Cox’s Conference: Diabetes Mellitus Pearls

In today’s Cox’s Conference, Dr. Patrick Nolan presented a case of new-onset type 2 diabetes mellitus to expert discussant Dr. Jessica Abramowitz. In this discussion, several pearls regarding diagnosis and management were discussed. 

Pearls:

Limitations of hemoglobin A1c

Remember that the hemoglobin A1c is supposed to be an estimation of the average blood glucose over 90-120 days. This is based on the assumption that the average erythrocyte has a lifespan of approximately 90-120 days.

If a condition causes a reduced lifespan in erythrocytes, there is less time during which non-enzymatic glycosylation of hemoglobin can occur. As a result, the hemoglobin will be less glycated for a given average blood glucose due to less duration of exposure of that red blood cell to circulating glucose. Thus, the hemoglobin A1c will be lower than expected for a given blood glucose level. As a general rule, conditions that cause increased erythropoesis, like hemolytic anemia, will decrease erythryocyte life span.

Conversely, if a condition causes a prolonged lifespan in erythrocytes, there is more time during which non-enzymatic glycosylation of hemoglobin can occur. As a result, the hemoglobin A1c will be higher than expected for a given average blood glucose level. As a general rule, conditions that cause decreased erythropoesis, like iron deficiency, will increase erythryocyte life span.

Moreover, blood transfusions can obscure the actual hemoglobin A1c due to the presence of blood that has not been exposed to the same glucose environment for the same time as a patient’s own blood. Other factors that mire the basic assumption that A1c reflects average blood glucose over the expected lifespan of an erythrocyte are things that can increase/decrease the glycosylation of hemoglobin (e.g. chronic salicylate ingestion, high doses of vitamin C and E, anti oxidants) or things that interfere with the laboratory assays for hemoglobin A1c.

factors affecting A1c
J Diabetes. 2009 Mar;1(1):9-17
Fructosamine:

Fructosamine is another measure of average blood glucose that can be used in place of hemoglobin A1c when it cannot be trusted for one of the above reasons. It measures the average glucose over 1-3 weeks. This has an additional advantage when the average blood glucose needs to be determined at a shorter interval than over 3-4 months (e.g. pilots cannot fly until their hemoglobin A1c is less than 9%, patients who cannot under go elective surgeries until hemoglobin A1c is less than 7%, etc.). However, conditions that affect protein concentrations (e.g. malnutrition, nephrotic syndrome, cirrhosis, thyroid disease, protein losing enteropathies) as well as conditions that influence immunoglobulin levels, especially IgA, result in lower than expected fructosamine levels. This significantly limits use of this assay in patients with those conditions. Also, note that fructosamine should not be used in the diagnosis of diabetes due to lower specificity.

The table below may guide in interpretation of frucosamine by correlating fructosamine levels with A1c and mean blood glucose.

fructosamine
Adapted from Ann Pediatr Endocrinol Metab. 2015 Mar; 20(1): 21–26.
Glycated albumin:

Glycated albumin is another measure of average blood glucose that, like fructosamine is not dependent on erythryocytes but, rather, glycosylation of proteins. It is, thus, not affected by anemia, hemolysis, iron deficiency, etc. and may serve as a better indicator of average glycemia in dialysis patients. Similar to fructosamine, it can estimate changes in average blood glucose over the past 14-21 days, which is useful for shorter monitoring intervals. While albumin levels can be affected like fructosamine in conditions that affect total protein concentrations, this flaw can be minimized by indexing the glycated albumin to total albumin. Thus, glycated albumin may be more versatile than fructosamine in the above mentioned conditions that affect protein concentrations.

While this test is gaining traction as a promising tool for the diagnosis, surveillance, and prognostication of glycemia, it is not yet widely used, has limited commercial reagents available for mass market use, and is not a familiar test among most practitioners.

The table below may help guide conversion of glycated albumin to A1c, with which providers are more familiar.

GA and A1c
PLoS One. 2016 Jan 14;11(1):e0146780.