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 in insulin resistance, and hyperglycaemia is one of the important factors inducing insulin resistance.


OBJECTIVE
To investigate the role of glucose in the interaction of insulin and beta-adrenergic signalling systems in vascular smooth muscle cells (VSMC).


METHODS
After cells were treated with D-glucose (525 mmol/l) and insulin (100 nmol/l), adenylyl cyclase activity was measured in the presence of isoproterenol, forskolin, and cholera toxin. Assays for insulin-induced activities 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 enhanced isoproterenol-, forskolin- and cholera toxin-stimulated adenylyl cyclase activities. This stimulatory effect was abolished by PI3-K inhibitors, wortmannin, or LY294002. In contrast, in the presence of high glucose concentrations (25 mmol/l), insulin attenuated isoproterenol-stimulated activity but not cholera toxin- or forskolin-stimulated activity. Insulin-stimulated activities of IRS-1 and PI3-K, but not MAPK activity, were also attenuated in the presence of high concentrations of glucose. The MAPK kinase inhibitor, PD98059, abolished the inhibitory effect of insulin on the beta-adrenergic signalling system. Troglitazone and pioglitazone prevented this inhibitory effect of insulin by restoring IRS-1 and PI3-K activities.


CONCLUSIONS
In the presence of low glucose concentrations, insulin stimulates the beta-adrenergic signalling system through the IRS-1/PI3-K pathway. However, in the presence of high glucose concentrations, the effect of insulin is switched to an inhibitory one, through the MAPK pathway. Our finding suggests that high glucose concentrations modify the cross-talk between insulin and the beta-adrenergic signalling systems in VSMC.
Kawabe
J
J
Department of Medicine, University of Medicine & Dentistry of New Jersey, Newark 07103-2714, USA. jkawabe1@att.net
Aizawa
Y
Y
Takehara
N
N
Hasebe
N
N
Kikuchi
K
K
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007545:Isoproterenol / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011943:Receptors, Adrenergic, beta; D013844:Thiazoles; D045162:Thiazolidinediones; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D005947:Glucose; D007545:Isoproterenol