Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
Lilly China Research and Development Center, Shanghai, China.
Mol Metab. 2018 May;11:205-211. doi: 10.1016/j.molmet.2018.02.008. Epub 2018 Feb 23.
GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action.
We demonstrated by in situ hybridization and immunostaining that GPR142 is expressed not only in β cells but also in a subset of α cells. Stimulation of GPR142 by a selective agonist increased glucagon secretion in both human and mouse islets. More importantly, the GPR142 agonist also potentiated glucagon-like peptide-1 (GLP-1) production and its release from islets through a mechanism that involves upregulation of prohormone convertase 1/3 expression. Strikingly, stimulation of insulin secretion and increase in insulin content via GPR142 engagement requires intact GLP-1 receptor signaling. Furthermore, GPR142 agonist increased β cell proliferation and protected both mouse and human islets against stress-induced apoptosis.
Collectively, we provide here evidence that local GLP-1 release from α cells defines GPR142's beneficial effects on improving β cell function and mass, and we propose that GPR142 agonism may have translatable and durable efficacy for the treatment of type 2 diabetes.
GPR142 激动剂因其胰岛素分泌作用而被作为新型糖尿病治疗药物进行研究。但 GPR142 在胰岛中的作用是否仅限于调节胰岛素分泌还不确定。本研究扩展了对其作用的研究。
我们通过原位杂交和免疫染色证明，GPR142 不仅在β细胞中表达，而且在一部分α细胞中也有表达。选择性激动剂刺激 GPR142 可增加人胰岛和鼠胰岛中的胰高血糖素分泌。更重要的是，GPR142 激动剂还通过上调前激素转化酶 1/3 的表达来增强胰高血糖素样肽-1（GLP-1）的产生及其从胰岛中的释放。引人注目的是，通过 GPR142 结合刺激胰岛素分泌和增加胰岛素含量需要完整的 GLP-1 受体信号。此外，GPR142 激动剂增加β细胞增殖并保护鼠和人胰岛免受应激诱导的细胞凋亡。
总之，我们在这里提供的证据表明，α细胞中局部 GLP-1 的释放定义了 GPR142 改善β细胞功能和质量的有益作用，我们提出 GPR142 激动剂可能对治疗 2 型糖尿病具有可转化和持久的疗效。
