GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats
GPR40 protein levels are crucial to the regulation of stimulated hormone secretion in pancreatic islets. Lessons from spontaneous obesity-prone and non-obese type 2 diabetes in rats
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DOI：
10.1016/j.mce.2013.07.025
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发表时间：
2013-12-05
影响因子：
4.1
通讯作者：
Salehi, Albert
中科院分区：
文献类型：
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作者：
Abaraviciene, Sandra Meidute;Muhammed, Sarheed J.;Salehi, Albert
胰岛GPR 40蛋白在糖尿病发病机制中的作用尚不清楚。我们探讨了GPR 40蛋白水平对自发性2型糖尿病大鼠模型胰岛激素分泌的影响。通过共聚焦显微镜、Western blot和qPCR分析了肥胖前Zucker（fa/fa）大鼠、糖尿病Goto-Kakizaki（GK）大鼠和对照组胰岛中GPR 40蛋白的表达。胰高血糖素和生长抑素细胞。GPR 40的表达强烈增加，胰岛的糖尿病fa/fa大鼠和棕榈酸诱导的胰岛素和胰高血糖素的释放和抑制生长抑素释放的浓度相关的增加相一致。相反，高血糖GK胰岛显示极微弱的GPR 40表达，高糖培养的对照胰岛也是如此。这反映在GK胰岛和高糖培养的对照胰岛中棕榈酸诱导的激素反应被取消。棕榈酸酯拮抗剂罗格列酮可促进高糖培养的胰岛中GPR 40的重现，并在葡萄糖刺激的胰岛素释放中起部分激动剂的作用; GPR 40蛋白在胰岛中大量表达，并调节刺激的激素分泌。肥胖倾向性糖尿病中的轻度糖皮质激素血症导致GPR 40表达增加，并增加棕榈酸酯诱导的胰岛素反应和脂毒性的风险，这是一种适合GPR 40拮抗剂治疗的代谢情况。慢性高血糖症产生废除的GPR 40表达和下调的胰岛素释放，适合于GPR 40激动剂治疗以避免葡萄糖毒性的代谢情况。GPR 40蛋白受游离脂肪酸和葡萄糖的相互调节，是2型糖尿病不同变体药物治疗的有前途的靶点。(C)2013爱思唯尔爱尔兰有限公司版权所有。
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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.