Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada.
Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences, University of California Davis, Davis, CA, USA.
Mol Metab. 2021 Mar;45:101166. doi: 10.1016/j.molmet.2021.101166. Epub 2021 Jan 20.
Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.
Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.
Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.
Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.
维持血糖稳态需要内分泌胰腺激素分泌的精确调节。游离脂肪酸受体 4（FFAR4/GPR120）是一种 G 蛋白偶联受体，其在胰岛中的激活促进胰岛素和胰高血糖素的分泌并抑制生长抑素的分泌。然而，单个胰岛细胞类型（α、β 和 δ 细胞）对 GPR120 胰岛素促分泌和胰高血糖素促分泌作用的贡献尚不清楚。由于 gpr120 mRNA 在分泌生长抑素的 δ 细胞中丰富，我们假设 GPR120 激活通过抑制生长抑素释放来刺激胰岛素和胰高血糖素的分泌。
在给予选择性 GPR120 激动剂化合物 A 后，在小鼠中进行葡萄糖耐量试验。在对分离的小鼠胰岛进行的静态孵育中，测量内源性（ω-3 多不饱和脂肪酸）和/或药理学（化合物 A 和 AZ-13581837）GPR120 激动剂对胰岛素、胰高血糖素和生长抑素分泌的影响。在具有 gpr120 全局或特异性 somatostatin 细胞敲除的小鼠中进一步测试化合物 A 对激素分泌的影响。通过 RNA 原位杂交在胰腺切片中评估 Gpr120 的表达。使用 cAMPER 和 GCaMP6 报告小鼠分别在完整胰岛中测量对药理学 GPR120 激动剂的 cAMP 和钙动力学的反应，以特异性测量 α、β 和 δ 细胞中的反应。
急性暴露于化合物 A 可增加体内葡萄糖耐量、循环胰岛素和胰高血糖素水平。内源性和/或药理学 GPR120 激动剂可减少分离胰岛中的生长抑素分泌，并同时表现出葡萄糖刺激的胰岛素分泌和精氨酸刺激的胰高血糖素分泌的剂量依赖性增强。Gpr120 在 δ 细胞中丰富。药理学 GPR120 激动剂降低了 δ 细胞中的 cAMP 和钙水平，但增加了 α 和 β 细胞中的这些信号。化合物 A 介导的生长抑素分泌抑制对百日咳毒素不敏感。在具有 gpr120 全局或特异性 somatostatin 细胞缺失的小鼠的胰岛中，化合物 A 对激素分泌的作用完全缺失，并且在 somatostatin 受体信号被环 somatostatin 阻断时部分降低。
δ 细胞中抑制性 GPR120 信号传导部分通过减轻生长抑素释放来促进胰岛素和胰高血糖素的分泌。
