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REVIEW ARTICLE
ABSTRACT
Hemoglobin A1C is used to screen and diagnose diabetes but measurement of glucose
in the blood is subject to several limitations, many of which are not widely appreciated.
Blood glucose testing should be taken into consideration before taking the patient to be
diabetic on the basis of abnormal HbA1c values.
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150 INDIAN JOURNAL OF MEDICAL SCIENCES
last few years many physicians have been All the major institutions like International
using hemoglobin A1C to screen for and Expert Committee Report, drawn from the
diagnose diabetes.[3] Although considered the International Diabetes Federation (IDF),
“gold standard” for diagnosis, measurement the European Association for the Study of
of glucose in the blood is subject to several Diabetes (EASD), and the American Diabetes
limitations, many of which are not widely Association (ADA), suggests the A1C level of
appreciated. Measurement of A1C for diagnosis 48 mmol/mol (6.5%) as a diagnostic level.[6]
is appealing but has some inherent limitations.
This review will provide an overview of the FPG test
glucose and A1C testing. The FPG test is the preferred test for
diagnosing diabetes because of its
GLYCATED HEMOGLOBIN convenience and low cost. However, it will
miss some diabetes or pre‑diabetes that can
Glycated hemoglobin is a form of hemoglobin be found with the OGTT. The FPG test is most
which is measured primarily to identify the reliable when done in the morning. Results
average plasma glucose concentration and their meaning are shown in Table 1.
over prolonged periods of time. It is formed People with a fasting glucose level of 100 to
in a non‑enzymatic glycation pathway by 125 milligrams per deciliter (mg/dL) have a
hemoglobin’s exposure to plasma glucose and form of pre‑diabetes called impaired fasting
binding to the N‑terminal of valine of βchain of glucose (IFG). Having IFG means a person has
hemogobin. Normal levels of glucose produce a an increased risk of developing type 2 diabetes
normal amount of glycated hemoglobin. As the but does not have it yet. A level of 126 mg/dL
average amount of plasma glucose increases, or above, confirmed by repeating the test on
the fraction of glycated hemoglobin increases in another day, means a person has diabetes.[7]
a predictable way. This serves as a marker for
average blood glucose levels over the previous OGTT
months prior to the measurement. OGTT is more sensitive than the FPG test
for diagnosing pre‑diabetes, but it is less
The 2010 American Diabetes Association convenient to administer. The OGTT requires
Standards of Medical Care in Diabetes added fasting for at least eight hours before the
the A1c ≥ 48 mmol/mol (≥6.5%) as another test. The plasma glucose level is measured
criterion for the diagnosis of diabetes.[4] immediately before and two hours after a
person drinks a liquid containing 75 grams of
In diabetes mellitus, higher amounts of glycated glucose dissolved in water. Results and their
hemoglobin, indicating poorer control of blood meaning are shown in Table 2. If the blood
glucose levels, have been associated with glucose level is between 140 and 199 mg/dL
cardiovascular disease, nephropathy, and two hours after drinking the liquid, the person
retinopathy. The HbA1c level is proportional to has a form of pre‑diabetes called impaired
average blood glucose concentration over the glucose tolerance (IGT). Having IGT, like having
previous four weeks to three months.[5] IFG, means a person has an increased risk of
Indian Journal of Medical Sciences, Vol. 67, No. 7 and 8, July and August 2013
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BLOOD GLUCOSE PROFILE AND DIABETES SCREENING 151
developing type 2 diabetes but does not have Table 1: Diagnostic values of HbA1c for diabetes
it yet. A 2‑hour glucose level of 200 mg/dL or HbA1c (%) Normal/abnormal Average blood glucose
4‑6.5 Normal for those 3‑8 mmol/L
above, confirmed by repeating the test on without diabetes
another day, means a person has diabetes.[8] 6.5‑7.5 Target range for 8‑10 mmol/L
those with diabetes
8‑9.5 High 11‑14 mmol/L
RANDOM PLASMA GLUCOSE TEST Greater Very high 15 and above
than 9.5
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152 INDIAN JOURNAL OF MEDICAL SCIENCES
In line with the above mentioned studies, Glycated hemoglobin estimation can be done to
C u r t L . R o h l f i n g e t a l . [11] d e f i n e d t h e assesses the microvascular and macrovascular
relationship between HbA1c and plasma complications of diabetes mellitus, as it has
glucose by measuring quarterly HbA1c and been supported by Yun Huang et al.[14] in their
corresponding seven point capillary blood study of finding the Glycosylated HbA1c, fasting
glucose profiles. They concluded that among plasma glucose and two hour post challenge
individual time points, afternoon and evening plasma glucose levels in relation to carotid
plasma glucose (post‑lunch, pre‑dinner, intima media thickness in Chinese population
post‑dinner and bedtime) showed higher with normal glucose tolerance [Table 3]. They
correlations with HbA1c than the morning found the increasing trend of carotid intima
time points (pre‑breakfast, post‑breakfast and media thickness was found in HbA1c quartiles
pre‑lunch). Knowing this relationship can help rather than fasting plasma glucose and
patients with diabetes and their healthcare postchallenge glucose quartiles. So, HbA1c
providers set day‑to‑day targets for plasma could be more informative of cardiovascular
glucose to chieve HbA1c goals. Christopher. risk factor as compared with fasting plasma
et al.[12] supported using HbA1c as a screening glucose and post challenge glucose in subject
and diagnostic test because it does not require with normal glucose tolerance.
