Insulin Synthesis and Mechanism of Action
Insulin is a hormone produced by pancreatic β-cells, the secretion of which is triggered in response to elevated blood glucose levels. Insulin is stored in secretory granules along with C-peptide, which is used in the differential diagnosis of diabetes types.
The mechanism of secretion involves several sequential stages:
- when plasma glucose levels exceed 5.5 mmol/L, the GLUT-2 transporter is activated, and glucose enters the β-cell;
- ATP-sensitive potassium channels close, leading to intracellular potassium accumulation;
- membrane depolarization occurs, opening voltage-gated calcium channels;
- Ca²⁺ ions initiate the exocytosis of granules containing insulin and C-peptide.
By binding to its tyrosine kinase receptor on muscle and fat cells, insulin triggers the translocation of GLUT-4 from intracellular storage depots to the cell membrane, facilitating glucose uptake into tissues.
Pathogenesis of Type 1 and Type 2 DM
Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of β-cells, developing predominantly in young patients, frequently following a viral infection. It is characterized by absolute insulin deficiency.
Type 2 diabetes mellitus is associated with tissue insulin resistance and relative insulin deficiency. Hyperinsulinemia leads to down-regulation of insulin receptors and GLUT-4 expression. Obesity plays a significant role: hypertrophied adipocytes experience hypoxia and secrete pro-inflammatory cytokines—TNF-α and interleukin-6—which impair the insulin receptor signaling pathway.
The clinical triad for both types includes polyuria (osmotic diuresis due to glucosuria), polydipsia, and polyphagia, accompanied by persistent hyperglycemia.
Acute Complications
Diabetic ketoacidosis most commonly develops in type 1 DM. Insulin deficiency disinhibits lipolysis, resulting in an excess of free fatty acids, which are converted in the liver into ketone bodies. Their accumulation causes metabolic acidosis. Management includes:
- intravenous insulin administration to suppress lipolysis;
- rehydration with normal saline (sodium chloride);
- mandatory monitoring of potassium levels—insulin therapy drives potassium into cells, potentially causing life-threatening hypokalemia.
Hyperosmolar hyperglycemic state is characteristic of type 2 DM: pronounced hyperglycemia retains water within the vascular bed, leading to tissue dehydration and the risk of cerebral edema. Management consists of intravenous insulin administration and rehydration.
Chronic Complications
Macroangiopathies are caused by accelerated atherosclerosis of large vessels: coronary artery disease, myocardial infarction, stroke, transient ischemic attack (TIA), and lower extremity arterial disease with the risk of gangrene.
Microangiopathies affect small-caliber vessels:
- Diabetic nephropathy: damage to the glomerular afferent arteriole, loss of nephrons, albuminuria, progressing to chronic kidney disease;
- Diabetic retinopathy: damage to retinal arteries, hemorrhages, risk of blindness;
- Diabetic neuropathy: involvement of the vasa nervorum of peripheral nerves, leading to sensory loss and the formation of diabetic foot syndrome.
Diagnostics
Diagnosis is established based on venous plasma glucose levels:
- fasting glucose ≥ 7.0 mmol/L on two separate measurements;
- random glycemia ≥ 11.1 mmol/L in the presence of symptoms;
- for values of 5.6–6.9 mmol/L, an oral glucose tolerance test (OGTT) is indicated; a 2-hour value ≥ 11.1 mmol/L confirms diabetes;
- glycated hemoglobin (HbA1c) ≥ 6.5% is a diagnostic criterion and an integrated marker of glycemic control over the past 3 months.
Upon diagnosis, the following are mandatory: eGFR assessment, ophthalmological examination, ECG, foot examination, and lipid profile.
Management of Type 1 DM and Classes of Glucose-Lowering Drugs
Type 1 DM is treated exclusively with insulin therapy (a combination of basal and bolus insulin) — this is pathogenetic replacement therapy.
For type 2 DM, the following are used:
- Metformin — first-line drug; inhibits mitochondrial complex I, activates AMPK, reduces hepatic gluconeogenesis, increases GLUT-4 expression and tissue insulin sensitivity;
- SGLT2 inhibitors (gliflozins) — block glucose reabsorption in the proximal tubules; adverse effect: genitourinary infections;
- GLP-1 receptor agonists — stimulate insulin secretion by β-cells and suppress glucagon secretion by α-cells;
- DPP-4 inhibitors (gliptins) — increase endogenous incretin concentrations;
- Sulfonylureas — block K⁺ channels in β-cells, enhancing insulin secretion;
- Thiazolidinediones (glitazones) — PPAR-γ agonists, increase GLUT-4 expression;
- α-Glucosidase inhibitors (acarbose) — reduce carbohydrate absorption in the intestine.
Type 2 DM Treatment Strategy
The target HbA1c level is individualized: for young patients without complications — less than 6.5%, for those with severe complications — less than 8.0%, and in terminal states, the priority is avoiding hypoglycemia.
The starting regimen depends on how much HbA1c exceeds the target:
- exceeding by less than 1.0% — metformin monotherapy;
- exceeding by 1.0–2.5% — combination of two drugs (metformin + SGLT2 inhibitor or another agent);
- exceeding by ≥ 2.5% — triple combination therapy or early initiation of insulin.
Self-monitoring of blood glucose is mandatory: 1–2 times per week without insulin therapy and 3–4 times daily when using insulin. Blood pressure, lipid profile, foot condition, and funduscopy are monitored. In patients with a BMI ≥ 35 kg/m² and ineffective medical therapy, bariatric (metabolic) surgery is considered, providing remission in a significant proportion of patients.
Key points
- Insulin is secreted by β-cells in response to hyperglycemia via a cascade: GLUT-2 → closure of K⁺ channels → depolarization → Ca²⁺ influx → exocytosis.
- Type 1 DM is autoimmune β-cell destruction with absolute insulin deficiency; type 2 DM is insulin resistance driven by obesity and chronic inflammation.
- Ketoacidosis requires insulin, NaCl rehydration, and strict potassium monitoring; hyperosmolar hyperglycemic state carries the danger of cerebral edema.
- Chronic complications include macro- and microangiopathies: coronary artery disease, nephropathy, retinopathy, neuropathy.
- Diagnostic criteria: fasting glucose ≥ 7.0 mmol/L, random glucose ≥ 11.1 mmol/L, HbA1c ≥ 6.5%.
- Metformin is the first-line drug for type 2 DM; the choice of subsequent medications depends on the extent to which the target HbA1c is exceeded.
- Target HbA1c is individualized: stricter for young patients without complications, less stringent for elderly and multimorbid patients.
- Bariatric surgery is effective in patients with a BMI ≥ 35 kg/m² when medical therapy fails.