Oral administration of osteocalcin improves glucose utilization by stimulating glucagon-like peptide-1 secretion |
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| Affiliation: | 1. Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan;2. Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan;3. Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan;1. Department of Stem Cell Biology and Regenerative Medicine and Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, W.M. Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA;2. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA;3. Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand;4. Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA;5. Department of Orthopedic Surgery, Harvard Medical School, Boston, MA 02115, USA;6. Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA;1. Department of Endocrinology, Ghent University Hospital, Belgium;2. Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium;3. Department of Pediatric Endocrinology, Ghent University Hospital, Belgium;4. Department of Hormonology, Ghent University Hospital, Belgium;5. Department of Pediatric Endocrinology, Brussels University Hospital, Belgium;1. Group for Bone Biology and Orthopedic Research, Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland;2. Department of Orthopaedic Surgery, Inselspital, Bern University Hospital, CH-3010 Bern, Switzerland |
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| 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 24 h. 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. |
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