Gaps in the Glycation Gap Hypothesis

Randomized trials have documented that lowering hemoglobin A^sub 1c^ (Hb A^sub 1c^)4 concentrations significantly reduces the onset and rate of progression of microvascular complications (1, 2). [...] Hb A^sub 1c^, which is formed by the nonenzymatic attachment of glucose (termed glycation) to hemoglobin and reflects the mean glucose concentration over the preceding 8 to 12 weeks (3, 4), correlates with the risk for developing microvascular and cardiovascular complications in diabetes (5, 6). [...] the models that use the GG in addition to Hb A^sub 1c^ are examining the effect of fructosamine when added to the Hb A^sub 1c^ value, because the GG itself is a linear function of the Hb A^sub 1c^ and fructosamine concentrations, namely the regression residual. [...] an alternative interpretation is that the fructosamine concentration, which reflects the mean blood glucose concentration in the extracellular space over the previous 10 to 14 days, is independently associated with the risk of nephropathy when added to the Hb A^sub 1c^ value, which reflects the mean blood glucose concentration over the last 8 to 12 weeks.