Berg, Anders , M.D., PhD
Development of a novel assay for hemoglobin A1c adjusted for age of patient's erythrocytes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Glucose Monitoring and Sensing
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
This project introduces a novel blood test for hemoglobin A1c to be used to monitor long-term blood glucose control in patients with diabetes mellitus. Hemoglobin A1c is red blood cell hemoglobin that has been chemically modified by glucose during the months red blood cells circulate. Accordingly, the amount of hemoglobin A1c that accumulates is determined by both patients' average blood glucose concentrations and the length of time that their red blood cells circulate. Individual difference in patients' red blood cell age can thus significantly influence hemoglobin A1c test results, independent of their blood glucose control--especially in the many diabetic patients suffering from anemia. This effect can make test results misleading, resulting in significant errors in patients' diabetes management.
This project seeks to develop a blood test that eliminates the influence of red cell age on hemoglobin A1c results. This proposal describes the discovery of a novel biomarker in red blood cells that is an indicator of their age in circulation, and presents preliminary methods for simultaneous measurement of this biomarker and hemoglobin A1c. Aims of this proposal include analytical validation of this red cell age-adjusted Hemoglobin A1c assay, demonstration of the relationship between red cell aging and this novel biomarker, and a preliminary demonstration in anemic patients that this blood test produces results that more accurately reflect patients' true average blood glucose concentrations. If the hypothesis proves correct, this assay represents a superior method of monitoring blood glucose which will improve disease management for all patients with diabetes mellitus.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This translational research project seeks to develop and validate a novel clinical assay for the diagnosis of diabetes mellitus and monitoring of blood glucose control in patients with this disease. The assay seeks to measure and report Hemoglobin A1c concentrations in patients' blood after adjusting for individual differences in the life span of their circulating erythrocytes. Variability in erythrocyte age is a significant confounding factor when interpreting hemoglobin A1c results, particularly in patients with anemia or hematological disorders. This assay will eliminate a significant source of analytical and interpretive error that compromises the effectiveness of this essential diagnostic test, and thus represents a significant improvement in existing clinical assays for glycated hemoglobin A1c.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Currently, there is no cure for diabetes mellitus, however you can prevent the complications of this disease by controlling your blood sugar levels. Some patients test their blood sugar by finger stick blood glucose monitors, and although this is a good way of adjusting your deaily insulin, it is not a very accurate method of testing your average daily blood sugar. The best test currently available for monitoring your blood sugar is by measuring a red blood cell protein called hemoglobin A1c (Hb A1c). Hemoglobin and other proteins in your blood are slowly modified by blood sugar (glucose), chemically bonding with a small proportion of blood hemoglobin, and this modified hemoglobin is called Hb A1c. The rate of formation of Hb A1c in the blood is proportional to your blood sugar level, and because this occurs slowly over time the accumulation of Hb A1c is proportional to your average daily blood sugar levels.
Because the accumulation of Hb A1c depends upon how long your hemoglobin is exposed to blood sugar, it also depends upon how long your red blood cells, which carry the hemoglobin, circulate in your blood. The life span of red blood cells vary from person-to-person, especially in patients who have anemias. This variability directly influences your Hb A1c results independent of how well you are controlling your blood sugar. As a result, variability in red cell life span introduces a source of error when physicians interpret Hb A1c results. In other words, older red cells accumulate more Hb A1c, so if your blood is older than most people's your Hb A1c will be misleadingly high even though your blood sugar may be well controlled. There is currently no way a doctor can know that your blood is older or younger than most other patients' blood, and so these errors go unnoticed.
