Open Access Open Badges Original investigation

Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Sefaa Al-aryahi1, Danielle Kamato1, Robel Getachew1, Wenhua Zheng2, Simon J Potocnik3, Neale Cohen4, Daniel Guidone1, Narin Osman15 and Peter J Little15*

Author Affiliations

1 Discipline of Pharmacy and Diabetes Complications Group, Health Innovations Research Institute, School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia

2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

3 Discipline of Cell Biology and Anatomy, School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Australia

4 Diabetes Clinical Services, BakerIDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia

5 Departments of Medicine, Nursing and Health Sciences and Immunology, Monash University School of Medicine (Central and Eastern Clinical School, Alfred Health), Prahran, VIC 3004, Australia

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Cardiovascular Diabetology 2014, 13:80  doi:10.1186/1475-2840-13-80

Published: 15 April 2014



Pharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases. Some anti-hyperglycaemic drugs have been found to have adverse cardiovascular effects in their own right, limiting their therapeutic role. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Glucokinase activators (GKAs) are novel agents for diabetes which act by enhancing the formation of glucose-6-phosphate leading to increased insulin production and subsequent suppression of blood glucose. Little, however, is known about the direct effects of GKAs on cardiovascular cells.


The effect of the GKAs RO28-1675 and Compound A on glucose utilisation in bovine aortic endothelial cells (BAEC) and rat MIN6 was observed by culturing the cells at high and low glucose concentration in the presence and absence of the GKAs and measuring glucose consumption. The effect of RO28-1675 at various concentrations on glucose-dependent signalling in BAEC was observed by measuring Smad2 phosphorylation by Western blotting. The effect of RO28-1675 on TGF-β stimulated proteoglycan synthesis was measured by 35S-SO4 incorporation and assessment of proteoglycan size by SDS-PAGE. The effects of RO28-1675 on TGF-β mediated Smad2C phosphorylation in BAEC was observed by measurement of pSmad2C levels. The direct actions of RO28-1675 on vascular reactivity were observed by measuring arteriole tone and lumen diameter.


GKAs were demonstrated to increase glucose utilisation in pancreatic but not endothelial cells. Glucose-activated Smad2 phosphorylation was decreased in a dose-dependent fashion in the presence of RO28-1675. No effect of RO28-1675 was observed on TGF-β stimulated proteoglycan production. RO28-1675 caused a modest dilation in arteriole but not contractile sensitivity.


GKA RO28-1675 did not increase glucose consumption in endothelial cells indicating the absence of glucokinase in those cells. No direct deleterious actions, in terms of atherogenic changes or excessive vasoactive effects were seen on cells or vessels of the cardiovascular system in response to GKAs. If reflected in vivo, these drugs are unlikely to have their use compromised by direct cardiovascular toxicity.

Transforming growth factor beta; Smads; Diabetes; Pleiotropic actions