PDF(Pubmed)
Abstract：
Uncarboxylated osteocalcin (ucOC) is a hormone secreted by osteoblasts that strengthens bone during mineralization and is a biomarker for ongoing bone formation. It also regulates glucose homeostasis by stimulating insulin secretion from pancreatic β-cells. However, its effect on β-cells under hyperglycemic diabetic conditions is unclear. The objective of this study was to investigate ucOC\'s effect on insulin secretion in β-cells maintained under high glucose conditions. We hypothesized that hyperglycemia potentiates insulin secretion in response to ucOC stimulation. Using INS-1 cells, we performed insulin secretion experiments, intracellular calcium recordings, and RT-qPCR to determine ucOC\'s effect on glucose-stimulated insulin secretion (GSIS)-related genes. The results reveal that ucOC significantly increased insulin secretion under hyperglycemic conditions compared to lower glucose levels. High glucose conditions also potentiated the effect of ucOC on calcium signals, which enhanced insulin secretion. The increase in intracellular calcium was due to an influx from the extracellular space via voltage-dependent calcium channels (VDCCs). Interestingly, the treatment of cells with NPS-2143, a GPRC6A blocker, failed to abolish the calcium signals. Uncarboxylated osteocalcin upregulated the expression of GSIS-related genes under high glucose conditions (450 mg/dL) compared to cells under standard culture conditions (200 mg/dL). In conclusion, hyperglycemia potentiates ucOC-induced insulin secretion in β-cells by opening VDCCs and upregulating GSIS genes. These findings provide a better understanding of ucOC\'s mechanism in the diabetic state and could lead to alternative treatments to stimulate insulin secretion.
摘要：
非羧化骨钙蛋白（ucOC）是成骨细胞分泌的激素，在矿化过程中增强骨骼，并且是正在进行的骨骼形成的生物标志物。它还通过刺激胰腺β细胞分泌胰岛素来调节葡萄糖稳态。然而,其对高血糖糖尿病患者β细胞的影响尚不清楚.本研究的目的是研究高糖条件下ucOC对维持β细胞胰岛素分泌的影响。我们假设高血糖会增强对ucOC刺激的胰岛素分泌。使用INS-1细胞，我们做了胰岛素分泌实验,细胞内钙记录，和RT-qPCR来确定ucOC对葡萄糖刺激的胰岛素分泌（GSIS）相关基因的影响。结果表明，与较低的葡萄糖水平相比，在高血糖条件下，ucOC显着增加了胰岛素分泌。高葡萄糖条件也增强了ucOC对钙信号的影响，增强胰岛素分泌。细胞内钙的增加是由于通过电压依赖性钙通道（VDCC）从细胞外空间流入。有趣的是,用GPRC6A阻断剂NPS-2143处理细胞，未能消除钙信号。与在标准培养条件(200mg/dL)下的细胞相比,在高葡萄糖条件(450mg/dL)下未羧化骨钙蛋白上调GSIS相关基因的表达。总之,高血糖通过打开VDCCs和上调GSIS基因增强ucOC诱导的β细胞胰岛素分泌.这些发现提供了一个更好的理解ucOC的机制在糖尿病状态，并可能导致替代治疗刺激胰岛素分泌。
