Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy.
Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy.
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DOI：
10.1161/circheartfailure.109.900282
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Shannon RP
中科院分区：
文献类型：
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作者：
Bhashyam S;Fields AV;Patterson B;Testani JM;Chen L;Shen YT;Shannon RP
我们已经证明，胰高血糖素样肽-1（GLP-1 [7-36]酰胺）刺激扩张型心肌病（DCM）心肌葡萄糖摄取，与促胰岛素作用无关。GLP-1诱导心肌葡萄糖摄取的细胞机制尚不清楚。在对照组（n=6）、DCM组（n=9）和输注GLP-1酰胺（n = 9）或溶剂（Veh，n=6）48小时后DCM组中，在清醒、长期使用仪器的犬中测量心肌底物和葡萄糖调节激素。在从四组中采集的肌膜中测量了GLP-1受体和涉及心肌葡萄糖摄取（MGU）的细胞通路。GLP-1刺激的MGU（DCM：20±7; DCM+GLP-1：61±12 nmol/min/g，p=0.001）与血浆胰岛素水平升高无关。GLP-1受体在肌膜中上调（Con：98±2; DCM：256±58 DU，p=0.046），并在DCM中以其活化（65 kDa）形式表达。GLP-1诱导的MGU增加不涉及腺苷酸环化酶或Akt激活，但与p38α MAP激酶活性的显著增加相关（DCM + Veh：97±22 DCM+GLP-1：170±36 pmol ATP/mg/min，p=0.051），诱导一氧化氮合酶2（NOS 2）（DCM +Veh：151±13; DCM+GLP-1：306±12 DU，p=0.001）和GLUT-1易位（DCM+Veh：21±3%; DCM+GLP-1：39±3%膜结合，p=0.005）。GLP-1对MGU的作用可被p38α MAP激酶抑制剂或非特异性NOS抑制剂硝基-L-精氨酸阻断。GLP-1通过非Akt-1依赖性机制刺激心肌葡萄糖摄取，激活细胞通路，这些通路在介导慢性冬眠和缺血预处理的晚期阶段中已被确定。
We have shown that glucagon-like peptide-1 (GLP-1 [7–36] amide), stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1 induced myocardial glucose uptake are unknown. Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at Control (n=6), DCM (n=9), and DCM following treatment with a 48-hour infusion of GLP-1 amide (n=9) or vehicle (Veh, n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake (MGU) were measured in sarcolemmal membranes harvested from the four groups. GLP-1 stimulated MGU (DCM: 20±7; DCM+GLP-1: 61±12 nmol/min/g, p=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were up-regulated in the sarcolemmal membranes (Con: 98±2; DCM: 256±58 DU, p=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1 induced increases in MGU did not involve adenylyl cyclase or Akt activation, but was associated with marked increases in p38α MAP kinase activity (DCM + Veh: 97±22 DCM+GLP-1: 170±36 pmol ATP/mg/min, p=0.051), induction of nitric oxide synthase 2 (NOS2) (DCM +Veh: 151±13; DCM+GLP-1: 306±12 DU, p=0.001), and GLUT-1 translocation (DCM+Veh: 21±3%; DCM+GLP-1: 39±3% membrane bound, p=0.005). The effects of GLP-1 on MGU were blocked by pretreatment with the p38α MAP kinase inhibitor or non-specific NOS inhibitor, nitro-L-arginine. GLP-1 stimulates myocardial glucose uptake through a non Akt-1 dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic pre-conditioning.