Diabetes is a disease characterized by decreased sensitivity to the action on insulin to
promote sugar (glucose) use and blood vessel relaxation (vasodilation) in muscle. Insulin's
ability to cause blood vessel relaxation is controlled, in part, by nitric oxide (NO).
Nitric oxide is a substance produced by the cells lining blood vessel walls (endothelium).
Increased blood flow to the muscle accounts for increased sugar (glucose) to areas of the
body. Therefore, if the cells of blood vessel walls (endothelium) are not functioning
properly it may contribute to insulin resistance.
Injections of Vitamin C directly into the arteries have been shown to improve blood vessel
reaction to nitric oxide in diabetic patients. Researchers believe this may be due to
Vitamin C's ability to increase the levels of nitric oxide in blood vessels.
The goal of this study is to determine the effects of vitamin C on both insulin sensitivity
and endothelium function of patients with type 2 diabetes. An additional goal of the study
is to determine the effects of vitamin C on patients with vitamin C deficiency.
Patients participating in this study will undergo a series of testes to determine insulin
sensitivity and blood vessel reactivity. Patients will be divided into two groups. One
group will receive doses of oral vitamin C. The other group will receive doses of a placebo
(inactive pill not containing vitamin C). Patients will receive the medications for four
weeks and then be tested again for insulin sensitivity and blood vessel reactivity.
Researchers believe that doses of vitamin C in diabetics or patients with vitamin C
deficiency will improve insulin sensitivity and function of endothelium. Results gathered
form this study may provide information about vitamin C levels in diabetics and may lead to
the development of new therapies to treat insulin resistance and endothelium dysfunction.
Diabetes is characterized by decreased sensitivity to the actions of insulin to promote both
glucose utilization and vasodilation in skeletal muscle beds. Insulin's vasodilator action
is mediated, in part, by endothelial-derived nitric oxide (NO). Increased blood flow
accounts for approximately 25% of the increase in skeletal muscle glucose disposal mediated
by insulin. Therefore, endothelial dysfunction may contribute to insulin resistance.
Intraarterial administration of vitamin C improves NO-dependent vascular reactivity in
diabetic subjects (but not normal subjects). This may be due to antioxidant properties of
vitamin C that result in relative increases in the level of NO in the diabetic vasculature.
In this exploratory protocol, our primary objective is to assess the effects of oral
administration of vitamin C on both insulin sensitivity and endothelial function in subjects
with type 2 diabetes. A secondary, peripheral objective, is to study these effects in
vitamin C-deficient clinical research volunteers. Hyperinsulinemic euglycemic glucose clamp
procedures and forearm blood flow measurements will be used to assess both insulin
sensitivity and vascular reactivity in diabetic subjects and clinical research volunteers
who have plasma vitamin C levels less than 30 microM. The subjects will then be given
either placebo or oral vitamin C supplementation (800 mg/day) for four weeks and assessment
of insulin sensitivity and vascular reactivity will be repeated. Plasma levels of vitamin C
will be measured to confirm that subjects in the experimental group have an appropriate
increase in vitamin C levels. We hypothesize that chronic oral administration of vitamin C
to diabetic or clinical research volunteers who are deficient in vitamin C will improve
insulin sensitivity and endothelial function. Our study will provide information about
vitamin C levels in diabetic subjects and may suggest a potential therapy to significantly
improve endothelial dysfunction and insulin resistance.
Males and non-pregnant females between the ages of 18 and 65 in good general health except
for type 2 diabetes controlled with diet and/or oral hypoglycemic agents.
Patients found to have plasma vitamin C levels less than 40 microliter M, will be enrolled
into the protocol and taken off hypoglycemic agents approximately one week prior to each
VITAMIN C-DEFICIENT CLINICAL RESEARCH VOLUNTEERS:
Adults between the ages of 18 and 35 in good general health and on no drugs or
Pregnancy, liver disease, pulmonary disease, renal insufficiency, coronary heart disease,
heart failure, peripheral vascular disease, coagulopathy, disease predisposing to
vasculitis or Raynaud's phenomenon, bleeding disorders, kidney stones, glucose-6-phosphate
dehydrogenase deficiency, family history of hemochromatosis/iron overload, platelet count
less than 150,000/ml blood, prothrombin time/partial thromboplastin time (PT/PTT) greater
than 1 second above the normal range, inability to give informed consent for all
procedures, and positive tests for HIV, or hepatitis B or C.
In addition, to the above exclusion criteria, the presence of proteinuria greater than 500
mg/24 hrs, proliferative retinipathy, or diabetic neuropathy
VITAMIN C-DEFICIENT CLINICAL RESEARCH VOLUNTEERS:
All the above exclusion criteria.