patient fasting and it reflects longer term
glycemia than does the plasma glucose. They A study conducted by Waqar Azim et al.[15]
also supported the fact that errors caused by pointed out that there is a direct correlation
nonglycemic factors affecting HbA1c such as between glycated hemoglobin and random
hemoglobinopathies are infrequent and can plasma glucose levels with no correlation
be minimized by confirming the diagnosis of between age of the patients and the glycated
diabetes with a plasma glucose specific test. hemoglobin or the age and the random plasma
glucose levels. They stated that for every 1%
Glycated hemoglobin value at baseline was rise in HbA1c, plasma glucose level rose by
associated with newly diagnosed diabetes and 2.3 mmol/L.
cardiovascular outcomes. Glycated hemoglobin
and death from any cause were found to have In contrast to the above mentioned studies
J‑shaped association curve as described by Ghazan farri et al.[16] stated that fasting blood
Elizabeth Selvin et al.[13] All these associations glucose is more reliable to separate diabetic
were significant after adjustment for baseline from non‑diabetic subjects than HbA1c. They
fasting glucose level. For coronary heart found that the association of HbA1c with
disease, measures of risk discrimination
Table 3: Diagnostic values of post prandial blood
showed significant improvement when glycated sugar for diabetes
hemoglobin was added to models including 2‑Hour plasma glucose Diagnosis
result (mg/dL)
fasting glucose. Therefore, in non diabetic
139 and below Normal
adults glycated hemoglobin is associated with 140 to 199 Pre‑diabetes
risks of cardiovascular disease and death from (impaired glucose tolerance)
200 and above Diabetes*
any cause as compared with fasting glucose.
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BLOOD GLUCOSE PROFILE AND DIABETES SCREENING 153
fasting blood glucose was relatively stronger Diagnosis of Diabetes Mellitus and Intermediate
particularly in diabetic subjects by determining Hyperglycermia: Report of a WHO/IDF
the sensitivity, specificity and predictive values Consultation. Geneva: World Health Organization;
in detection of abnormal values. Similarly, Rajni 2006.
3. S a u d e k C D , H e r m a n W H , S a c k s D B ,
Dawar Mahajan et al.[17] suggested that though
Bergenstal RM, Edelman D, Davidson MB. A new
HbA1c has advantages over fasting plasma
look at screening and diagnosing diabetes mellitus.
blood glucose levels for diagnosing diabetes
J Clin Endocrinol Metab 2008;93:2447‑53.
but its use as a single diagnostic agent is 4. “Executive summary: Standards of medical
limited because of number of biochemical, care in diabetes‑2010”. Diabetes Care
clinical and economical factors. In developing 2010;33(Suppl 1):S4‑10.
countries and underdeveloped countries the 5. Larsen ML, Hørder M, Mogensen EF. Effect of
laboratories are not standardized for HbA1c. long‑term monitoring of glycosylated hemoglobin
Also the clinician should consider the overall levels in insulin‑dependent diabetes mellitus.
patient profile and a number of local variations N Engl J Med 1990;323:1021‑5.
and disorders as hemoglobinopathies or 6. The International Expert Committee. International
expert committee report on the role of the A1C
anemias. It is also not cost effective, so HbA1c
assay in the diagnosis of diabetes. Diabetes Care
cannot be used as a sole and independent test
2009;32:1327‑34.
to diagnose diabetes mellitus.
7. American Diabetes Association. January
2006 Diabetes Care. “Standards of Medical
PERSPECTIVE Care‑Table 6 and Table 7, Correlation
between A1C level and Mean Plasma Glucose
Notwithstanding the use of glucose (FPG Levels on Multiple Testing over 2–3 months.”
and/or the OGTT) as the “gold standard” for the 29:(Suppl 1):51‑580.
diagnosis of diabetes for many years, glucose 8. USDA National Nutrient Database for Standard
testing suffers from several deficiencies, but Reference, Release 22 (2009).: http://www.ars.
the clinician must consider the overall profile of usda.gov/nutrientdata/sr (updated annually)
the patient before taking into consideration the Search page: http://www.nal.usda.gov/fnic/
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154 INDIAN JOURNAL OF MEDICAL SCIENCES
Indian Journal of Medical Sciences, Vol. 67, No. 7 and 8, July and August 2013