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Rosiglitazone reverses insulin secretion altered by chronic exposure to free fatty acid via IRS-2-associated phosphatidylinositol 3-kinase pathway.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2003-05-13
Li Yang 1 , Han-Xiang An , Xiu-Ling Deng , Lu-Lu Chen , Zhuo-Ya Li
Affiliation  

AIM To study the effect of rosiglitazone (RSG) on insulin secretion in isolated pancreatic islets under chronic exposure to free fatty acid (FFA) and to investigate the potential signaling mechanism of RSG action. METHODS Rat pancreatic islets were cultured with or without FFA (2 mmol/L, oleate:palmitate, 2:1) in the presence or absence of RSG (0.05-10 micromol/L). The insulin release was measured by radioimmuoassay, the expression level of insulin receptor substrate-2 (IRS-2) protein and the association of IRS-2 with p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) were determined by immunoprecipitation and Western blot. RESULTS The islets exposed to high FFA concentration showed an increased basal and a decreased glucose-induced insulin release as compared with control islets (P<0.01). IRS-2 protein level was decreased by 65 % (P<0.01) and the association of IRS-2 with p85 subunit of PI 3-kinase and was decreased by 73 % (P<0.01). When islets were cultured with FFA in the presence of RSG 5 micromol/L, both basal and glucose-induced insulin secretion were reversed to a pattern of control islets (P<0.01, P<0.05). The addition of RSG in the cultured medium increased significantly the expression of IRS-2 protein by 2.6 fold (P<0.01) and the association of IRS-2 with p85 by 2.7-fold (P<0.01) as compared with islets incubated with FFA alone. The effects of RSG on insulin secretion were blocked by a PI 3-kinase inhibitor, wortmannin. CONCLUSION The effects of RSG on insulin secretion could be mediated through an IRS-2-associated PI 3-kinase signaling pathway.

中文翻译:

罗格列酮逆转了胰岛素分泌,该胰岛素分泌是通过与IRS-2相关的磷脂酰肌醇3激酶途径长期暴露于游离脂肪酸而改变的。

目的研究罗格列酮(RSG)对慢性暴露于游离脂肪酸(FFA)下胰岛胰岛胰岛素分泌的影响,并探讨其潜在的信号传导机制。方法在有或没有RSG(0.05-10μmol/ L)的条件下,在有或没有FFA(2 mmol / L,油酸盐:棕榈酸盐,2:1)的条件下培养大鼠胰岛。通过放射免疫法测定胰岛素的释放,通过免疫沉淀和Western blot检测胰岛素受体底物2(IRS-2)蛋白的表达水平以及IRS-2与磷脂酰肌醇3-激酶(PI 3-激酶)的p85亚基的关系。污点。结果与对照胰岛相比,暴露于高FFA浓度的胰岛显示出基础的增加和葡萄糖诱导的胰岛素释放的减少(P <0.01)。IRS-2蛋白水平降低了65%(P <0.01),IRS-2与PI 3-激酶p85亚基的相关性降低了73%(P <0.01)。当在RSG 5 micromol / L存在下用FFA培养胰岛时,基础和葡萄糖诱导的胰岛素分泌均反转为对照胰岛的模式(P <0.01,P <0.05)。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。01)和IRS-2与PI 3-激酶p85亚基的相关性降低了73%(P <0.01)。当在RSG 5 micromol / L存在下用FFA培养胰岛时,基础和葡萄糖诱导的胰岛素分泌均反转为对照胰岛的模式(P <0.01,P <0.05)。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RSG对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。01)和IRS-2与PI 3-激酶p85亚基的相关性降低了73%(P <0.01)。当在RSG 5 micromol / L存在下用FFA培养胰岛时,基础和葡萄糖诱导的胰岛素分泌均反转为对照胰岛的模式(P <0.01,P <0.05)。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。当在RSG 5 micromol / L存在下用FFA培养胰岛时,基础和葡萄糖诱导的胰岛素分泌均反转为对照胰岛的模式(P <0.01,P <0.05)。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。当在RSG 5 micromol / L存在下用FFA培养胰岛时,基础和葡萄糖诱导的胰岛素分泌均反转为对照胰岛的模式(P <0.01,P <0.05)。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。与用FFA孵育的胰岛相比,在培养基中添加RSG可使IRS-2蛋白的表达显着增加2.6倍(P <0.01),并使IRS-2与p85的缔合增加2.7倍(P <0.01)。单独。RS 3对胰岛素分泌的作用被PI 3-激酶抑制剂wortmannin阻断。结论RSG对胰岛素分泌的影响可以通过IRS-2相关的PI 3激酶信号通路来介导。
更新日期:2019-11-01
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