As the prevalence of diabetes continues to rise globally, understanding the underlying biochemical processes leading to complications is more crucial than ever. One significant breakthrough in this pursuit is the growing insight into the progression of labile Hemoglobin A1c (Hb A1c), a marker for long-term blood glucose levels that has long been used to monitor and diagnose diabetes. A recent study published in the journal ‘Hemoglobin’ by researchers from Idaho State University offers new explanations for how this process occurs, providing a substantial leap in our understanding of nonenzymatic glycation (NEG) and its implications for diabetic patients.

DOI: 10.1080/03630269.2019.1597731

Background on Hb A1c and Its Importance in Diabetes

Hb A1c forms through the nonenzymatic reaction of glucose with hemoglobin, the protein responsible for transporting oxygen in red blood cells. This process, referred to as glycation, happens naturally over time, but at an accelerated rate in hyperglycemic conditions, like diabetes. As Hb A1c correlates with average blood glucose levels over the preceding two to three months, medical professionals use it as a reliable biomarker for assessing glycemic control in diabetic patients.

However, the formation of Hb A1c involves a series of complex steps that scientists are still deciphering. At the forefront is the initial phase, where labile Hb A1c is produced, which is reversible but leads to the stable and irreversible Hb A1c levels measured in medical tests.

The New Study: Insights into the Labile Hb A1c Formation

The research conducted by Christina R. Mottishaw, Stephanie Becker, Brandy Smith, Gentry Titus, R.W. Holman, and Kenneth J. Rodnick at Idaho State University delves into the intricacies of labile Hb A1c formation. It has been supported by the National Institute of General Medical Sciences (NIGMS) through grant number P20 GM103408 and does not present any conflict of interest.

This study hinges on the understanding that the initial noncovalent, reversible steps of NEG involve the interaction of glucose with amino acid residues in hemoglobin and can be affected by various effector reagents, highlighting the complex nature of labile Hb A1c formation.

Key Findings and Implications

The researchers discovered the multifaceted roles of 2,3-diphosphoglycerate (2,3-BPG), a molecule which normally binds to hemoglobin within red blood cells to facilitate oxygen release. In their findings, 2,3-BPG acts as an effector agent in the formation of labile Hb A1c. This suggests that 2,3-BPG may impact not only respiratory function but also glycation processes.

Adding to the complexity, their study indicates that the multimeric structure of hemoglobin, combined with the inherent dynamics of glucose binding, contributes to site selectivity in glycation. These observations are essential for understanding how certain glycation sites may have more profound implications for hemoglobin function and diabetic complications.

The study also explores the dynamic equilibrium of labile Hb A1c, which can shift in response to physiological factors, likened to the principle of Le Chatelier and Braun in chemical reactions. Further investigation into these equilibrium shifts may explain the variability in Hb A1c levels independent of blood glucose concentrations.

The broader consequences of NEG, including the formation of advanced glycation end-products (AGEs), have pervasive effects on protein function and contribute to the chronic complications observed in diabetes. Insights into the initial stages of NEG could thus pave the way for novel therapeutic strategies targeting early glycation products and possibly hinder progression to AGEs.

Looking Ahead

While the research offers significant insights, there remains much to uncover about the formation of labile Hb A1c and its progression. Considering that the study focused on in vitro conditions, there is a need to further explore these mechanisms within the human body, accounting for additional factors like intracellular conditions and individual variations in glycation rates.

The study also offers an opportunity to rethink clinical guidelines related to Hb A1c measurement. Given the variability in the initial stages of NEG, it may be necessary to consider additional biomarkers or refine current Hb A1c testing methods to ensure they accurately reflect an individual’s glycemic control.


The Idaho State University study marks a significant moment in our comprehension of NEG as it pertains to diabetic hemoglobin glycation. Their work lays the groundwork for future research, clinical practice, and, ultimately, the care and treatment of diabetic patients.

Given the complex biochemistry involved in the formation of labile Hb A1c, and consequently stable Hb A1c used in diabetes monitoring, continued research in this field is not just academic—it has the potential to translate into real-world benefits for millions of people living with diabetes.

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Last Update: March 9, 2024