Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
Nutrients. 2024 Jul 23;16(15):2384. doi: 10.3390/nu16152384.
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.
未羧化骨钙素（ucOC）是成骨细胞分泌的一种激素，它在矿化过程中增强骨骼，并作为骨形成的生物标志物。它还通过刺激胰岛β细胞分泌胰岛素来调节葡萄糖稳态。然而，其在高血糖糖尿病条件下对β细胞的影响尚不清楚。本研究旨在探讨 ucOC 在高葡萄糖条件下对β细胞胰岛素分泌的影响。我们假设高血糖增强了对 ucOC 刺激的胰岛素分泌反应。使用 INS-1 细胞，我们进行了胰岛素分泌实验、细胞内钙记录和 RT-qPCR，以确定 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，与较低葡萄糖水平相比，ucOC 在高血糖条件下显著增加了胰岛素分泌。高葡萄糖条件还增强了 ucOC 对钙信号的作用，从而增强了胰岛素分泌。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。与标准培养条件（200mg/dL）相比，ucOC 在高葡萄糖条件（450mg/dL）下上调了 GSIS 相关基因的表达。总之，高血糖通过打开 VDCC 和上调 GSIS 基因增强了 ucOC 诱导的β细胞胰岛素分泌。这些发现为 ucOC 在糖尿病状态下的作用机制提供了更好的理解，并可能导致刺激胰岛素分泌的替代治疗方法。
