Effect of Red Blood Cell Survival on a Commonly Used Diabetes Lab Test-HbA1c

NCT01204216 | Terminated Results

• 2 other identifiers: ENDA-006-09S09100601
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Prevention of complications in veterans with diabetes depends heavily on assessment of blood glucose and HbA1c. The HbA1c is a blood test that measures the exposure of hemoglobin (Hb) to a person's average blood glucose over the lifespan of a red blood cell (RBC). The test is heavily relied upon as a measure of blood glucose control. It is normally assumed that all people (those with and without diabetes) have a narrow range of red blood cell survival. It has been recently shown that this is not a valid assumption. A more precise test of red blood cell survival, using a biotin label method, demonstrated a substantial difference of red blood cell survival among otherwise normal people. There is sufficient difference in red blood cell survival to alter the estimate of glycemic control from the HbA1c test by as much as 30 per cent. This introduces concern that HbA1c values do not mean the same thing in a significant number of people. Although the evidence is clear that there is variation in RBC survival among people, attributing this variation to differences between individuals depends on answering several simple questions which surprisingly remain unanswered: whether RBC survival is stable over time within an individual and whether blood glucose control affects its stability. Therefore, the goal of the proposed studies is to define these characteristics.

Conditions

Diabetes Mellitus; Impaired Fasting Glucose; Prediabetes

Keywords

Hemoglobin A1c; HbA1c; glycated serum proteins; fructosamine; glycated albumin; glycation gap

Outcome Measures

Primary Outcomes (1)

• Specific Aim 1: To Determine the Stability of MRBC (Mean RBC Age)Over Time at Stable Glycemia. The Hypothesis is MRBC Will be Stable in Subjects Without Diabetes and in Subjects With Diabetes at Stable Glycemic Control.

  The investigators will determine MRBC and MBG (by both 7 point profile and continuous glucose monitoring), twice in 10 subjects without diabetes and in 10 subjects with diabetes at stable glycemic control. Since the time course study for following the disappearance of re-infused labeled RBCs is approximately 4 months, performing the biotin labeling of the cells for the second study at least 8 months after completion of sampling for the first, effectively samples MRBC at two time points at least one year apart.

  Baseline and 8 months later

Secondary Outcomes (1)

• Specific Aim 2: To Determine the Impact of Glycemic Control on MRBC.

  Baseline and 8 months later

Study Arms (2)

Aim 1

ACTIVE COMPARATOR

Subjects in this arm will be 10 people without diabetes as well as 10 people with diabetes and stable glycemic control. Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (\< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.

Biological: re-infusion of biotin labeled cells

Aim 2

ACTIVE COMPARATOR

For Aim 2, 10 additional subjects with diabetes in poor glycemic control will be studied initially and then again in improved glycemic control after at least 8 months (with up to 5 additional subjects entered as needed to ensure 10 completed paired studies) to assess the potential role of MRBC variation in the discordances seen between HbA1c and blood glucose testing. Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (\< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate.

Biological: Re-infusion of biotin labeled cells; Behavioral: Diabetes education/diabetes medication adjustment

Interventions

Re-infusion of biotin labeled cells BIOLOGICAL

Subjects will participate in experiments involving re-infusion of biotin-labeled cells in which a small volume (\< 10 ml) of autologous, biotinylated erythrocytes will be re-infused to determine cell lifespan and in vivo HbA1c formation rate. These experiments require a series of small, precisely timed post-infusion blood samples over a period of 4 months, with each subject undergoing the procedure twice separated by an interval of at least 8 month

Aim 1

Diabetes education/diabetes medication adjustment BEHAVIORAL

Between the initial 3-4 month trial period and the second infusion of biotin labeled cells approximately 8 months later,subjects will receive diabetes education from a CDE. In addition,if needed, diabetes medications may be adjusted by the study endocrinologist to improve subject's glycemic control.

Aim 2

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects will be between ages 18 and 85 for Aim 1 and between 18 and 80 years for Aim 2 and non-pregnant
• Subjects with both types 1 and 2 diabetes
• Subjects without diabetes (as determined by an OGTT test at screening)
• veterans receiving care at VAMC will be given preference but open to both veterans and non-veterans.

You may not qualify if:

• known hemoglobinopathy or RBC disorder
• positive pregnancy test (in women of child-bearing potential or are breast feeding or planning pregnancy during the course of the study;
• baseline serum creatinine \>1.5 mg/dl
• CBC outside the normal range
• history of GI blood loss or coagulopathy
• urine microalbumin \>100 mcg/mg creatinine (spot collection);
• transaminases \>3 X the upper limit of normal
• presence of serum antibodies to biotinylated proteins (which could interfere with the biotin RBC labeling protocol)
• greater than or equal to NYHA stage 3 heart failure;
• active infection;
• known rheumatologic disease
• uncontrolled hypo-or hyperthyroidism or an underlying illness known to be associated with either body wasting or changes in serum proteins
• plans to move out of the area within the time frame of the Aim for which they are recruited
• unwillingness to perform self monitoring of blood glucose

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of Cincinnati: collaborator

Study Sites (1)

Cincinnati VA Medical Center, Cincinnati, OH

Cincinnati, Ohio, 45220, United States

Location

Related Publications (2)

• Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, Palascak MB, Joiner CH. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008 Nov 15;112(10):4284-91. doi: 10.1182/blood-2008-04-154112. Epub 2008 Aug 11.

  PMID: 18694998 BACKGROUND

• Cohen RM, Lindsell CJ. When the blood glucose and the HbA(1c) don't match: turning uncertainty into opportunity. Diabetes Care. 2012 Dec;35(12):2421-3. doi: 10.2337/dc12-1479. No abstract available.

  PMID: 23173128 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Prediabetic State

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

The protocol interrupted due to termination of IND. Insufficient time to complete the protocol within the term despite new IND for same biotin labelling of RBCs. Remaining grant funds applied to similar physiologic studies using 15N-glycine labelling of RBCs. see PMID: 25293624 for results. Those results led to funding of NIH Grant 1R01DK123330-01A1 "Towards optimizing diabetes management and diagnosis by personalizing HbA1c targets."

Results Point of Contact

• Title: Robert M Cohen, MD, Physician,
• Organization: Research Service, Cincinnati VA Medical Center

robert.cohen@uc.edu

5136748676

Study Officials

• Robert M Cohen, MD

  Cincinnati VA Medical Center, Cincinnati, OH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

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

Study Record Dates

• First Submitted: September 15, 2010
• First Posted: September 17, 2010
• Study Start: September 1, 2010
• Primary Completion: July 1, 2016
• Study Completion: September 1, 2016
• Last Updated: May 31, 2023
• Results First Posted: May 31, 2023

Record last verified: 2023-05

Locations

US (1)