Abstract
BackgroundPharmaceutical 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.MethodsThe 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.ResultsGKAs 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.ConclusionsGKA 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.
Highlights
Pharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases
Transforming growth factor beta (TGF-β) stimulation of the synthesis of the lipid-binding proteoglycan, biglycan, and the elongation of the GAG chains on biglycan represents one component of an in vitro model of atherogenesis because increased GAG chains have enhanced signalling for atherogenic lipoproteins; in this model, RO128-1675 had no effects on TGF-β stimulated biglycan synthesis even at the highest concentration tested (10 μM) so we would conclude that Glucokinase activators (GKAs) are silent in this assay in contrast for example to glitazones which are anti-atherogenic [46]
Our results showed that TGF-β increased proteoglycan synthesis, GAG elongation but the GKA had no effect on radiolabeled sulfate incorporation into proteoglycans and does not play a role in TGF-β mediated GAG elongation in Bovine aortic endothelial cells (BAECs)
Summary
Pharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases. 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. The defining metabolic parameters of Type 2 diabetes are insulin resistance and pancreatic beta cell failure and they are associated with increased rates of cardiovascular disease [3,4,5]. The rapid increase in the occurrence of obesity-related Type 2 diabetes commenced in the early 1980s [6] This event was not fully appreciated by the pharmaceutical industry which in the relevant period and area was concentrating on the development of anti-hypertensive agents; there was a large gap in the discovery and introduction of new classes of drugs for the treatment of hyperglycemia. The cardiovascular risk associated with these effects warrants investigation notwithstanding that it must be appreciated that there is currently no GKA in current clinical use
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