Effect of Arginine on Microcirculation in Patients With Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with diabetes have dysfunction of the lining of the arteries which lead to impaired
      circulation in the small blood vessels. This is thought to be secondary to reduced chemicals
      in the blood viz: nitric oxide. This chemical is derived from an amino acid (protein)
      L-arginine. Therefore, the researchers investigated whether giving patients L-arginine
      (versus dummy powder) would improve the blood flow in the small blood vessels in the lower
      limbs of patients with damage to their nerves (neuropathy).
    

Detailed description: 
      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.

      Each of the twenty patients that is randomised to L-arginine will be given a tin containing 1
      kilogram of the food supplement L-arginine. They are to take a spoonful (three grams) of the
      L-arginine and dissolve it in a glass of sugar free cold drink of their choice such as orange
      or lemon squash. They are to take it before food three times a day. The twenty patient
      randomised to placebo will receive a tin containing one kilogram of placebo and the
      instruction is as for the L-arginine group.

      20 patients will receive L-arginine powder (3G TDS) and 20 patients will receive placebo,
      lactose powder (3G TDS)

      Clinical examination as part of routine care:

        1. BMI, BMI will be calculated by weight/height (kg/m2).

        2. Lying and standing blood pressure will be measured twice, in the right arm using
           Dinamap™ (Critikon, UK), after resting for 10 minutes. Hypertension will be defined
           according to WHO criteria (systolic blood pressure (sBP) >140 mm Hg and/or diastolic
           blood pressure (dBP) >90 mm Hg or if the patient is on current antihypertensive
           treatment.

        3. Overnight microalbumin excretion rate.

        4. Neuropathic Disability Score and Vibration Perception threshold.

      Additional examination:

        1. TcPO2 of the right foot.

        2. Micro-circulation of the right foot using Moore Laser Doppler iontophoresis.

      Blood from an antecubital vein will be collected after an overnight fast and after resting
      for fifteen minutes in the supine position for:

        1. as part of routine care - FBC, U&E's, fasting glucose, glycated haemoglobin, fasting
           lipid profile

        2. additional blood test - CRP, cell adhesion molecules, nitric oxide
    

Intervention name(s): L-arginine; Placebo Lactose powder
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 3gm TDS for three months; 3gm TDS for 3 months
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Type 2 diabetes; Peripheral neuropathy; Microcirculation