Osteocalcin Effect on Human β-Cells Mass and Function

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 9; pp. 3137 - 3146
• Main Authors: Sabek, Omaima M, Nishimoto, Satoru Ken, Fraga, Daniel, Tejpal, Neelam, Ricordi, Camillo, Gaber, A. O
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.09.2015
• Subjects: Adult; Animals; C-Peptide - metabolism; Cattle; Cell Proliferation; Cells, Cultured; Female; Humans; Insulin - biosynthesis; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Islets of Langerhans Transplantation; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Osteocalcin - pharmacology; Osteocalcin - therapeutic use
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/EN.2015-1143

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.