There is a possibility that these errors may prompt your doctor to prescribe higher doses of insulin (or other glucose control medications) than you need, or not prescribing enough to adequately control your blood sugar. This project seeks to develop a novel assay for Hemoglobin A1c that simultaneously measures the age of your erythrocytes, and adjusts Hb A1c values accordingly. Adjusting for red cell life span/age will make measurements of Hb A1c more accurately representative of your true average blood sugar. This improvement in Hb A1c testing would allow your doctor to make the most accurate assessment of your blood glucose control, allowing your doctor to tailor treatment options to your specific needs, optimizing your blood glucose control while avoiding problems with hypoglycemia.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes mellitus is a condition that afflicts a significant proportion of the world's population, its prevalence is growing, and most importantly, it is a treatable and in some cases preventable disease. I have been interested in endocrinology and the problems of diabetes mellitus since my first years of medical school, and I have participated in diabetes-related research since the start of my doctor thesis project in the laboratory of Dr. Philipp Scherer. In Dr. Scherer's laboratory I helped investigate the connections between obesity, adipocyte secretory functions and cell biology, insulin resistance, inflammation, and diabetes mellitus and completed a thesis project on the function of the adipocyte secretory protein adiponectin, and then moved on to start a translational research career looking for novel biomarkers and clinical assays seeking to improve and/or facilitate the prevention, early detection, and therapeutic monitoring of diabetes mellitus. Diabetes mellitus is a terrible disease with terrible consequences on individual sufferers and on society, and represents a global epidemic whose ramifications cannot be overstated. My personal interest in this disease stems simply from having taken care of patients with diabetes.
Before entering medical school I worked as a nursing assistant with diabetic patients in long-term care facilities, I took care of diabetic patients during medical school, and I was especially affected while spending a month of medical school rotating through the vascular surgery service, participating in vascular bypass surgeries and amputations. This award will support my early development as an independently-funded investigator, and although I plan to maintain a role as a clinical laboratory medical director, I hope to be able to always devote at least 75% effort to research. This award will provide me with the financial support needed for my 75% effort (which in my opinion is the minimum necessary to develop a robust research program).
In what direction do you see the future of diabetes research going?
My project is designed to serve as the first step in developing a research program of biomarker development for the diagnostic problems of diabetes mellitus. Novel clinical assays are needed for advanced prediction of future onset of this disease, screening and earlier detection of diabetes, more accurate evaluation of blood glucose control, and discovery of prognostic markers associated with the chemical pathology associated with this disease (oxidative and carbonyl stress, advanced glycation end products, diabetes-associated inflammation, and markers of vasculopathy, markers of diabetic renal pathology). The most immediate and attainable goal is optimal management of patients with established diabetes mellitus, and this goal is the impetus for this particular project.
Although optimum glycemic control represents the most attainable target currently, blood glucose is not an absolute predictor of diabetic complications. Emerging evidence has implicated downstream mechanisms of chemical pathology (oxidative and carbonyl stress, advanged glycation end products, hyperglycemic inflammation) which are the more proximal mediators of vascular damage. We need to develop biomarker assays for these indicators of chemical pathology in order to develop better predictors of long-term outcomes and test them in clinical studies. The chemical pathology of diabetes mellitus also includes the uremia and metabolic dysfunctions that occur as a result of diabetic kidney disease. Related to this, in addition to this project I am concurrently working on a prognostic assay related to the chemical mechanisms and pathophysiology of uremia in end-stage renal failure (unfunded).
In addition to projects like this that seek to improve therapeutic management, the long-term goals of diabetes research are to find novel avenues for prevention and cure. The most ambitious path to a cure to diabetes mellitus lies in islet replacement therapy. This is also one of the most daunting challenges in all of medicine, however, and my opinion is that solutions are not likely to be soon in coming. Although cellular therapies will take some time to come, glucose-responsive insulin pumps are a more immediate possibility, and I think that they will prove to be a tremendous improvement upon injectable insulin. Insulin pump and even islet replacement therapies will never perfectly approximate the metabolic control of a healthy pancreas, however, and given the current global diabetes epidemic it could be argued that finding effective approaches to prevention of diabetes mellitus should be given at least as much effort as we put towards looking for a cure.
The future of preventive therapies for type 2 diabetes mellitus begins with tools for the prediction of disease before it occurs. Although we know that diet, exercise, and insulin-sensitizing therapies can in many cases prevent the development of type 2 diabetes mellitus, we do not yet have diagnostic tools for accurately predicting the future onset of this disease. Risk factors alone often do not provide the kind of objective evidence required to inspire patients to change their habits, nor do they provide the amount of positive predictive value required to justify prophylactic medicinal therapies (like metformin) in pre-diabetics. Once we know how to predict the disease with certainty, we will have a tool that allows us to find even better ways of preventing it.
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