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 : January 3, 2022
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 E Dietary Supplement: Vitamin C||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|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 :||February 29, 2024|
|Estimated Study Completion Date :||February 29, 2024|
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 E
Dietary Supplement: Vitamin C
500mg twice a day after discharge, for a minimum of 8 weeks
- 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.
- 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.
- Whether acute glycemic control affects urinary leakage of ascorbate. [ Time Frame: end of study ]Whether acute glycemic control affects urinary leakage of ascorbate.
- 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
- Whether RBC deformability is affected by vitamin C supplementation. [ Time Frame: end of study ]Whether RBC deformability is affected by vitamin C supplementation.
- 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.
- 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.
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
|Contact: Irene T Rozga, R.N.||(301) email@example.com|
|Contact: Ifechukwude C Ebenuwa, M.D.||(301) firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator:||Ifechukwude C Ebenuwa, M.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|