaber
mesh_terms: D000328:Adult; D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D015675:Osteocalcin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002096:C-Peptide; D007328:Insulin; D015675:Osteocalcin