α-Adrenergic stimulation mediates glucose uptake through phosphatidylinositol 3-kinase in rat heart

Abstract

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 μCi/mL) and sodium oleate (0.4 mmol/L). In the absence or presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin (3 μmol/L), we added insulin (1 mU/mL), epinephrine (1 μmol/L), phenylephrine (100 μmol/L) plus propranolol (10 μmol/L, selective α-adrenergic stimulation), or isoproterenol (1 μmol/L) plus phentolamine (10 μmol/L, selective β- 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 α- and β- adrenergic stimulation. Insulin and epinephrine, as well as selective α- and β-receptor stimulation, increased glucose uptake (the following values are in μmol/[min · g dry weight]: basal, 1.19 ± 0.13; insulin, 3.89 ± 0.36; epinephrine, 3.46 ± 0.27; α-stimulation, 4.08 ± 0.40; and β-stimulation, 3.72 ± 0.34). Wortmannin completely inhibited insulin-stimulated and selective α-stimulated glucose uptake, but it did riot affect the epinephrine-stimulated or selective β-stimulated glucose uptake. Sequential addition of insulin and epinephrine or insulin and α-selective stimulation showed additive effects on glucose uptake in both cases. Wortmannin further blocked the effects of insulin on glycogen synthesis. We conclude that α- adrenergic stimulation mediates glucose uptake in rat heart through a PI3-K- dependent pathway. However, the additive effects of α-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 α-adrenergic signaling cascade. The stimulating effects of both the α- and the β-adrenergic pathways on glucose uptake are independent of changes in cardiac performance.