L-Arginine and Endothelial Dysfunction in Type 2 Diabetic Patients

Peripheral neuropathy is one of the most common complications of diabetes mellitus (DM) with a prevalence of around 30 - 45%. In addition, diabetic patients are at increased risk of macrovascular disease, as well as other complications such as retinopathy and nephropathy.

The majority of patients will have developed peripheral neuropathy 10-20 years after the onset of diabetes, which is an important cause of foot ulceration, Charcot joints, amputation and increased morbidity and mortality. In view of this the cost to the National Health Service in 1987 was a staggering £13.5 million. Therefore there is an urgent need for prevention of diabetic neuropathy and its sequelae.

The exact pathogenesis of diabetic neuropathy is unclear, with both metabolic and vascular factors having been implicated. Microvascular disease is possibly the initial event in the development of diabetic complications. Microvascular disease may play an important role in the causation and exacerbation of diabetic neuropathy. Histopathological studies have shown thickening of vessel walls, hyperplasia of capillary endothelial cells and increased plugging of vessels in neuropathic patients. Endothelial dysfunction is thought to be an important initiating factor for the development of these complications. Endothelial dysfunction is thought to develop as a consequence of changes in nitric oxide and cell adhesion molecules in the plasma of diabetic patients. L-arginine is an amino acid, which is the only source of NO in the body.

We therefore propose to study the efficacy of arginine supplementation ( this is available over the counter as a food supplement) on endothelial function and other biomarkers of impaired endothelial function. We hope with this study to demonstrate that L-arginine supplementation will enhance nitric oxide availability, thereby improve the microcirculation and subsequently improve peripheral nerve function. We will use surrogate markers to assess the efficacy of L-arginine supplementation to show an improvement in diabetic complications such as microalbuminuria in the urine, and TcPO2 in the skin of the lower limbs. In addition microcirculation will be assessed using the Moor Laser Doppler flow machine and the Radiometer TcPO2 device. Endothelial function will also be assessed indirectly by measuring the cell adhesion molecules ICAM-1, VCAM-1, P-selectin and E-selectin. This will be performed using standard ELISA techniques.

A total of 40 patients will be recruited for the study. Half will be randomised to taking the food supplement L-arginine and half to placebo. At baseline all patient will have a clinical assessment of their neuropathy status in the lower limb, blood pressure and BMI. Fasting bloods for glucose, lipids profile, U&E's, FBC, CRP, cell adhesion molecules and nitric oxide will be done at baseline and three months later at the end of the study. The TcPO2 and micro-circulation will be assessed at baseline and also at three month.