Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, Sweden; Department of Stem Cell Biology, State Research Institute Centre of Innovative Vilnius, Lithuania.
Mol Cell Endocrinol. 2013 Dec 5;381(1-2):150-9. doi: 10.1016/j.mce.2013.07.025. Epub 2013 Aug 2.
The role of islet GPR40 protein in the pathogenesis of diabetes is unclear. We explored the influence of GPR40 protein levels on hormone secretion in islets from two rat models of spontaneous type 2 diabetes displaying either hyperlipidaemia or hyperglycaemia. GPR40 expression was analysed by confocal microscopy, Western blot and qPCR in islets from preobese Zucker (fa/fa) rats, diabetic Goto-Kakizaki (GK) rats, and controls. Confocal microscopy of control islets showed expression of GPR40 protein in insulin, glucagon and somatostatin cells. GPR40 expression was strongly increased in islets of hyperlipidaemic fa/fa rats and coincided with a concentration-related increase in palmitate-induced release of insulin and glucagon and its inhibition of somatostatin release. Conversely, hyperglycaemic GK islets displayed an extremely faint expression of GPR40 as did high-glucose-cultured control islets. This was reflected in abolished palmitate-induced hormone response in GK islets and high-glucose-cultured control islets. The palmitate antagonist rosiglitazone promoted reappearance of GPR40 in high-glucose-cultured islets and served as partial agonist in glucose-stimulated insulin release. GPR40 protein is abundantly expressed in pancreatic islets and modulates stimulated hormone secretion. Mild hyperlipidaemia in obesity-prone diabetes creates increased GPR40 expression and increased risk for an exaggerated palmitate-induced insulin response and lipotoxicity, a metabolic situation suitable for GPR40 antagonist treatment. Chronic hyperglycaemia creates abrogated GPR40 expression and downregulated insulin release, a metabolic situation suitable for GPR40 agonist treatment to avoid glucotoxicity. GPR40 protein is interactively modulated by both free fatty acids and glucose and is a promising target for pharmacotherapy in different variants of type 2 diabetes.
胰岛 GPR40 蛋白在糖尿病发病机制中的作用尚不清楚。我们探讨了 GPR40 蛋白水平对两种自发性 2 型糖尿病大鼠模型（高脂血症或高血糖）胰岛激素分泌的影响。通过共聚焦显微镜、Western blot 和 qPCR 分析肥胖 Zucker（fa/fa）大鼠、糖尿病 Goto-Kakizaki（GK）大鼠和对照组胰岛中的 GPR40 表达。在对照组胰岛的共聚焦显微镜下显示胰岛素、胰高血糖素和生长抑素细胞中存在 GPR40 蛋白表达。高脂血症 fa/fa 大鼠胰岛中 GPR40 表达强烈增加，与棕榈酸诱导的胰岛素和胰高血糖素释放呈浓度相关增加以及对生长抑素释放的抑制作用相一致。相反，高血糖 GK 胰岛显示 GPR40 的表达极其微弱，高葡萄糖培养的对照组胰岛也是如此。这反映在 GK 胰岛和高葡萄糖培养的对照组胰岛中棕榈酸诱导的激素反应被废除。棕榈酸拮抗剂罗格列酮促进高葡萄糖培养的胰岛中 GPR40 的重新出现，并作为葡萄糖刺激的胰岛素释放的部分激动剂。GPR40 蛋白在胰岛中大量表达并调节刺激激素分泌。肥胖倾向糖尿病中的轻度高脂血症会导致 GPR40 表达增加，增加棕榈酸诱导的胰岛素反应和脂毒性的风险增加，这种代谢情况适合 GPR40 拮抗剂治疗。慢性高血糖导致 GPR40 表达被废除和胰岛素释放下调，这种代谢情况适合 GPR40 激动剂治疗以避免糖毒性。游离脂肪酸和葡萄糖可交互调节 GPR40 蛋白，是治疗不同类型 2 型糖尿病的有前途的药物治疗靶点。
