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

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ClinicalTrials.gov Identifier: NCT02107976
Recruitment Status : Recruiting
First Posted : April 9, 2014
Last Update Posted : June 24, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Brief Summary:

Diabetes type two is a debilitating disease that leads to chronic morbidity such as accelerated microvascular disease. Accelerated microvascular disease may produce blindness, end stage renal disease, myocardial infarction, stroke, and limb ischemia. Strategies to prevent or delay microvascular disease have the potential to improve the lives of millions and prevent catastrophic illness. The major focus of prevention of microvascular disease in diabetes has been on the endothelium and its role in protection of blood vessels. 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 subjects. Based on new and emerging data, vitamin C concentrations in RBCs may be inversely related to glucose concentrations found in diabetes. Based on animal data, we hypothesize that RBCs with low vitamin C levels may have decreased deformability, leading to slower flow in capillaries and microvascular hypoxia, the hallmark of diabetic microangiopathy. Low vitamin C concentrations in RBCs of diabetic subjects may be able to be increased, by using vitamin C supplements. Findings in animals may not accurately reflect effects in humans because of species differences in mechanisms of vitamin C entry into RBCs. Therefore, clinical research is essential to characterize vitamin C physiology in RBCs of diabetic subjects. In this protocol we will investigate physiology of vitamin C in RBCs of diabetic subjects as a function of glycemia, without vitamin C supplementation (arm 1) and with vitamin C supplementation (arm 2). We will screen type II diabetic subjects on insulin and/or oral hypoglycemic medication(s) and select those with hemoglobin A1C concentrations of less than or equal to 12%. Selected subjects may be hospitalized twice, each time for approximately one week. The primary objective of the first hospitalization (arm 1) will be to evaluate the effect of hyperglycemia on vitamin C RBC physiology regardless of baseline vitamin C concentrations (without any vitamin C supplementation). The second hospitalization (arm 2) investigates the effect (if any) of vitamin C supplementation to changes in RBC physiology during euglycemic and hyperglycemic states. As inpatients, subjects will have two venous sampling periods each of approximately 24 hours. On admission, subjects may be fitted with continuous glucose monitors (CGMs), oral hypoglycemic agents will be discontinued, and basal-bolus insulin regimen initiated. 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). The first sampling period will be performed under conditions of euglycemic control for 24 hours. The second sampling period will be performed under controlled hyperglycemia induced by withholding basal and bolus insulin and providing a high carbohydrate load diet (70-75% carbohydrate). Correction-scale insulin will be provided for glucoses >350-400mg/dl. Hyperglycemia will not exceed 9 hours, and will be reversed by reinstituting insulin.

During the two sampling periods, samples will be withdrawn via venous catheter for RBC deformability, vitamin C concentrations and other related research studies. Following completion of arm 1, subjects considered for participation in arm 2 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 subjects may also be given a prescription for 400 international units (IU) of vitamin E (RRR alpha tocopherol) daily. Subjects 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 during various phases of arms 1 and 2. All subjects will be seen as outpatients at biweekly or monthly intervals with regular measurement of plasma and RBC vitamin C concentrations. Target RBC vitamin C concentration >30uM is required prior to arm 2 inpatient sampling studies. Vitamins C and E supplementation will be discontinued upon inpatient admission for arm 2. 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. After a minimum of 8 weeks (depending on RBC vitamin C levels), subjects will be hospitalized again, and sampling repeated as described. In this manner, each subject 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.

Subjects will be required to consume standardized meals during inpatient stays. All meals will be prepared by the NIH Clinical C...


Condition or disease Intervention/treatment Phase
Diabetes Type 2 Dietary Supplement: Vitamin C Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Famine From Feast: Linking Vitamin C, Red Blood Cell Fragility, and Diabetes
Actual Study Start Date : June 14, 2019
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin C

Arm Intervention/treatment
Experimental: Stage 1
Upon admission, diabetic subjects maywill discontinue their oral hypoglycemic medications and/or insulin regimen per investigators discretion. Oral hypoglycemic agents and/or insulin doses will be adjusted and may be supplemented with a correction scale and/or and transitioned to a basal-bolus insulin regimen. In order to achieve optimal glycemic monitoring and for safety reasons, subjects may be fitted with a Dexcom continuous glucose monitor (CGM) upon inpatient admission. CGM will be used to supplement, rather than replace, fingerstick glucose measurements. CGM monitoring will include a sensor fitted subcutaneously, a wireless transmitter that allows for remote glucose monitoring by the research team.
Dietary Supplement: Vitamin C
500mg twice a day after discharge, for a minimum of 8 weeks

