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Abstract
Background Osteocalcin (OCN) has been proved to be closely related with the development of type 2 diabetes mellitus (T2DM). We aimed to study if OCN could improve the disorder of islet cell caused by lipotoxicity. Methods Alizarin red staining was used to investigate the mineralization. Western blotting and ELISA methods were used to measure protein expression. Immunofluorescence staining was used to investigate the protein nuclear transfer. Results High glucose and high fat inhibited the differentiation of osteoblast precursors. Overexpression of insulin receptor (InsROE) significantly promoted the Runx2 and OCN expression. The increase of insulin, Gprc6a, and Glut2 by osteoblast culture medium overexpressing insulin receptor was reversed by osteocalcin neutralizing antibody. Undercarboxylated osteocalcin (ucOC) suppressed the lipotoxic islet β-cell damage caused by palmitic acid. The FOXO1 from intranuclear to extranuclear was also significantly increased after ucOC treatment compared with the group PA. Knockdown of Gprc6a or suppression of PI3K/AKT signal pathway could reverse the upregulation of GPRC6A/PI3K/AKT/FoxO1/Pdx1 caused by ucOC. Conclusion OCN could activate the FOXO1 signaling pathway to regulate GLUT2 expression and improve the insulin secretion disorder caused by lipotoxicity.
Highlights
Type 2 diabetes mellitus (T2DM) is one of the most common diseases threatening human health [1, 2], and its pathogenesis is complex
We found that the mineralized nodules were significantly increased in the group induction differentiation (ID)+InsR ovexpression (InsROE) and ID+Insulin compared with the group ID (Figure 3(c))
We found that palmitic acid (PA) remarkably reduced the levels of Gprc6a, Glut2, and insulin compared with the group control (Figures 4(a)–4(c))In addition, the levels of Gprc6a, Glut2, and insulin were remarkably increased by Conditioned Medium (CM), but the increased effects were suppressed by AntiOCN (Figures 4(a)–4(c))
Summary
Osteocalcin (OCN) has been proved to be closely related with the development of type 2 diabetes mellitus (T2DM). We aimed to study if OCN could improve the disorder of islet cell caused by lipotoxicity. Western blotting and ELISA methods were used to measure protein expression. Immunofluorescence staining was used to investigate the protein nuclear transfer. Overexpression of insulin receptor (InsROE) significantly promoted the Runx and OCN expression. The increase of insulin, Gprc6a, and Glut by osteoblast culture medium overexpressing insulin receptor was reversed by osteocalcin neutralizing antibody. Undercarboxylated osteocalcin (ucOC) suppressed the lipotoxic islet β-cell damage caused by palmitic acid. The FOXO1 from intranuclear to extranuclear was significantly increased after ucOC treatment compared with the group PA. Knockdown of Gprc6a or suppression of PI3K/AKT signal pathway could reverse the upregulation of GPRC6A/PI3K/AKT/FoxO1/Pdx caused by ucOC. OCN could activate the FOXO1 signaling pathway to regulate GLUT2 expression and improve the insulin secretion disorder caused by lipotoxicity
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