Acute effects of glucose and insulin on vascular endothelium

Abstract

Aims/hypothesis. Chronic exposure to high concentrations of glucose has consistently been demonstrated to impair endothelium-dependent, nitric oxide (NO)-mediated vasodilation. In contrast, several clinical investigations have reported that acute exposure to high glucose, alone or in combination with insulin, triggers vasodilation. The aim of this study was to examine whether elevated glucose itself stimulates endothelial NO formation or enhances insulin-mediated endothelial NO release. Methods. We measured NO release and vessel tone ex vivo in porcine coronary conduit arteries (PCAs). Intracellular Ca 2+ was monitored in porcine aortic endothelial cells (PAECs) by fura-2 fluorescence. Expression of the Na + /glucose cotransporter-1 (SGLT-1) was assayed in PAECs and PCA endothelium by RT-PCR. Results. Stimulation of PCAs with D-glucose, but not the osmotic control L-glucose, induced a transient increase in NO release (EC 50 ≈10 mmol/l), mediated by a rise in intracellular Ca 2+ levels due to an influx from the extracellular space. This effect was abolished by inhibitors of the plasmalemmal Na + /Ca 2+ exchanger (dichlorobenzamil) and the SGLT-1 (phlorizin), which was found to be expressed in aortic and coronary endothelium. Alone, D-glucose did not relax PCA, but did augment the effect of insulin on NO release and vasodilation. Conclusions/interpretation. An increased supply of extracellular D-glucose appears to enhance the activity of the endothelial isoform of nitric oxide synthase by increasing intracellular Na + concentrations via SGLT-1, which in turn stimulates an extracellular Ca 2+ influx through the Na + /Ca 2+ exchanger. This mechanism may be responsible for glucose-enhanced, insulin-dependent increases in tissue perfusion (including coronary blood-flow), thus accelerating glucose extraction from the blood circulation to limit the adverse vascular effects of prolonged hyperglycaemia.

Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?

“…The same group, however, failed to show changes in BAECs after a 24-h exposure to high glucose (Kaiser et al 1993). Taubert et al (2004) demonstrated that, in a study with passage 2 porcine aortic endothelial cells, 20 mmol/L Dglucose, but not L-glucose, induced an increase in intracellular calcium and a transient release of NO that was inhibited by either the sodium/calcium exchange (NCX) inhibitor, dichlorobenzamil, or the SGLT-1 inhibitor, phlorizin. D-glucose also augmented the vasodilator action of insulin and enhanced insulin-induced relaxation of porcine artery ring preparations as well as insulin-mediated NO response in porcine aortic endothelial cells; interestingly prolonged exposure to 25 mmol/L D-glucose resulted in a progressive loss of NO release and after 2 h complete inhibition (Taubert et al 2004).…”

“…Increased production of hydrogen peroxide in endothelial cells will also increase PKC activity (Taher et al 1993) and this will lead to a decrease in eNOS activity via PKC-mediated phosphorylation of eNOS specifically at Thr497 (Matsubara et al 2003). However, as already noted, in vivo the contribution of both endothelial and platelet eNOS activation by glucose must be considered (Massucco et al 2005;Taubert et al 2004).…”

“…BH 4 also increases insulin sensitivity in patients with type 2 diabetes (Nystrom et al 2004). Indeed, in pro-oxidant states where an uncoupled eNOS is favoured, the glucose-mediated activation of endothelial and platelet eNOS described by Taubert et al (2004) and Massucco et al (2005), respectively, will lead to the generation of superoxide rather than NO. Thus, a scenario can be envisaged in which postprandial glucose produces reversible ED in normal subjects but the progressive development of ED in vulnerable individuals.…”

“…For example, high local levels of glucose have a vasodilator effect on resistance vessels in skeletal muscle of the forearm that is not modified by local hyperinsulinaemia (van Veen et al 1999). Enhanced blood flow that results from an increase in plasma glucose may be in part due to a glucose-mediated activation of endothelial eNOS (Taubert et al 2004) and in part by, possibly via an osmotic action, activation of platelet eNOS (Massucco et al 2005). Cipolla et al (1997) studied the effects of increasing extracellular glucose (up to 44 mmol/L) on basal tone and myogenic activity in isolated rat cerebral arteries and reported an NO-mediated vasodilator action of glucose that was inhibited by endothelium removal or by the NOS inhibitor, L-NNA with indomethacin having a marginal inhibitory action.…”

Survival Benefits of Intensive Insulin Therapy in Critical Illness

“…For both hyperglycemic groups, we selected target glycemia of 250 -350 mg/dl, because this level is in the range commonly chosen by other authors in experimental (17)(18)(19)(20)(21) and clinical studies (6,22). Thus, these levels allow us to compare our results with those from previous clinical and experimental studies.…”