Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats
Effects of glucagon-like peptide-1 and exendins on kinase activity, glucose transport and lipid metabolism in adipocytes from normal and type-2 diabetic rats
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DOI：
10.1677/jme.1.01747
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Villanueva-Peñacarrillo, ML
中科院分区：
文献类型：
--
作者：
Sancho, V;Trigo, MV;Villanueva-Peñacarrillo, ML
人和大鼠心肌细胞对胰高血糖素样肽-1(GLP-1)、Exendin-4(Ex-4)和Exendin-9(Ex-9)的代谢反应中涉及多种激酶。我们研究了GLP-1、Ex-4和Ex-9对大鼠脂肪细胞磷脂酰肌醇-3-激酶(PI3K)、蛋白激酶B(PKB)、p42/44 MAP-K(MAPKs)和p70s6K(P70S6K)活性的影响，以及这些酶和蛋白激酶C(PKC)在2-脱氧-(D)-葡萄糖摄取、脂解和脂肪生成中的作用。这项研究是在正常大鼠中进行的，并扩展到链脲佐菌素诱导的2型糖尿病模型(STZ大鼠)。通过使用潜在的激酶抑制剂，包括Wortmannin、PD98059、雷帕霉素、H-7和RO31-8220来评估不同的激酶的参与。在正常大鼠脂肪细胞中，GLP-1和这两种Exendins与胰岛素一样，对所有被研究的激酶(PKB除外)、PI3K、P44和P42MAPK以及可能的PKC的活性都有增强作用，这些都是它们刺激葡萄糖摄取所必需的。EX-4和Ex-9与GLP-1和胰岛素一样具有降脂作用，而只有Ex-4与GLP-1具有相同的降脂作用，而其作用被Ex-9所拮抗。MAP激酶和PKC似乎在GLP-11和Ex-4的脂解作用中起着至关重要的作用，就像PI3K在Ex-4中的作用一样。对于Ex-4、Ex-9和GLP-1的造脂作用，需要增加PI3K和MAPKs的活性，而对于Ex-4和Ex-9，也需要刺激p70S6K的活性。在STZ大鼠的细胞中，上述参数的大小总体上与正常动物相当，但有一些例外：基础PI3K活性和脂肪生成较高，GLP-1、Ex-4和Ex-9不能改变基础脂肪生成但增加PKB活性，胰岛素不影响MAPKs的活性，胰岛素诱导的葡萄糖摄取受到损害。与GLP-1和Exendins不同，胰岛素对STZ大鼠某些变量的影响受损，增加了对GLP-1和Ex-4在糖尿病状态下有益作用的机制的了解。
Several kinases have been implicated in the metabolic response of human and rat myocytes to glucagon-like peptide-1 (GLP-1), exendin-4 (Ex-4) and exendin-9 (Ex-9). We have investigated, in isolated rat adipocytes, the changes caused by GLP-1, Ex-4 and Ex-9 compared with those provoked by insulin or glucagon, upon the activity of phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB), p42/44 MAP kinases (MAPKs) and p70s6 kinase (p70s6k), and the participation of these kinases and protein kinase C (PKC) in their action upon 2-deoxy-(D)-glucose uptake, lipolysis and lipogenesis. The study was conducted in normal rats, and extended to a streptozotocin-induced type-2 diabetic model (STZ-rats). The participation of distinct kinases was estimated by using potential kinase inhibitors, including wortmannin, PD98059, rapamycin, H-7 and RO31-8220. In normal rat adipocytes, GLP-1 and both exendins share with insulin an increasing action upon the activity of all kinases studied (except PKB), PI3K, p44 and p42 MAPKs and possibly PKC, all being required for their stimulating effect upon glucose uptake. Ex-4 and Ex-9, like GLP-1 and insulin, have lipogenic action, while only Ex-4 shares with GLP-1 its lipolytic effect which is antagonized by Ex-9. MAP kinases and PKC seem to have an essential role in the GLP-11 and Ex-4 lipolytic action, as does PI3K in that of Ex-4. An increase in PI3K and MAPKs activity for the lipogenic effect of Ex-4, Ex-9 and GLP-1 are required, and in the case of Ex-4 and Ex-9, a stimulation of p70s6k activity is also needed. In cells from STZ-rats the magnitude of the above parameters was, in general, comparable to that in normal animals, with some exceptions: basal PI3K activity and lipogenesis were higher, GLP-1, Ex-4 and Ex-9 failed to modify basal lipogenesis but increased PKB activity, insulin failed to affect the activity of MAPKs and the insulin-induced glucose uptake was impaired. The impaired insulin effects upon some of the variables in the STZ-rat, distinct from those of GLP-1 and exendins, adds knowledge to the mechanism of the beneficial action of GLP-1 and Ex-4 in diabetic states.