背景:尽管体内研究表明内源性大麻素与代谢功能障碍有关,人们对直接的了解很少,人胰岛内源性大麻素系统(ECS)的慢性激活。因此,这项研究调查了长期暴露于大麻素激动剂对人胰岛基因表达和功能的影响。
方法:在不存在或存在CB1r(ACEA)或CB2r(JWH015)激动剂的情况下,将人胰岛维持2天和5天。通过RT-PCR定量基因表达,放射免疫测定的激素水平和caspase活性的细胞凋亡。
结果:人类胰岛表达ECS,具有编码生物合成和降解酶NAPE-PLD的mRNA,FAAH和MAGL比DAGLα丰富得多,参与2-AG合成的酶,或CB1和CB2受体mRNA。CB1r和CB2r的延长激活改变了编码ECS组分的mRNA的表达,但对胰岛激素分泌没有重大影响。JWH015在2天增加胰岛素和胰高血糖素含量,但5天后没有效果。用ACEA或JWH015治疗长达5天,对胰岛活力没有明显影响,通过形态学和胱天蛋白酶活性评估。
结论:在存在CB1和CB2受体激动剂的情况下维持人胰岛长达5天,会导致ECS元件基因表达的改变,但对胰岛功能或生存能力没有任何重大影响。
结论:这些数据表明,人类肥胖和糖尿病中与ECS过度激活相关的代谢功能障碍不太可能继发于胰岛功能受损。
BACKGROUND: Although in vivo studies have implicated endocannabinoids in metabolic dysfunction, little is known about direct, chronic activation of the endocannabinoid system (ECS) in human islets. Therefore, this study investigated the effects of prolonged exposure to cannabinoid agonists on human islet gene expression and function.
METHODS: Human islets were maintained for 2 and 5 days in the absence or presence of CB1r (ACEA) or CB2r (JWH015) agonists. Gene expression was quantified by RT-PCR, hormone levels by radioimmunoassay and apoptosis by caspase activities.
RESULTS: Human islets express an ECS, with mRNAs encoding the biosynthetic and degrading enzymes NAPE-PLD, FAAH and MAGL being considerably more abundant than DAGLα, an enzyme involved in 2-AG synthesis, or CB1 and CB2 receptor mRNAs. Prolonged activation of CB1r and CB2r altered expression of mRNAs encoding ECS components, but did not have major effects on islet hormone secretion. JWH015 enhanced insulin and glucagon content at 2 days, but had no effect after 5 days. Treatment with ACEA or JWH015 for up to 5 days did not have marked effects on islet viability, as assessed by morphology and caspase activities.
CONCLUSIONS: Maintenance of human islets for up to 5 days in the presence of CB1 and CB2 receptor agonists causes modifications in ECS element gene expression, but does not have any major impact on islet function or viability.
CONCLUSIONS: These data suggest that the metabolic dysfunction associated with over-activation of the ECS in obesity and diabetes in humans is unlikely to be secondary to impaired islet function.