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Vascular endothelial dysfunction in Type 2 Diabetes - Prenatal causes and effect of ACE-inhibition

Thomas S. Hermann

Summary

This PhD-thesis is based on the conclusions from studies of human vascular function, which are published in paper 1 and 2. The studies are performed from March 2001 to March 2004.

Background:
The incidence of type 2 diabetes is increasing in the western world. Patients with type 2 diabetes have a two to six fold increased risk of cardiovascular disease, which can by reduced with intensive medical treatment. Several factors are involved in the pathogenesis of type 2 diabetes. Over the past decade there has been growing attention on the impact of prenatal life and low birth weight on diabetes risk. Subjects with low birth weight may have early defects in insulin action and simultaneously endothelial dysfunction, which can lead to atherosclerosis and cardiovascular disease. Patients with type 2 diabetes have endothelial dysfunction and impaired insulin-stimulated endothelial function, both which can be improved by hypoglycaemic treatment. The renin-angiotensin system has gained increased attention, as inhibition of angiotensin converting enzyme prevents the development and the progression of diabetic nephropathy and cardiovascular disease. The beneficial effects on the clinical outcome of these serious conditions may be explained by improved endothelial function. The purpose of this thesis was to 1) Examine whether subjects with birth weight below the 10th percentile had simultaneously endothelial dysfunction, impaired insulin-stimulated endothelial function and impaired insulin-stimulated forearm glucose uptake (study I). 2) Investigate whether endothelial function, insulin-stimulated endothelial function and glucose uptake was ameliorated by angiotensin converting enzyme (ACE) inhibition in patients affected by type 2 diabetes (study II).

Methods:
In the low birth weight study, 14 subjects with low birth weight and 16 matched subjects with normal birth weight subjects were included. The study subjects had previously undergone examination of whole body glucose metabolism. Blood flow was measured by venous occlusion plethysmography. Endothelium-dependent vasodilation was stimulated by the infusion of acetylcholine. Endothelium-independent vasodilation was assessed by infusion of sodium nitroprusside (SNP). The degree of NO-dependent vasodilation was assessed by infusion of LNMMA, a competitive antagonist of endothelial nitric oxide synthase (eNOS). Insulin-stimulated endothelial function and insulin-stimulated glucose uptake was assessed by intra-arterial infusion of
insulin for 20 minutes in a rate of 0.05 mU/kg body weight/min. Insulin-stimulated glucose uptake was calculated by the product of blood flow and the arterio-venous glucose difference. In the study of quinapril and endothelial function, 24 patients with type 2 diabetes and 15 age matched healthy controls were studied. Blood flow was measured by venous occlusion plethysmography.
Endothelium-dependent vasodilation was stimulated by the infusion of serotonin. Endotheliumindependent vasodilation was assessed by infusion of sodium nitroprusside (SNP). The degree of NO-dependent vasodilation during agonist-stimulated vasodilation was assessed by infusion of LNMMA.Insulin-stimulated endothelial function and insulin-stimulated glucose uptake was assessed by intra-arterial infusion of insulin for sixty minutes in the rate of 0.05 mU/kg body weight/min. Insulin-stimulated forearm glucose uptake was calculated. A standard oral glucose tolerance test (75g glucose) was performed before and after treatment. Gene expression of adiponectin was measured in vascular and adipose samples by real-time polymerase chain reaction (PCR).
Results: In the study of low birth weight subjects no difference was seen in endothelial function or insulin-stimulated endothelial function between the groups, while insulin-stimulated forearm glucose uptake was significant lower in the low birth weight group. In the quinapril study, patients with type 2 diabetes both had endothelial dysfunction and impaired insulin-stimulated endothelial function, which was improved by 2 months treatment, while insulin-stimulated glucose uptake was unchanged. Quinapril also increased the gene expression of adiponectin in vascular tissue.

Conclusions:
Study I indicate, that muscle specific defects in glucose uptake are present in early adulthood in low birth weight subjects. The impairment of insulin´s effect in muscle tissue however, is not temporarily present in vascular tissue. In study II, ACE-inhibitor treatment was able to improve endothelial function and insulin-stimulated endothelial function, whereas no change was seen in forearm glucose uptake. Increased vascular adiponectin production could be one possible mechanism. These observations indicate, that the beneficial effects of ACE-inhibition in patients with type 2 diabetes, are primarily confined to vascular tissue.