Glucose modifies the cross-talk between insulin and the beta-adrenergic signalling system in vascular smooth muscle cells

Background Abnormalities in the vascular function of insulin are observed i n insulin resistance, and hyperglycaemia is one of the important factors in ducing insulin resistance. Objective To investigate the role of glucose in the interaction of insulin and beta -adrenergic signalling systems in vascular smooth muscle cells (VS MC). Methods After cells were treated with D-glucose (5-25 mmol/l) and insulin ( 100 nmol/l), adenylyl cyclase activity was measured in the presence of isop roterenol, forskolin, and cholera toxin. Assays for insulin-induced activit ies of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-K ) and mitogen-activated protein kinase (MAPK) were performed. Results In the presence of low glucose concentrations (5 mmol/l), insulin e nhanced isoproterenol-, forskolin- and cholera toxin-stimulated adenylyl cy clase activities, This stimulatory effect was abolished by PI3-K inhibitors , wortmannin, or LY294002. In contrast, in the presence of high glucose con centrations (25 mmol/l), insulin attenuated isoproterenol-stimulated activi ty but not cholera toxin- or forskolin-stimulated activity. Insulin-stimula ted activities of IRS-1 and PI3-K, but not MAPK activity, were also attenua ted in the presence of high concentrations of glucose. The MAPK kinase inhi bitor, PD98059, abolished the inhibitory effect of insulin on the beta -adr energic signalling system. Troglitazone and pioglitazone prevented this inh ibitory effect of insulin by restoring IRS-1 and PI3-K activities. Conclusions In the presence of low glucose concentrations, insulin stimulat es the beta -adrenergic signalling system through the IRS-1/PI3-K pathway. However, in the presence of high glucose concentrations, the effect of insu lin is switched to an inhibitory one, through the MAPK pathway. Our finding suggests that high glucose concentrations modify the cross-talk between in sulin and the beta -adrenergic signalling systems in VSMC. J Hypertens 18:1 457-1464 (C) 2000 Lippincott Williams & Wilkins.