title: Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion.
abstract: Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation. We previously showed that the effect of GluOC on insulin secretion is mediated largely by glucagon-like peptide-1 (GLP-1) secreted from the intestine in response to GluOC exposure. We have now examined the effect of oral administration of GluOC on glucose utilization as well as the fate of such administered GluOC in mice. Long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level and improved glucose tolerance in mice without affecting insulin sensitivity. It also increased the fasting serum insulin concentration as well as the β-cell area in the pancreas. A small proportion of orally administered GluOC reached the small intestine and remained there for at least 24h. GluOC also entered the general circulation, and the serum GLP-1 concentration was increased in association with the presence of GluOC in the intestine and systemic circulation. The putative GluOC receptor, GPRC6A was detected in intestinal cells, and was colocalized with GLP-1 in some of these cells. Our results suggest that orally administered GluOC improved glucose handling likely by acting from both the intestinal lumen and the general circulation, with this effect being mediated in part by stimulation of GLP-1 secretion. Oral administration of GluOC warrants further study as a safe and convenient option for the treatment or prevention of metabolic disorders.
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizokami
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan; Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yasutake
authors.affiliation: Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan.
authors.forename: Sen
authors.initials: S
authors.lastname: Higashi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kawakubo-Yasukochi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Chishaki
authors.affiliation: Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takahashi
authors.affiliation: Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: hirata1@dent.kyushu-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000008:administration & dosage*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D015675:Osteocalcin; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: Drug delivery; GPRC6A; Glucagon-like peptide-1 (GLP-1); Insulin; Osteocalcin