Darryl Meeking

Review: Endothelial dysfunction and pre-symptomatic atherosclerosis in type 1 diabetes — pathogenesis and identification

The vascular endothelium offers an attractive model for detecting functional abnormalities prior to structural changes in the vasculature. Demonstration of progression from endothelial dysfunction through to atherosclerosis is required. Measurements of forearm bloodflow, biochemical markers and biophysical assessments of the endothelium have been employed as research tools for investigating pre-symptomatic atherosclerosis. However, studies examining endothelial function in type 1 diabetes have been sparse and conflicting. Differences in methodology and the study populations were potential confounding factors. Augmented vasodilatory prostanoids compensate for reduced nitric oxide bioavailability in determining endothelial function in type 1 diabetes. Hyperglycaemia appears to be the initiating event in type 1 diabetes which promotes a variety of biochemical events which are pathogenic to the endothelium. Improved understanding of the endothelium may facilitate the development of novel diagnostic tools and interventions targeting the accelerated atherosclerosis associated with type 1 diabetes.

Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria

Aims  The purpose of this study was to examine the associations between endothelial function, plasma homocysteine and oxidative stress in patients with Type 1 diabetes mellitus (DM) and microalbuminuria compared with DM patients with normoalbuminuria and non‐diabetic control subjects. We wished to test the hypothesis that increased cardiovascular risk in patients with Type 1 diabetes and microalbuminuria may be in part as a result of hyperhomocysteinaemia‐mediated oxidative stress leading to impaired endothelial function.

The effect of oral folic acid upon plasma homocysteine, endothelial function and oxidative stress in patients with type 1 diabetes and microalbuminuria.

Aims:  The purpose of this study was to investigate the effect of oral folic acid supplementation upon plasma homocysteine (HCY), endothelial function and oxidative stress on patients with type 1 diabetes and microalbuminuria to test the hypothesis that oral folic acid would lower plasma HCY and thereby improve endothelial function and reduce oxidant stress in this high‐risk group of patients.

The contribution of nitric oxide and vasodilatory prostanoids to bradykinin-mediated vasodilation in Type 1 diabetes.

Aims  To investigate the effect of bradykinin on endothelial tone in normoalbuminuric Type 1 diabetic patients and specifically whether any changes are mediated through nitric oxide or prostaglandins.

Diabetic erectile dysfunction – an indicator of generalised endothelial function per se?

Erectile dysfunction (ED) affects up to 70% of men with diabetes. However, the pathophysiology of ED in diabetes remains uncertain with both neuronal and vascular factors cited. We examined whether ED is an indicator of generalized endothelial dysfunction. A unique group of diabetic patients free from established conventional cardiac risk factors were investigated. Forearm bloodflow responses to nitroprusside and acetylcholine on 11 diabetic men with ED and 11 potent diabetic men were measured by venous plethysmography. Patient characteristics between the impotent and potent patients were similar except for Hba1c which was higher in the group with ED (8.35% vs. 7.03%: p = 0.003). Both groups showed increases in FBF to incremental infusions of nitroprusside and acetylcholine but the area under curve (AUC) were similar in the ED and the non‐ED groups (p = 0.16 and p = 0.17, respectively). We demonstrated that ED in patients with type 2 diabetes is not associated with additional generalized endothelial dysfunction.

Angiotensin II does not affect endothelial tone in Type 1 diabetes—results of a double-blind placebo controlled trial

Aims  Previously, we have demonstrated that patients with normoalbuminuric Type 1 diabetes are characterized by impaired nitric oxide bioavailability compensated for by increased vasodilatory prostanoid‐mediated vasodilation. Experimental evidence suggests vascular responses to endogenous angiotensin II involve the nitric oxide and prostaglandin pathways. We examined whether selective blockade of angiotensin II influences endothelial tone with particular reference to the nitric oxide/prostaglandin pathways in patients with Type 1 diabetes free from vascular complications.

