oa Mimicking A Postprandial Increase In Glucose Has A Biphasic Action On Microvascular Function

Background and Objectives: The high morbidity and mortality associated with both type 1 and type 2 diabetes are closely associated with an elevated incidence of cardiovascular disease. The importance of good glycaemic control for the reduction of risk, notably of microvascular disease, has been emphasised by the results from clinical trials such as the DCCT for type 1 diabetes and UKPDS for type 2 diabetes. Data from clinical studies also indicate that an oral glucose load results in a reduction in the forearm flow-mediated dilatation (FMD) that coordinates and sustains local blood flow. The reduction was greater and more prolonged in patients with diabetes, probably reflecting uncoupling of endothelial nitric oxide synthase secondary to glucose metabolism and elevated oxidative stress. These data suggested that the hyperglycaemia associated with poor glycaemic control may reduce blood flow as a result of an endothelium-dependent reduction in FMD. However, the mechanisms whereby glucose may alter this and other aspects of microvascular function are unknown. In the current study, we designed protocols that allowed us acutely to change glucose concentration and compare endothelium-dependent and endothelium-independent vasodilation in mouse and rat microvessels from the mesenteric and gracilis circulation. Methods: Small mesenteric and rat gracilis arteries with resting lumen diameters of approximately 200-250 µm and 110-120 µm were used in the study. The vessels were mounted in a pressure myograph, pressurised to 60 mmHg and endothelium-dependent vasodilatation (EDV) was assessed against agonist-mediated or myogenic tone. EDV was compared under normoglycaemic (11.0 mM for mouse and 5.5 mM for rat) versus hyperglycaemic conditions (25 or 40 mM - as based on rodent models of diabetes) with mannitol used as the osmotic control. Results: A short (10-15 minute) exposure to hyperglycaemia increased EDV in gracilis but reduced EDV in mesenteric arteries, whereas after 60-120 minutes EDV was reduced in both tissues, as indicated by both a reduced maximal response (EMAX) and reduced sensitivity (EC50) to agonist. Further analysis revealed that a 60-minute exposure to hyperglycaemia reduced both nitric oxide and non-nitric oxide-mediated EDV. Conclusion: These data indicate that an increase in glucose concentration has a biphasic effect on EDV and hence blood flow. Further studies are underway to determine the cellular mechanisms involved as well as the long-term effects hyperglycaemia on the regulation of microvascular function. Supported by NPRP 4-910-3-244