Cheng Kai-Chun, Li Ying-Xiao, Shieh Po-Chuen, Cheng Juei-Tang, Hsu Chia-Chen
Department of Pharmacy, College of Pharmacy, Tajen University, Pingtung 907, Taiwan.
Pharmacological Department of Herbal Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
Pharmaceuticals (Basel). 2020 Nov 20;13(11):407. doi: 10.3390/ph13110407.
Liraglutide, an acylated analog of glucagon-like peptide 1 (GLP-1), could improve glycemic control in diabetes. Moreover, endogenous opioid peptides play a role in blood sugar regulation. Since GLP-1 receptors are also expressed in extra-pancreatic tissues, this study investigates the effect of liraglutide on endogenous opioid secretion in type 1-like diabetes. The endogenous opioid level was determined by enzyme-linked immunosorbent assay. The direct effect of liraglutide on endogenous opioid secretion was determined in the isolated adrenal medulla. Acute treatment with liraglutide dose-dependently attenuated hyperglycemia, and increased the plasma opioid neuropeptide, beta-endorphin (BER) levels in diabetic rats. These effects have been blocked by GLP-1 receptor antagonist, naloxone. Additionally, the effects of liraglutide were markedly reduced in adrenalectomized diabetic rats. In the isolated adrenal medulla, liraglutide induced BER secretion and increased the BER mRNA levels. Subcellular effects of liraglutide on the adrenal gland were further identified to mediate through the exchange proteins directly activated by cAMP, mainly using the pharmacological blockade. After repeatedly administering liraglutide, metabolic changes in diabetic rats were investigated, and genes associated with gluconeogenesis in the liver were downregulated. Naloxone pretreatment inhibited these effects of liraglutide, indicating the involvement of endogenous opioids. The present study indicated that liraglutide had an acute effect of reducing hyperglycemia by regulating endogenous opioid BER and modifying the glucose homeostasis.
利拉鲁肽是胰高血糖素样肽1（GLP-1）的酰化类似物，可改善糖尿病患者的血糖控制。此外，内源性阿片肽在血糖调节中发挥作用。由于GLP-1受体也在胰腺外组织中表达，本研究调查了利拉鲁肽对1型糖尿病样模型中内源性阿片分泌的影响。内源性阿片水平通过酶联免疫吸附测定法测定。在分离的肾上腺髓质中测定利拉鲁肽对内源性阿片分泌的直接作用。利拉鲁肽急性治疗可剂量依赖性地减轻高血糖，并增加糖尿病大鼠血浆阿片神经肽β-内啡肽（BER）水平。这些作用已被GLP-1受体拮抗剂纳洛酮阻断。此外，在肾上腺切除的糖尿病大鼠中，利拉鲁肽的作用明显减弱。在分离的肾上腺髓质中，利拉鲁肽诱导BER分泌并增加BER mRNA水平。利拉鲁肽对肾上腺的亚细胞作用进一步确定主要通过环磷酸腺苷直接激活的交换蛋白介导，主要采用药理学阻断方法。反复给予利拉鲁肽后，研究了糖尿病大鼠的代谢变化，肝脏中与糖异生相关的基因被下调。纳洛酮预处理抑制了利拉鲁肽的这些作用，表明内源性阿片参与其中。本研究表明，利拉鲁肽通过调节内源性阿片BER和改变葡萄糖稳态，具有降低高血糖的急性作用。
