The insulin secretion in the pancreatic beta-cell under influence of different cannabinoid receptors and endocannabinoid metabolism

内源性大麻素系统(ECS)由大麻素受体、合成和降解酶及内源性配体组成。ECS影响神经元信号，以及胰岛激素的分泌。内源性大麻素系统通过调节胰岛素的分泌来影响胰岛β细胞的活动。不同的大麻素受体连接到细胞内信号通路，介导内源性大麻素的作用。然而，与这些途径相关的第二信使知之甚少。在该提案中，我们计划通过使用成熟的大鼠胰岛素瘤β细胞模型INS-1和新鉴定的人类β细胞模型EndocBetaH1、EndocBetaH1的转基因变体、分离的人胰岛和大麻素受体基因敲除小鼠来实现以下方面的研究。我们将集中于：(1)ECS参与调节生理或糖尿病刺激的胰岛素分泌，同时研究涉及的信号成分；(2)内源性大麻素代谢和受体变化对调节胰岛素分泌和2型糖尿病的重要性。前瞻性地，该研究可能有助于我们了解G蛋白偶联受体信号通路在胰岛中的影响，并将有助于进一步了解ECS在胰岛素分泌中的作用。积极影响ECS为治疗临床上高度相关的2型糖尿病疾病开辟了新的选择。

The endocannabinoid system (ECS) consisted of cannabinoid receptors, enzymes for the synthesis and degradation and endogenous ligands, the so called endocannabinoids. The ECS influences neuronal signaling, as well as hormonal secretion of the pancreatic islet. The endocannabinoid system affects the activity of pancreatic beta-cells by modulation of insulin secretion. Different cannabinoid receptors coupled to intracellular signaling pathways mediate effects of endocannabinoids. However, little is known about the second messengers associated with these pathways.In the proposal we plan to the following aspects by using the well-established rat insulinoma beta beta cell model INS-1 and a newly characterized human beta cell model EndoC-betaH1, genetically modified variants of EndoC-betaH1, isolated human pancreatic islets and cannabinoid receptor knockout mice. We will focus on: (1) Participation of ECS on modulation of physiologically or diabetic stimulated insulin secretion, while simultaneously investigating the signaling components involved, and (2) the importance of endocannabinoid metabolism and the receptor alterations for regulating insulin secretion and type 2 diabetes.Prospectively, the proposed study might contribute to our knowledge of the impact of G-protein-coupled receptor signaling pathways in pancreatic islets and will shed new light on the role of the ECS for the insulin secretion. Actively influencing the ECS opens new options for the treatment of the clinically highly relevant disease of type 2 diabetes.