Glycation gap: when HbA1c and fructosamine disagree

When glucose is high for a time, it attaches to proteins, a process called glycation. HbA1c measures glucose attached to haemoglobin inside red blood cells and is accepted as reflecting average glucose over the preceding 2 to 3 months. Fructosamine measures glucose attached to proteins in the serum, mainly albumin, which turn over in about 2 to 3 weeks, according to Lab Tests Online UK.

In theory both should tell the same story. In practice the correlation is good but not perfect. A research paper in PLoS ONE describes the glycation gap as the difference between the HbA1c measured and the level predicted from its regression on fructosamine. A positive gap means HbA1c reads higher than the fructosamine would predict, and a negative gap means it reads lower.

Several things explain disagreement. The two markers cover different time periods, so recent changes in treatment show first in fructosamine. Lab Tests Online UK also lists conditions in which HbA1c is unreliable: inherited haemoglobin variants such as sickle cell trait or thalassaemia, haemolytic anaemia and other conditions that change red cell lifespan; it adds that heavy bleeding or haemolysis can give falsely low HbA1c and iron deficiency can raise it.

Beyond those, the researchers point to biology inside the red cell: glycation depends on how glucose enters the cell and on intracellular glucose and protein handling, and HbA1c levels are partly inherited, with heritability above 50 per cent. Fructosamine measures extracellular glycated protein and so does not depend on those red cell dynamics.

In the study of 508 people with type 2 diabetes, the glycation gap was measured on two samples about 30 weeks apart and was reproducible and consistent over time, suggesting a stable individual trait. Serum creatinine, MCHC and blood glucose (with an inverse relationship) and HbA1c and metformin treatment (a direct relationship) were independently related to the gap. People taking metformin had higher HbA1c values despite similar fructosamine concentrations than those who did not take it.

Other studies have linked a high gap to some diabetic complications, particularly kidney disease, but the authors of the paper stress the need for caution, and the finding has not changed routine UK practice. These are observational associations, not proof that the gap causes harm.

Clinicians do not usually calculate a glycation gap. They notice when HbA1c does not match home meter readings or CGM data, and then consider causes such as anaemia, haemoglobin variants or recent changes. Lab Tests Online UK says fructosamine is not routinely used, is not standardised between laboratories so results cannot be compared across labs, and cannot diagnose diabetes.

Glucose diaries and continuous monitoring are often more informative than either marker when results disagree, and the NICE advice summarised by the same source is that capillary checks remain a back-up for CGM.

Both HbA1c and fructosamine are blood tests that need no preparation; the NHS describes the diabetes team as setting individual targets. If you are concerned that your HbA1c seems out of step with your readings, ask your diabetes team whether a fructosamine test, a full blood count or a haemoglobin variant check could help. Never change insulin or tablets on the strength of a single laboratory figure without advice.