Chemical Structure and Biosynthesis
The hormone is synthesized in the B-cells ($\beta$-cells) of the pancreatic islets of Langerhans. The process takes place in the Golgi apparatus and involves several stages:
- Formation of preproinsulin.
- Conversion into proinsulin — a single long polypeptide chain where the future A and B chains are connected by a connecting C-peptide (C-protein).
- Maturation via proteolysis: enzymes cleave the C-peptide at the junction sites (which contain paired arginine and lysine residues).
成熟 The mature molecule consists of two chains: the A-chain (21 amino acid residues) and the B-chain (30 residues). The spatial structure is rigidly stabilized by disulfide bonds between cysteine residues: two interchain and one intrachain (within the A-chain). The finished active hormone is packaged into granules and released via exocytosis.
Physiology of Secretion
Normally, secretion is pulsatile with an interval of 15–30 minutes. The primary stimulus for hormone release is an increase in blood glucose levels.
Molecular cascade in the $\beta$-cell:
- Glucose enters the cell via the insulin-independent GLUT-2 transporter.
- During glucose metabolism, the intracellular concentration of energy in the form of ATP increases sharply.
- Excess ATP blocks ATP-dependent potassium channels, which stops the efflux of $K^+$ ions and causes depolarization of the cell membrane.
- Depolarization opens voltage-gated calcium channels. $Ca^{2+}$ ions rush into the cytoplasm down their concentration gradient.
- The rise in calcium levels triggers exocytosis of vesicles containing the ready hormone into the bloodstream.
Additionally, production is stimulated by the parasympathetic nervous system (via $M_3$-cholinergic receptors), amino acids, and incretins (e.g., GLP-1). Conversely, the sympathetic system (via $\alpha_2$-adrenergic receptors) and somatostatin inhibit incretion.
Pharmacodynamics and Receptor Apparatus
Insulin exerts a pronounced anabolic effect: it stimulates the synthesis of proteins, lipids, and glycogen. Its primary effect is hypoglycemic (lowering blood sugar).
The hormone acts via a specific receptor on the membrane of target cells. The receptor consists of two $\alpha$-subunits (extracellular, ligand-binding) and two $\beta$-subunits (transmembrane). The binding of the molecule to the $\alpha$-subunits induces autophosphorylation of the $\beta$-subunits. The complex undergoes endocytosis into the cytoplasm, triggering a cascade of reactions:
- Transport pathway: stimulates the synthesis and translocation to the membrane of GLUT-4 transporter proteins, which ensure glucose uptake by adipose and striated muscle tissue (via facilitated diffusion).
- Metabolic pathway: activates intracellular enzymes. Hexokinase phosphorylating glucose, 'trapping' it inside the cell. Pyruvate kinase and phosphofructokinase enhance glycolysis, while glycogen synthase initiates glycogen storage.
Note: The brain receives glucose independently of insulin via the GLUT-1 transporter.
Insulin Preparations in Clinical Practice
In type 1 diabetes mellitus (absolute deficiency), preparations are prescribed for life. In type 2 diabetes mellitus (relative deficiency), they are used when oral synthetic agents are ineffective or in severe cases.
Historically, animal insulins (porcine, bovine) were used, but due to protein impurities (proinsulin, glucagon), they frequently caused allergies. Today, recombinant DNA human insulin preparations are the standard. They are administered exclusively parenterally.
Classification by duration of action:
- Rapid-acting: begin working in 30 minutes, total duration 4–6 hours. Used for systematic treatment and management of diabetic coma (intravenous administration is acceptable).
- Intermediate-acting: act for 8–12 hours.
- Long-acting: effect lasts 20–30 hours.
To create prolonged formulations, the hormone is precipitated with protamine or zinc ions are added. The resulting suspensions create a subcutaneous 'depot' from which the substance is absorbed gradually. Important: suspensions are strictly contraindicated for intravenous administration!
Side Effects and Emergency Conditions
The primary danger during insulin therapy is hypoglycemia, which occurs due to drug overdose or insufficient carbohydrate intake with food. Severe forms progress to hypoglycemic coma (loss of consciousness, convulsions, cardiovascular collapse).
For emergency care in coma, 20–40 ml of a 40% glucose solution is administered intravenously (the maximum allowable volume is 100 ml). Other side effects include allergic reactions and local lipodystrophy (disruption of adipose tissue at frequent injection sites).