Several studies have reported that diabetic subjects have lower plasma vitamin C concentrations than non-diabetic subjects. Although urinary vitamin C loss in diabetic subjects was reported to be increased in two studies, these are difficult to interpret due to lack of controlled vitamin C intake, inadequate sampling, lack of control subjects, or methodology uncertainties in vitamin C assay and sample processing. Consequently, it is unclear whether diabetic subjects truly have both low plasma and high urine vitamin C concentrations. We propose that low plasma vitamin C concentrations in diabetic subjects are due in part to inappropriate renal loss of vitamin C in these subjects but not in healthy controls. We will study vitamin C concentrations in patients with type 1 and type 2 diabetes and in matched healthy research subjects. Vitamin C concentrations in plasma, neutrophils (as a proxy for tissue concentrations) and in urine will be measured in outpatients. In those willing to be admitted to the Clinical Center, we will measure 24-hour urinary excretion of vitamin C while on a vitamin C free diet, and creatinine clearance, a measure of glomerular filtration rate. On day 2 of the inpatient study, subjects will receive a single 200mg dose of oral vitamin C and we will measure vitamin C concentrations in frequent blood and urine samples to determine the renal threshold and relative bioavailability for vitamin C. Single nucleotide polymorphisms (SNPs) will be determined in genomic DNA responsible for the two proteins mediating sodium-dependent vitamin C transport, SVCT1 and SVCT2. If low plasma and high urine vitamin C concentrations are found in diabetic subjects, further studies will be needed to explore mechanisms and to determine recommended dietary allowances for this patient population.

Several studies have reported that diabetic subjects have lower plasma vitamin C concentrations than non-diabetic subjects. Although urinary vitamin C loss in diabetic subjects was reported to be increased in two studies, these are difficult to interpret due to lack of controlled vitamin C intake, inadequate sampling, lack of control subjects, or methodology uncertainties in vitamin C assay and sample processing. Consequently, it is unclear whether diabetic subjects truly have both low plasma and high urine vitamin C concentrations. We propose that low plasma vitamin C concentrations in diabetic subjects are due in part to inappropriate renal loss of vitamin C in these subjects but not in healthy controls. We will study vitamin C concentrations in patients with type 1 and type 2 diabetes and in matched healthy research subjects. Vitamin C concentrations in plasma, neutrophils (as a proxy for tissue concentrations) and in urine will be measured in outpatients. In those willing to be admitted to the Clinical Center, we will measure 24-hour urinary excretion of vitamin C while on a vitamin C free diet, and creatinine clearance, a measure of glomerular filtration rate. On day 2 of the inpatient study, subjects will receive a single 200mg dose of oral vitamin C and we will measure vitamin C concentrations in frequent blood and urine samples to determine the renal threshold and relative bioavailability for vitamin C. Single nucleotide polymorphisms (SNPs) will be determined in genomic DNA responsible for the two proteins mediating sodium-dependent vitamin C transport, SVCT1 and SVCT2. If low plasma and high urine vitamin C concentrations are found in diabetic subjects, further studies will be needed to explore mechanisms and to determine recommended dietary allowances for this patient population.

• Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med. 1986 Apr 3;314(14):892-902. Review. No abstract available.
• Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA. 1983 Jun 3;249(21):2917-21.
• Fata FT, Herzlich BC, Schiffman G, Ast AL. Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels. Ann Intern Med. 1996 Feb 1;124(3):299-304.

• INCLUSION CRITERIA:

We propose to study 150 male and female subjects between the ages of 18 and 65. This will include 50 healthy subjects and 100 subjects with type 1 or type 2 diabetes. To be included in the study, study subjects should:

• Be non smokers and be in good general health.
• Have no significant illnesses other than the complications of diabetes mellitus but should not have neuropathy affecting the functioning of internal organs such as the stomach and urinary bladder.
• Have serum creatinine less than 2.
• Be normotensive at the time of the study, with a blood pressure less than or equal to 140/90.

Acceptable medications include insulin and ACE inhibitors or ARBs for type 1 diabetes and oral hypoglycemic agents and ACE inhibitors or ARBs in the case of type 2 diabetes. Type 1 and type 2 diabetic subjects on aspirin are also eligible provided they are not taking it for known ischemic heart disease or cerebrovascular disease. The aim of this study is to determine whether diabetic subjects lose vitamin C in the urine in their normal clinical condition (i.e while on treatment) and not in the native untreated state of uncontrolled hyperglycemia. Therefore the patients will not discontinue medication.

EXCLUSION CRITERIA:

Exclusion criteria will include the following:

• Significant organ malfunction including liver disease, pulmonary disease, ischemic heart disease, heart failure, stroke, peripheral vascular disease, and anemia.
• Other serious or chronic illness; history of serious or chronic illness; coronary artery disease, or peripheral vascular disease.
• Pregnancy or acromegaly.
• Alcohol abuse, drug addiction or the use of illegal drugs.
• Use of vitamin supplements within 2 weeks prior to sample procurement.
• Positive HIV or hepatitis (B or C) screening tests (subjects will be notified of these test results).
• Presence of other concomitant conditions which in the judgment of the investigators can influence vitamin C metabolism or vitamin C renal handling.

For inpatient subjects, an additional exclusion criterion is consumption during the hospitalization of any foods or beverages other than those in the vitamin C free diet.