Hyperglycemia causes acute vasodilation in healthy adults [13
]. The vasodilation is due to osmotic effects of hyperglycemia since similar changes in FVR occur during mannitol infusion but not during 0.2% saline. The current study indicates that acute hyperglycemia has similar effects in adolescents with type 1 diabetes. The vasodilatory effect of hyperglycemia was demonstrated both by an increase in FBF and a decrease in FVR. The changes in both during hyperglycemia were different from the lack of increase during similar volume infusion (0.9% saline) with maintenance of euglycemia and thus cannot be attributed to volume or continued insulin infusion.
The mechanism for hyperglycemia-induced vasodilation is not clear. One possible mechanism would be increased vascular volume and baroreflex suppression since systolic blood pressure increased during hyperglycemia. Against this hypothesis is that a similar, although not statistically significant, increase occurred during the same time period of the control, euglycemic saline infusion study without changes in FBF or FVR. Also, against this hypothesis is the previous study which showed that hyperglycemia increases, not decreases, sympathetic nerve activity [13
]. Since hyperglycemia increases reactive oxygen species which decrease nitric oxide availability [2
], it is highly unlikely that hyperglycemic vasodilation is endothelially mediated. Thus, further study will be necessary to investigate potential mechanisms.
In contrast to the acute vasodilatory effect of hyperglycemia during constant insulin infusion, we also saw vasodilation with correction of hyperglycemia from baseline to euglycemia during both studies. This is likely due to the vasodilator effect of insulin infusion [17
]. This demonstrates the importance of studying changes in glucose without changes in insulin.
The direct impact of hyperglycemia-induced vasodilation in patients with type 1 diabetes is not certain. One primary area of interest would be its effect on diabetes complications, nephropathy in particular. Specifically, hyperglycemia-mediated decreased vascular resistance may be responsible for increased renal blood flow and increased glomerular filtration rate seen early in diabetic nephropathy [18
]. Additional evidence that hyperglycemia-induced vasodilation plays a role in microvascular complications comes from the fact that hyperglycemia increases retinal blood flow in type 2 diabetes [19
] and that increased retinal blood flow has been associated with more rapid progression of diabetic retinopathy [20
]. In adolescents with type 1 diabetes, hyperglycemia is frequently present postprandially and acute vasodilation caused by these recurrent hyperglycemic episodes may play a long-term role in the microvascular damage that occurs in patients with type 1 diabetes. It is, thus, important to assure that appropriate rapid acting insulin is given before each meal to decrease hyperglycemia induced vascular dysfunction.
The effect of hyperglycemia on endothelial function in our study is unclear. The total postocclusion fall in FVR was less during hyperglycemia but the percent fall in FVR was not different. The smaller absolute postocclusion vasodilatory response during hyperglycemia is most likely due to the increased preocclusion vasodilation and decreased reserve capacity for additional stress-induced vasodilation or, in other words, a ceiling effect in maximal vasodilation. Kawano et al. [14
] previously reported that hyperglycemia decreases brachial artery flow-mediated vasodilation during hyperglycemia in healthy adults and subjects with impaired glucose tolerance and type 2 diabetes. Chittari et al. [19
] confirmed these findings in adults with type 2 diabetes. Neither study reports whether the decrease was due to pre- or postocclusion differences. The current study adds to these two studies in two ways. First, they assessed the flow-mediated increase in brachial artery diameter, a conduit vessel, while the current study measured FBF and FVR and assessed resistance vessel function. Second, since both of these studies used oral glucose tolerance testing to induce hyperglycemia, insulin levels increased at the same time as plasma glucose levels. In the current study hyperglycemia was induced following euglycemic insulin clamp with continued insulin infusion in insulin deficient type 1 diabetes so that insulin levels should not have changed. Thus, the effects seen are clearly due to hyperglycemia and not hyperinsulinemia. In vitro studies, in isolated rat mesenteric arteries confirm that hyperglycemia, directly, impairs the vasodilatory response to acetylcholine [21
]. This finding also indicates that diminution of endothelial function by hyperglycemia extends beyond simply increasing baseline flow.
Multiple past studies have evaluated endothelial function in adolescents with type 1 diabetes [4
]. These studies have consistently demonstrated impaired endothelial function in subjects with type 1 diabetes compared to control subjects [4
]. Unfortunately, since these studies did not control for varying fasting blood glucose levels, the fact that hyperglycemia acutely alters postocclusion responses raises concerns regarding the interpretation of these findings. Future studies comparing endothelial function between subjects with diabetes and controls will need to account for differences in plasma glucose levels. Unfortunately, our results also indicate that this cannot be done simply by acute infusion of insulin since preocclusion FBF was increased and FVR decreased during the euglycemia compared to fasting. This is likely due to the well-established vasodilatory properties of insulin [17
]. This led to a trend toward a decreased reactive hyperemic response during simple euglycemia.
Limitations to this study are the short duration of hyperglycemia and the study of males and females combined. The lack of effects of hyperglycemia on markers of endothelial damage, inflammation or oxidation, may be secondary to the short duration of hyperglycemia in our study. It is possible that more prolonged hyperglycemia may have induced changes in some of these areas. Although gender differences have been found in endothelial function in adults, no differences were apparent in this study.
In conclusion, acute hyperglycemia has profound effects on blood flow, vascular resistance, and endothelial function. These findings have implications for future studies of endothelial function in type 1 diabetes. More importantly, hyperglycemic-induced vasodilation may play a significant role in the development of macrovascular and microvascular complications in patients with type 1 diabetes.