Rapid 'glycaemic swings' induce nitrosative stress, activate poly(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus

Postpandrial hyperglycaemia is a significant risk factor for the development of macrovascular diseases. There is no clear agreement in the field whether these alterations result from hyperglycaemic episodes or from exaggerated alterations ('glycaemic swings') in blood glucose. We compared the effect of stable high glucose with a model of poorly maintained insulin-controlled diabetes (on average lower glucose, but with large glycaemic swings) on the development of endothelial dysfunction in rats. Intermediate- or long-acting insulin was used to reduce mean blood glucose levels. One group of animals had stable low glucose levels, while animals in the other group exhibited rapid changes ('swings') in their blood glucose concentration. Acetylcholine-induced endothelium-dependent vascular relaxation of the thoracic aorta was measured. Immunohistochemistry, western blot analysis and flow cytometry were used to determine nitrotyrosine formation and poly(ADP-ribose) accumulation in the aorta, in circulating leucocytes and in bone marrow cells. Steady normalisation of blood glucose levels (a model of well-controlled diabetes) protected against the development of endothelial dysfunction, poly(ADP-ribose) polymerase (PARP) activation and nitrotyrosine production. However, impairment of endothelium-dependent relaxation was found in the animals undergoing glycaemic swings, even though the fructosamine levels in these animals were lower than in the untreated diabetic rats. This was associated with elevated PARP activation in the aorta and in bone marrow cells that was similar to or even more pronounced than that seen in the untreated diabetic animals. Large glycaemic swings exert deleterious cardiovascular effects in diabetes mellitus, in part via enhanced activation of the PARP pathway.