Famine From Feast: Linking Vitamin C, Red Blood Cell Fragility, and Diabetes

NCT02107976 | Completed Results

• 2 other identifiers: 14006014-DK-0060
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

An unexpected means to prevent microvascular disease in diabetes may be coupled to the function of vitamin C in red blood cells (RBCs) of diabetic participants. Based on new and emerging data, vitamin C concentrations in RBCs may be inversely related to glucose concentrations found in diabetes. In this protocol, we will investigate physiology of vitamin C in RBCs of diabetic participants as a function of glycemia, without vitamin C supplementation (baseline) and with vitamin C supplementation (8-week follow-up). As inpatients, participants will have two venous sampling periods each of approximately 24 hours. Insulin doses will be clinically determined and titrated to achieve euglycemia (fasting and pre-meal glucoses \<140mg/dl) prior to the first sampling period (euglycemic sampling). During the two sampling periods, samples will be withdrawn via venous catheter for RBC deformability, vitamin C concentrations and other related research studies. Following baseline measurements, participants will be provided a prescription for vitamin C 500mg twice daily. Given that vitamin C and vitamin E are related antioxidants, and that both vitamins appear to be associated with RBC rigidity, diabetic participants may also be given a prescription for 400 international units (IU) of vitamin E (RRR alpha tocopherol) daily. Participants will continue vitamin C and E supplementation for a minimum of 8 weeks depending on RBC vitamin C concentrations. To evaluate any effect of vitamin E supplementation, plasma and RBC vitamin E levels may be measured concurrently with vitamin C levels, after baseline. All participants will be seen as outpatients at biweekly or monthly intervals with regular measurement of plasma and RBC vitamin C concentrations. Vitamins C and E supplementation will be discontinued upon inpatient admission at the 8-week follow-up period. Risk of both vitamin supplements are minimal as both supplementation doses are safe. Outcomes are to measure RBC rigidity and vitamin concentrations before and after supplementation. In this manner, each participant serves as his/her own control, and deformability of red blood cells can be determined in relation to glycemia and to vitamin C concentrations in RBCs and plasma.

Conditions

Diabetes Type 2

Keywords

Diabetes; Red Blood Cells; Vitamin C; Plasma Vitamin C Levels

Outcome Measures

Primary Outcomes (1)

• Diff AUC SS0.5 Hyperglycemic

  Difference in mean AUC for RBC deformability half maximal shear stress (SS0.5) from baseline to the 8-week follow-up visit, using controlled hyperglycemia conditions (glucose 200-400 mg/dL). The insulin regimen will be withheld to produce controlled hyperglycemia \< 400 mg/dl. Subjects were provided a high carbohydrate diet (70-75% carbohydrate) on the day of hyperglycemia. During the hyperglycemic condition, blood samples will be drawn every one to two hours for RBC deformability measurements, between 7am and 10pm. AUC calculated from these serial measurements used the trapezoid rule and final measure are in units of Pa\*hr.

  Baseline to 8-week follow-up

Secondary Outcomes (4)

• Diff AUC RBC EI

  Baseline to 8-week follow-up

• Diff AUC RBC EImax, Hyperglycemic

  Baseline to 8-week follow-up

• Diff AUC RBC EImax Euglycemic

  Baseline to 8-week follow-up

• Diff AUC SS0.5 Euglycemic

  Baseline to 8-week follow-up

Study Arms (2)

Diabetes

EXPERIMENTAL

Male or female 18-65 years old with diabetes type 2, HgA1C = 12% on insulin and/or oral hypoglycemic agents, or any prior history or diagnosis of diabetes

Dietary Supplement: Vitamin E; Dietary Supplement: Vitamin C

Healthy

EXPERIMENTAL

Male or female 18-65 years old without any prior history or diagnosis of diabetes.

Dietary Supplement: Vitamin E; Dietary Supplement: Vitamin C

Interventions

Vitamin E DIETARY_SUPPLEMENT

400 IU per day after discharge, for a minimum of 8 weeks after baseline

Diabetes; Healthy

Vitamin C DIETARY_SUPPLEMENT

500mg twice a day after discharge, for a minimum of 8 weeks after baseline

Diabetes; Healthy

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Study Initiation
• Male or female 18-65 years old, able to give informed consent.
• Diabetes type 2 HgA1C \<= 12% on insulin and/or oral hypoglycemic agents or nondiabetic without any prior history or diagnosis of diabetes.
• In general good health with no other significant illness.
• Mild concomitant disease such as mild hypothyroidism (TSH \<10) is acceptable.
• Blood pressure with or without medication \<160/90 mmHg with no known significant target organ damage (end organ damage includes the following: proliferative retinopathy, serum creatinine \>1.5 or EGFR \< 55 mL/min, symptomatic ischemic heart disease, severe congestive heart failure, advanced peripheral vascular disease.
• Willingness to use effective contraceptive methods such as barrier method for the duration of study (female subjects).
• week follow-up
• Above criteria with addition of RBC vitamin C concentration \>30 uM prior to inpatient studies.

You may not qualify if:

• Entire duration of study
• Diabetic type 1 subjects will be excluded due to the possibility of ketosis and hemodynamic instability with lack of insulin.
• Any subjective or objective evidence of microangiopathy such as history of claudication, symptomatic peripheral vascular disease, symptomatic coronary artery disease, stroke, retinopathy, nephropathy (serum creatinine \>1.5 or EGFR \< 55 mL/min).
• Diabetic subjects with retinopathy to avoid accelerated retinopathy with hyperglycemia.
• Concomitant disease such as severe heart failure, severe liver disease (transaminases \> 3 times normal), or severe systemic disease of any sort.
• Pregnancy, breastfeeding.
• History of diabetic ketoacidosis or hyperosmolar coma.
• Subjects with clear evidence of non-compliance with protocol/study instructions.
• Subjects who are unwilling or lack capacity to provide informed consent.

Sponsors & Collaborators

• National Institutes of Health Clinical Center (CC): lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Ali SM, Chakraborty SK. Role of plasma ascorbate in diabetic microangiopathy. Bangladesh Med Res Counc Bull. 1989 Dec;15(2):47-59.

  PMID: 2629696 BACKGROUND

• Baskurt OK, Hardeman MR, Uyuklu M, Ulker P, Cengiz M, Nemeth N, Shin S, Alexy T, Meiselman HJ. Comparison of three commercially available ektacytometers with different shearing geometries. Biorheology. 2009;46(3):251-64. doi: 10.3233/BIR-2009-0536.

  PMID: 19581731 BACKGROUND

• Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002 May 15;287(19):2570-81. doi: 10.1001/jama.287.19.2570.

  PMID: 12020339 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Vitamin E; Ascorbic Acid

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates

Limitations and Caveats

28 were enrolled, completed baseline assessments, and were included in analysis. Protocol overlapped the initial COVID-19 pandemic period and may have introduced additional bias.

Results Point of Contact

• Title: Dr. Ifechukwude Ebenuwa
• Organization: NIDDK

ifechukwude.ebenuwa@nih.gov

301.435.6582

Study Officials

• Ifechukwude C Ebenuwa, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: A high carbohydrate diet (70-75% carbohydrate) will be included as part of testing and a regimen of oral vitamin C 500 mg twice daily for a minimum of 8 weeks are given to non-diabetes and diabetes cohorts.

Study Record Dates

• First Submitted: April 5, 2014
• First Posted: April 9, 2014
• Study Start: June 14, 2019
• Primary Completion: March 5, 2025
• Study Completion: March 5, 2025
• Last Updated: May 12, 2026
• Results First Posted: May 12, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)