Experimental: Stage 2
Subjects may be considered for arm stage 2 inpatient study no less than 8 weeks duration from arm stage 1 study. Once the RBC vitamin C concentrations are optimal (>30 uM), subjects may be re-admitted to Clinical Center metabolic unit and undergo the same protocol as described above in arm stage 1. Oral vitamin C and E supplementation may be discontinued on admission. The inpatient diet, glucose monitoring and sampling scheme will be the same as described for the first inpatient study.
Dietary Supplement: Vitamin C
500mg twice a day after discharge, for a minimum of 8 weeks




Primary Outcome Measures :
  1. Whether RBCs have low vitamin C concentrations in patients with poorly controlled diabetes, as measured by Hba1C. [ Time Frame: end of study ]
    Whether RBCs have low vitamin C concentrations in patients with poorly controlled diabetes, as measured by Hba1C.

  2. Whether ascorbate in RBCs of diabetic subjects is inversely related to acute glycemic control, over hours. [ Time Frame: end of study ]
    Whether ascorbate in RBCs of diabetic subjects is inversely related to acute glycemic control, over hours.

  3. Whether acute glycemic control affects urinary leakage of ascorbate. [ Time Frame: end of study ]
    Whether acute glycemic control affects urinary leakage of ascorbate.

  4. d) Whether acute changes in glycemia and/or red blood cell ascorbate modify RBC [ Time Frame: end of study ]
    Whether acute changes in glycemia and/or red blood cell ascorbate modify RBC


Secondary Outcome Measures :
  1. Whether RBC deformability is affected by vitamin C supplementation. [ Time Frame: end of study ]
    Whether RBC deformability is affected by vitamin C supplementation.

  2. c) To obtain preliminary estimates for future studies of whether any clinically/physiologically interpretable functional of the above secondary goals quantifiable relationships differ markedly by baseline phenotypes, whether only by sex (as o... [ Time Frame: end of study ]
    To obtain preliminary estimates for future studies of whether any clinically/physiologically interpretable functional of the above secondary goals quantifiable relationships differ markedly by baseline phenotypes, whether only by sex (as observed in prior protocols, such as 04-DK-0021, or additionally by yet-to-be ascertained factors per accruing data), thus requiring adaptation of enrollment targets within and/or between stages.

  3. Whether RBC vitamin C concentrations can be increased by vitamin C supplementation over several weeks in diabetic subjects. [ Time Frame: end of study ]
    Whether RBC vitamin C concentrations can be increased by vitamin C supplementation over several weeks in diabetic subjects.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Arm 1

  • Male or female 18-65 years old, able to give informed consent.
  • Diabetes type 2 HgA1C less than or equal to 12 percent on insulin and/or oral hypoglycemic agents.
  • 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).

Arm 2

Above criteria with addition of RBC vitamin C concentration greater than micrM prior to inpatient studies.

EXCLUSION CRITERIA (Arm ! and 2):

  • 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).
  • 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.
  • Participation in each protocol delineated evaluation procedure will be judged on a case by case basis with patient safety as the paramount consideration.
  • Pregnancy, breastfeeding.
  • History of diabetic ketoacidosis or hyperosmolar coma.
  • Subjects with clear evidence of non-compliance with protocol/study instructions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02107976


Contacts
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Contact: Irene T Rozga, R.N. (301) 496-1069 irene.rozga@nih.gov
Contact: Ifechukwude C Ebenuwa, M.D. (301) 435-6582 ifechukwude.ebenuwa@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Ifechukwude C Ebenuwa, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
Publications:
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT02107976    
Other Study ID Numbers: 140060
14-DK-0060
First Posted: April 9, 2014    Key Record Dates
Last Update Posted: June 24, 2022
Last Verified: April 18, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Diabetes
Red Blood Cells
Vitamin C
Plasma Vitamin C Levels
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Ascorbic Acid
Vitamins
Micronutrients
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents