Doenst T, Taegtmeyer H
Department of Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston, USA.
Circ Res. 1999 Mar 5;84(4):467-74. doi: 10.1161/01.res.84.4.467.
We examined whether insulin and catecholamines share common pathways for their stimulating effects on glucose uptake. We perfused isolated working rat hearts with Krebs-Henseleit buffer containing [2-3H]glucose (5 mmol/L, 0.05 microCi/mL) and sodium oleate (0.4 mmol/L). In the absence or presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin (3 micromol/L), we added insulin (1 mU/mL), epinephrine (1 micromol/L), phenylephrine (100 micromol/L) plus propranolol (10 micromol/L, selective alpha-adrenergic stimulation), or isoproterenol (1 micromol/L) plus phentolamine (10 micromol/L, selective beta-adrenergic stimulation) to the perfusate. Cardiac power was found to be stable in all groups (between 8.07+/-0.68 and 10.7+/-0. 88 mW) and increased (25% to 47%) with addition of epinephrine, but not with selective alpha- and beta-adrenergic stimulation. Insulin and epinephrine, as well as selective alpha- and beta-receptor stimulation, increased glucose uptake (the following values are in micromol/[min. g dry weight]: basal, 1.19+/-0.13; insulin, 3.89+/-0.36; epinephrine, 3.46+/-0.27; alpha-stimulation, 4.08+/-0.40; and beta-stimulation, 3.72+/-0.34). Wortmannin completely inhibited insulin-stimulated and selective alpha-stimulated glucose uptake, but it did not affect the epinephrine-stimulated or selective beta-stimulated glucose uptake. Sequential addition of insulin and epinephrine or insulin and alpha-selective stimulation showed additive effects on glucose uptake in both cases. Wortmannin further blocked the effects of insulin on glycogen synthesis. We conclude that alpha-adrenergic stimulation mediates glucose uptake in rat heart through a PI3-K-dependent pathway. However, the additive effects of alpha-adrenergic stimulation and insulin suggest 2 different isoforms of PI3-K, compartmentation of PI3-K, potentiation, or inhibition by wortmannin of another intermediate of the alpha-adrenergic signaling cascade. The stimulating effects of both the alpha- and the beta-adrenergic pathways on glucose uptake are independent of changes in cardiac performance.
我们研究了胰岛素和儿茶酚胺对葡萄糖摄取的刺激作用是否共享共同途径。我们用含有[2-³H]葡萄糖（5 mmol/L，0.05 μCi/mL）和油酸钠（0.4 mmol/L）的 Krebs-Henseleit 缓冲液灌注离体工作大鼠心脏。在不存在或存在磷脂酰肌醇 3-激酶（PI3-K）抑制剂渥曼青霉素（3 μmol/L）的情况下，我们向灌注液中加入胰岛素（1 mU/mL）、肾上腺素（1 μmol/L）、去氧肾上腺素（100 μmol/L）加普萘洛尔（10 μmol/L，选择性α-肾上腺素能刺激）或异丙肾上腺素（1 μmol/L）加酚妥拉明（10 μmol/L，选择性β-肾上腺素能刺激）。发现所有组的心脏功率均稳定（在 8.07±0.68 和 10.7±0.88 mW 之间），加入肾上腺素后心脏功率增加（25%至 47%），但选择性α-和β-肾上腺素能刺激未使其增加。胰岛素和肾上腺素以及选择性α-和β-受体刺激均增加了葡萄糖摄取（以下值以 μmol/[min·g 干重]为单位：基础值，1.19±0.13；胰岛素，3.89±0.36；肾上腺素，3.46±0.27；α-刺激，4.08±0.40；β-刺激，3.72±0.34）。渥曼青霉素完全抑制胰岛素刺激的和选择性α-刺激的葡萄糖摄取，但不影响肾上腺素刺激的或选择性β-刺激的葡萄糖摄取。依次加入胰岛素和肾上腺素或胰岛素和α-选择性刺激在两种情况下对葡萄糖摄取均显示出相加作用。渥曼青霉素进一步阻断了胰岛素对糖原合成的作用。我们得出结论，α-肾上腺素能刺激通过 PI3-K 依赖性途径介导大鼠心脏中的葡萄糖摄取。然而，α-肾上腺素能刺激和胰岛素的相加作用提示存在两种不同的 PI3-K 同工型、PI3-K 的区室化、增强作用或渥曼青霉素对α-肾上腺素能信号级联反应的另一种中间体的抑制作用。α-和β-肾上腺素能途径对葡萄糖摄取的刺激作用均与心脏功能的变化无关。
