Movahed Miranda, Louzada Ruy A, Blandino-Rosano Manuel
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA.
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA.
Mol Metab. 2025 Feb;92:102088. doi: 10.1016/j.molmet.2024.102088. Epub 2024 Dec 28.
Dynorphin, an endogenous opioid peptide predominantly expressed in the central nervous system and involved in stress response, pain, and addiction, has intrigued researchers due to its expression in pancreatic β-cells. In this study, we aimed to characterize dynorphin expression in mouse and human islets and explore the mechanisms regulating its expression.
We used primary mouse and human islets with unbiased published datasets to examine how glucose and other nutrients regulate dynorphin expression and secretion in islets.
The prodynorphin gene is significantly upregulated in β-cells under hyperglycemic conditions. In vitro studies revealed that increased glucose concentrations correlate with increased dynorphin expression, indicating a critical interplay involving Ca, CamKII, and CREB pathways in β-cells. Perifusion studies allowed us to measure the dynamic secretion of dynorphin in response to glucose from mouse and human islets for the first time. Furthermore, we confirmed that increased dynorphin content within the β-cells directly correlates with enhanced dynorphin secretion. Finally, our findings demonstrate a synergistic effect of palmitate in conjunction with high glucose, further amplifying dynorphin levels and secretion in pancreatic islets.
This study demonstrates that the opioid peptide prodynorphin is expressed in mouse and human β-cells. Prodynorphin levels are regulated in parallel with insulin in response to glucose, palmitate, and amino acids. Our findings elucidate the signaling pathways involved, with CamKII playing a key role in regulating prodynorphin levels in β-cells. Finally, our findings are the first to demonstrate active dynorphin secretion from mouse and human islets in response to glucose.
强啡肽是一种主要在中枢神经系统表达且参与应激反应、疼痛和成瘾过程的内源性阿片肽，因其在胰腺β细胞中的表达而引起了研究人员的兴趣。在本研究中，我们旨在描述强啡肽在小鼠和人类胰岛中的表达特征，并探索调节其表达的机制。
我们使用原代小鼠和人类胰岛以及公开的无偏数据集，来研究葡萄糖和其他营养物质如何调节胰岛中强啡肽的表达和分泌。
在高血糖条件下，前强啡肽基因在β细胞中显著上调。体外研究表明，葡萄糖浓度升高与强啡肽表达增加相关，这表明β细胞中涉及钙、钙调蛋白激酶II（CaMKII）和环磷腺苷反应元件结合蛋白（CREB）途径的关键相互作用。灌流研究首次使我们能够测量小鼠和人类胰岛中强啡肽对葡萄糖的动态分泌。此外，我们证实β细胞内强啡肽含量的增加与强啡肽分泌增强直接相关。最后，我们的研究结果表明棕榈酸酯与高葡萄糖协同作用，进一步放大了胰岛中强啡肽的水平和分泌。
本研究表明阿片肽前强啡肽在小鼠和人类β细胞中表达。前强啡肽水平与胰岛素一样，对葡萄糖、棕榈酸酯和氨基酸作出平行调节。我们的研究结果阐明了其中涉及的信号通路，CaMKII在调节β细胞中前强啡肽水平方面发挥关键作用。最后，我们的研究结果首次证明了小鼠和人类胰岛对葡萄糖作出反应时会主动分泌强啡肽。
