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The page below is a sample from the LabCE course Diabetes: Diagnosis, Laboratory Testing, and the Current American Diabetes Association Guidelines (2018). Access the complete course and earn ASCLS P.A.C.E.-approved continuing education credits by subscribing online.

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Glycated Proteins and Hb A1C

There are many possible post-translational modifications to proteins after ribosomal synthesis. Glycated proteins are examples of modified proteins and are formed by the addition of glucose molecules to amino acid chains. Hb A1C is an important glycated protein assayed to diagnose and monitor diabetes. Fructosamine is another less assayed modified protein.
Hb A1C
Hb A comprises the majority of normal adult hemoglobin (Hb) and includes the minor hemoglobins, Hb A1A, Hb A1B, and Hb A1C. Sometimes these three are referred to as Hb A1, but A1C is the major fraction and composes 80% of Hb A1. Following synthesis of Hb A, a nonenzymatic reaction adds glucose to the N-terminal valine on either beta chain forming glycated Hb.
As the red blood cells (RBCs) circulate, an irreversible rearrangement of the pre-A1C base occurs forming a stable ketoamine, A1C. Over the life span of the RBCs (120 days) this process continues and the concentration of A1C is proportional to the concentration of the blood glucose. The concentration of A1C then relates to an individual's average glucose over time and can be used as an index relating to the extent of carbohydrate control during a two to three-month period.
There is also a direct relationship between the concentration of Hb A1C and risk of complications in diabetic patients. Therefore, the ADA has recommended using Hb A1C measurements to monitor glycemic control.
The Hb A1C assay is currently considered the standard biomarker for glycemic management. In the past, there was a lack of standardization, however, most current Hb A1C assays are now highly standardized. ADA practice recommendations clearly indicate that the Hb A1C measurement be a National Glycohemoglobin Standardization Program (NGSP) method and traceable to the Diabetes Control and Complications Trial (DCCT) reference assay.
The recent ADA recommendations (2018) include additional language and recommendations to help ensure appropriate use of the A1C test to diagnose diabetes and for monitoring glycemic control in people with diabetes. The ADA emphasizes that the A1C test can give skewed results in people with certain genetic traits that alter the molecules in their RBCs. In addition, the ADA stresses that health care providers need to be aware of these limitations, to use the correct type of A1C test, and to consider alternate diagnostic tests (fasting plasma glucose test or oral glucose tolerance test) if there is disagreement between A1C and blood glucose levels.
Specifically the ADA issues the following A1C recommendations:
  • To avoid misdiagnosis or missed diagnosis, the A1C test should be performed using a method that is certified by the NGSP and standardized to the DCCT assay.
  • Marked discordance between measured A1C and plasma glucose levels should raise the possibility of A1C assay interference due to hemoglobin variants (eg, hemoglobinopathies) and consideration of using an assay without interference or plasma blood glucose criteria to diagnose diabetes.
  • In conditions associated with increased red blood cell turnover, such as sickle cell disease, pregnancy (second and third trimesters), hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only plasma blood glucose criteria should be used to diagnose diabetes.