title: Diabetes and the maternal resistance vasculature
Creators: name: Ang, Christine W.M.
Publisher: name: University of Glasgow
Year: 2001
Subjects: subject: Medicine, obstetrics, pregnancy, diabetes.

description: Diabetes is the most common endocrine disorder worldwide with complications that include the development of both macro- and micro-vascular disease contributing significantly to patient morbidity and mortality. The severity of diabetic complications is thought to be amplified during pregnancy, resulting in a higher incidence of adverse pregnancy outcomes such as pre-eclampsia, placental insufficiency and stillbirth. Vascular dysfunction is thought to underlie many of these complications with the greatest effect taking place at the level of the resistance vasculature, where even small alterations in vascular reactivity can significantly modify blood flow and tissue perfusion. It is likely that problems associated with diabetic pregnancies are related, in part, to abnormal vascular function particularly dysfunction of the vascular endothelium. Healthy pregnant women develop progressive insulin resistance and hyperinsulinaemia as a result of physiological changes in carbohydrate metabolism. Although pathological insulin resistant conditions such as type 2 diabetes and obesity are associated with abnormal vascular function, similar changes may not be demonstrable in the physiological insulin resistance of normal pregnancy. The published literature on the vascular effects in pregnancy and diabetes has been extensively reviewed, with emphasis on how modifications in the synthesis, release and action of endogenous vasoactive substances may contribute to clinically demonstrable pathology. The varying effects of diabetes on different vascular beds, in terms of both vessel size and location, reflecting the complexity of disease development has been well documented. However, the effect of pregnancy superimposed on pre-existing type 1 diabetes has never been fully explored. Questions still persist regarding the importance of insulin itself as a direct vasodilator, its mechanism of action, and how this may alter in the insulin-resistant state of pregnancy. There has been little published literature on vascular function in pregnant women with type 1 diabetes mellitus, yet a greater understanding of the role of endothelium-dependent factors involved in the control of vascular tone is important in both healthy and diabetic pregnancies, since they are generally considered to be altered in comparison with non-pregnant subjects. The importance of endothelium-dependent hyperpolarization in human subcutaneous resistance arteries has never been investigated in either diabetes or pregnancy, while the implicit importance of endothelin-1 in these conditions requires further investigation. This thesis has examined these questions and has produced evidence that, in some cases, supports the consensus and, in others, offers new insight. Those mechanisms most likely to be important in the control of vascular function in pregnancy have been examined here using small vessel wire myography, a laboratory-based in vitro technique that allows the study of isolated small resistance arteries. The direct vasodilator effect of insulin was investigated (Chapter 3) providing the first demonstration of an endothelium-independent, insulin-mediated attenuation of vascular tone in healthy pregnancy. The role of the vascular endothelium in pregnant women with and without diabetes was also examined, with particular emphasis on endothelium-dependent relaxing factors. These data provide the first confirmation that pregnant women with type 1 diabetes mellitus do not demonstrate impaired endothelial function generally considered to be a correlate of the diabetic condition, and goes on to provide some support that, in this study sample at least, this may reflect the level of glycaemic control (Chapter 4). Furthermore, the study shows that a non-nitric oxide-dependent endothelial hyperpolarization, and not nitric oxide per se, contributes largely to endothelium-dependent relaxation in subcutaneous resistance arteries obtained from pregnant women whether diabetes is present or not (Chapter 4). These observations clearly point to the perturbation of different aspects of endothelin-dependent vasoconstriction mechanisms being associated with pregnancy and diabetes (Chapter 5). Another aspect of metabolic control that is sensitive to both pregnancy and diabetes is lipid metabolism. This thesis provides important insight into the interactions between diabetes and pregnancy and points to those areas where further insight and studies are required.