Gastrointestinal symptoms and pancreatic exocrine insufficiency in type 1 and type 2 diabetes

Our review of clinical practice demonstrates that gastrointestinal (GI) symptoms were common in patients with type 1 and type 2 diabetes seen within our diabetes service. In those patients who are symptomatic, we observed that 42% had low faecal elastase 1 levels consistent with the diagnosis of pancreatic exocrine insufficiency (PEI). The presence of steatorrhoea and weight loss alone were insufficient to screen for PEI, and other GI symptoms (such as diarrhoea, abdominal cramps/pain and bloating) need to be additionally sought. Copyright

Comparison of vasodilator effects of substance P in human forearm vessels of normoalbuminuric Type 1 diabetic and non-diabetic subjects

Aims To compare the vasodilatory responses to substance P in human forearm vessels in Type 1 normoalbuminuric diabetic and non‐diabetic subjects.

The use of plasmapheresis in managing primary biliary cirrhosis presenting with profound hypercholesterolaemia

Case history A 39-year-old woman had a fasting lipid profile after a wellwoman check in March 2005. Her TC was 44.9 mmol/L, TG 15.9 mmol/L (normal range 0.6–1.5mmol/L), HDL cholesterol 0.33 mmol/L (normal range 0.9–2.4), TC:HDL ratio 36.1. Other results included fasting glucose 5.7 mmol/L, urea 3.6 mmol/L, creatinine 63 μmol/L, potassium 3.6 mmol/L and sodium 125 mmol/L, consistent with pseudohyponatraemia due to the lipaemic sample. She was asymptomatic with no prior medical illnesses. There was no significant family history of hyperlipidaemia or vascular disease. She did not smoke but drank 20 units of alcohol per week. Pravastatin 20 mg was commenced but stopped a week later because of a generalised rash. She was referred to endocrinology as this was before the establishment of a lipid service. Over the next 10 weeks, she became gradually more unwell with fatigue, widespread itching and easy bruising. She lost 10 kg and became jaundiced. On examination, she had palpable hepatosplenomegaly. No stigmata of chronic liver disease or hyperlipidaemia were found. Bloods showed a TC 83 mmol/L, TG 16.3 mmol/L, HDL 0.46, TC:HDL ratio 181.5. Her LFTs were ALP 1589 iu/L (30–95), AST 220 iu/L (12–40), bilirubin 58 μmol/L (3–20), total protein 81 g/L (63–81), albumin 33 g/L (37–50). Other results were sodium 107 mmol/L, haemoglobin 12.1 g/dL (12–16) and INR 0.9 (0.8–1.2). Abdominal ultrasound showed hepatomegaly, marked splenomegaly of 19 cm, with patent portal vein, hepatic veins and arteries. Further blood results revealed bile acids 363 μmol/L (0–20); hepatitis B and C serology were negative. Her ANA and anti-LKM antibodies were negative but she was moderately positive for anti-SmM and AMA. Thyroid function was normal. Serum electrophoresis showed polyclonal increase in gamma region with uninterpretable immunoglobulin levels due to the lipaemia. In view of the risk of hyperviscosity syndrome, she was started on plasmapheresis, continuing as regular fortnightly sessions. Cholestyramine 4 g four times a day and UDCA 250 mg twice daily were commenced. The use of plasmapheresis in managing primary biliary cirrhosis presenting with profound hypercholesterolaemia

Vasodilator prostanoids compensate for attenuated nitric oxide mediated vasodilation in type 1 diabetes

Background Previous research examining endothelial function and the biochemical pathways mediating vasodilation in type 1 diabetes has been conflicting. Both impaired and preserved nitric oxide (NO) mediated vasodilation have been reported whilst some authors have suggested enhanced vasodilator prostanoid (P) activity. The aim of this study was to determine the relative contributions of NO and P to endothelial function in a homogenous group of type 1 diabetic patients free of other confounding factors that may influence vascular behaviour.^f ^Methods and results Endothelial function was assessed using forearm venous plethysmography in 16 patients with uncomplicated type 1 (duration of diabetes 16.8±2.5 years (mean±SEM), HbA1C 7.53±0.21% ) and 15 non-diabetic age and sex matched healthy control subjects. Forearm responses to the endothelium-dependent vasodilator, acetylcholine (ACh) (7.5, 15 and 30 µg/min), were recorded at baseline and after intra-arterial infusion of L-NMMA (a NO synthase inhibitor). Res...