Glycated hemoglobin

Mechanism of formation and pathogenetic significance

The formation of glycated hemoglobin is based on the process of non-enzymatic glycosylation. In chronic hyperglycemia, excess blood glucose begins to spontaneously and without enzyme participation bind to various body proteins. Primarily, this process affects hemoglobin inside erythrocytes, converting it into HbA1c.

However, hemoglobin is not the only protein subject to glycosylation. Glucose actively attaches to blood vessel proteins, extracellular matrix components, and low-density lipoproteins (LDL). From a biochemical perspective, this leads to severe structural changes:

• Thickening of the vascular basement membranes occurs.
• Specific vascular complications develop — microangiopathy and macroangiopathy.
• Microcirculation is altered, which can affect the pharmacokinetics of many medications.

Role in the diagnosis and monitoring of diabetes mellitus

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia. It arises due to absolute or relative insulin deficiency and disrupts all types of metabolism. Glycated hemoglobin acts as a key marker for detecting this pathology.

• Norm: up to 6.0% (42 mmol/mol).
• Manifest diabetes mellitus: diagnosed at HbA1c $\ge$ 6.5% values.
• Target values: in an already established diagnosis and ongoing glucose-lowering therapy, targets are individualized, but physicians most commonly aim to keep the parameter at <7.0–7.5%.

Strict requirements apply to laboratory methods for determining HbA1c: they must be certified by the international NGSP system and standardized according to DCCT. At the same time, there is an important clinical limitation: this test is not recommended for diagnosing gestational diabetes mellitus (recommendation grade C, evidence level 4).

Place among other carbohydrate metabolism parameters

For a comprehensive assessment of a patient's condition, glycated hemoglobin is always evaluated in conjunction with other biochemical tests:

1. Fasting glucose: normally ranges from 3.3–5.5 mmol/L for capillary blood and up to 6.1 mmol/L for venous plasma. A diabetes diagnosis is made when the threshold of $\ge$7.0 mmol/L (in venous plasma) is exceeded on two occasions. Hyperglycemia is also considered, for example, a value of 130 mg/dL (with a norm of <100–110 mg/dL).
2. Oral glucose tolerance test (OGTT): the patient is given a glucose load (1 g/kg) and blood sugar is measured after 120 minutes. In type 2 diabetes, this value is $\ge$ 11.1 mmol/L (200 mg/dL). The test is indispensable for detecting impaired glucose tolerance and gestational diabetes.
3. Insulin and C-peptide levels: used for differential diagnosis. In type 1 diabetes, absolute deficiency, autoimmune destruction of $\beta$-cells, presence of autoantibodies, and low (or undetectable) C-peptide are observed, which is especially characteristic 5 years after disease onset. In type 2 diabetes, against the background of insulin resistance, C-peptide and insulin levels remain normal or elevated, and autoantibodies are absent.

Biochemical consequences of hyperglycemia

A high HbA1c level indicates prolonged hyperglycemia, which triggers a cascade of pathological biochemical reactions forming the classic symptoms of diabetes:

• Osmotic diuresis: excess glucose exceeds the renal threshold, resulting in glucosuria. Glucose "pulls" water with it, leading to polyuria (frequent urination) and compensatory polydipsia (extreme thirst).
• Enhanced lipolysis: due to cellular energy starvation (manifested as polyphagia), fats are broken down, causing ketonemia and ketonuria.
• Enhanced protein catabolism: breakdown of tissue proteins leads to hyperazotemia and general fatigue.

Significance of parameters for pharmacotherapy

Glycemic control is critically important when prescribing medications. Pharmacists and physicians must consider the following factors:

• Glucose-lowering drugs (metformin, sulfonylureas) require strict monitoring of renal and hepatic function due to the risk of hypoglycemia and lactic acidosis.
• Certain medications can increase blood glucose levels. These include glucocorticoids, thiazide diuretics, and a number of antipsychotics.
• Statins and antipsychotics may increase the risk of developing metabolic syndrome; therefore, carbohydrate metabolism monitoring is necessary while taking them.
• When counseling patients on self-monitoring, it is important to explain the difference between portable glucometer readings (capillary blood) and laboratory assays.

Class and exam questions

What else to study on this topic

• Mechanisms of non-enzymatic protein glycosylation and the development of angiopathies.
• Differential diagnosis of types of diabetes mellitus: the role of C-peptide and autoantibodies.
• Oral glucose tolerance test (OGTT): indications and interpretation of results.
• Effect of medications on carbohydrate metabolism (glucocorticoids, diuretics, statins).
• Pathogenesis of clinical symptoms of diabetes: the connection between hyperglycemia, polyuria, and ketonemia.

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Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.