Osteocalcin protects pancreatic beta cell function and survival under high glucose conditions

• Published in: Biochemical and biophysical research communications Vol. 462; no. 1; pp. 21 - 26
• Main Authors: Kover, Karen, Yan, Yun, Tong, Pei Ying, Watkins, Dara, Li, Xiaoyu, Tasch, James, Hager, Melissa, Clements, Mark, Moore, Wayne V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-06-2015
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APOPTOSIS; Apoptosis - drug effects; Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 3 - metabolism; Caspase 7 - metabolism; Cell Line, Tumor; CELL PROLIFERATION; Cell Survival - drug effects; Cells, Cultured; Diabetes; Dose-Response Relationship, Drug; ENZYME IMMUNOASSAY; Gene Expression - drug effects; GENES; GLUCOSE; Glucose - pharmacology; Glucose toxicity; HYDROGEN PEROXIDE; HYPOTHESIS; INSULIN; Insulin - genetics; Insulin - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; MITOCHONDRIA; Mitochondria - drug effects; Mitochondria - metabolism; Osteocalcin; Osteocalcin - pharmacology; OXIDATION; Oxidative stress; Oxidative Stress - drug effects; PANCREAS; Pancreatic beta cells; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RATS; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; SECRETION; STRESSES; TOXICITY; VIABILITY; Oxidative stress; Glucose toxicity; Osteocalcin; Pancreatic beta cells; Diabetes
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.04.095

Diabetes is characterized by progressive beta cell dysfunction and loss due in part to oxidative stress that occurs from gluco/lipotoxicity. Treatments that directly protect beta cell function and survival in the diabetic milieu are of particular interest. A growing body of evidence suggests that osteocalcin, an abundant non-collagenous protein of bone, supports beta cell function and proliferation. Based on previous gene expression data by microarray, we hypothesized that osteocalcin protects beta cells from glucose-induced oxidative stress. To test our hypothesis we cultured isolated rat islets and INS-1E cells in the presence of normal, high, or high glucose ± osteocalcin for up to 72 h. Oxidative stress and viability/mitochondrial function were measured by H2O2 assay and Alamar Blue assay, respectively. Caspase 3/7 activity was also measured as a marker of apoptosis. A functional test, glucose stimulated insulin release, was conducted and expression of genes/protein was measured by qRT-PCR/western blot/ELISA. Osteocalcin treatment significantly reduced high glucose-induced H2O2 levels while maintaining viability/mitochondrial function. Osteocalcin also significantly improved glucose stimulated insulin secretion and insulin content in rat islets after 48 h of high glucose exposure compared to untreated islets. As expected sustained high glucose down-regulated gene/protein expression of INS1 and BCL2 while increasing TXNIP expression. Interestingly, osteocalcin treatment reversed the effects of high glucose on gene/protein expression. We conclude that osteocalcin can protect beta cells from the negative effects of glucose-induced oxidative stress, in part, by reducing TXNIP expression, thereby preserving beta cell function and survival.
•Osteocalcin reduces glucose-induced oxidative stress in beta cells.•Osteocalcin preserves beta cell function and survival under stress conditions.•Osteocalcin reduces glucose-induced TXNIP expression in beta cells.