Chemical structure and biosynthesis
The hormone is synthesized in B-cells ($\beta$-cells) of the islets of Langerhans in the pancreas. 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 linking C-peptide (C-protein).
- Maturation via proteolysis: enzymes cleave off the C-peptide at the junction sites (which contain paired arginine and lysine residues).
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 main stimulus for hormone release is an increase in blood glucose levels.
Molecular cascade in the $\beta$-cell:
- Glucose enters the cell through the insulin-independent transporter GLUT-2.
- During glucose metabolism, the intracellular energy concentration in the form of ATP increases sharply.
- Excess ATP blocks ATP-sensitive 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 the concentration gradient.
- The rise in calcium levels triggers the 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, fats, and glycogen. Its main 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 (external, ligand-binding) and two $\beta$-subunits (transmembrane). Binding of the molecule to the $\alpha$-subunits causes autophosphorylation of the $\beta$-subunits. The complex plunges into the cytoplasm (endocytosis), triggering a cascade of reactions:
- Transport pathway: the synthesis and translocation to the membrane of GLUT-4 transporter proteins are stimulated, ensuring glucose uptake by adipose and striated muscle tissue (via facilitated diffusion).
- Metabolic pathway: intracellular enzymes are activated. Hexokinase phosphorylates glucose, "trapping" it inside the cell. Pyruvate kinase and phosphofructokinase enhance glycolysis, while glycogen synthase triggers glycogen storage formation.
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), medications 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 human insulin preparations are the standard. They are administered exclusively parenterally.
Classification by duration of action:
- Rapid-acting: begin to work 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: the 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 must strictly never be administered intravenously!
Side effects and emergency conditions
The main danger in insulin therapy is hypoglycemia, which occurs with a drug overdose or insufficient carbohydrate intake with food. Severe forms progress to hypoglycemic coma (loss of consciousness, seizures, cardiovascular failure).
For emergency care during a 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 (disorders of adipose tissue at frequent injection sites).
Briefly: answers to topical questions
What modern ultra-short-acting recombinant insulin analogs exist?
Modern ultra-short-acting insulin analogs are represented by chemically modified molecules that do not form aggregates in solution. These include:
- Insulin lispro — a modification with an amino acid sequence inversion at positions 28 and 29 of the B-chain.
- Insulin aspart — an analog that prevents the formation of dimers and hexamers.
- Insulin glulisine — a drug with a similar principle of action.
These preparations remain in monomeric form, ensuring their rapid absorption. The onset of their action is noted in 5–15 minutes, and the total duration of the effect is 4–5 hours.
What is the complete algorithm of medical care for severe hypoglycemic coma?
Medical care for a severe hypoglycemic state consists of emergency intravenous administration of a hypertonic glucose solution. The complete step-by-step algorithm for recovering from severe hypoglycemic coma is not presented in the materials. Out-of-hospital diagnosis of the condition is difficult due to its rapid development, so having a diabetes mellitus patient ID card is important for verifying the diagnosis. Laboratory confirmation of the pathology shows decreased blood glucose levels with normal urine specific gravity and the absence of glucose and acetone in it.
What are the absolute clinical indications for prescribing insulin therapy in type 2 diabetes mellitus?
The materials indicate the following grounds for prescribing insulin therapy in type 2 diabetes mellitus:
- inefficacy of synthetic oral agents or lack of results when using their high doses;
- pronounced symptoms of carbohydrate metabolism decompensation;
- failure to reduce HbA1c by at least 1.5% or to achieve the target level after 3–6 months of therapy with a combination of 2 or 3 drugs;
- planning pregnancy and the period of pregnancy in female patients with type 2 diabetes mellitus.
Remembering the $\beta$-cell secretion cascade is helped by the GAK-DKE mnemonic: Glucose entered $\rightarrow$ ATP increased $\rightarrow$ Katrium (Potassium) channel closed $\rightarrow$ Depolarization of the membrane $\rightarrow$ Calcium channel opened $\rightarrow$ Exocytosis of insulin.
Class and exam questions
Why are insulin preparations not produced in tablet form?
Insulin has a peptide nature. When taken orally, it is completely destroyed by gastrointestinal tract enzymes into inactive amino acids before it can enter the systemic circulation.
What is the difference between GLUT-1, GLUT-2, and GLUT-4 transporters?
GLUT-1 provides basal nutrition to the brain and is insulin-independent. GLUT-2 acts as a sugar level sensor in the pancreatic $\beta$-cells. GLUT-4 is an insulin-dependent transporter that captures glucose in muscles and adipose tissue only when hormone receptors are stimulated.
Can prolonged-acting insulins be administered intravenously for a rapid effect?
Absolutely not. Prolonged formulations are amorphous or crystalline suspensions (with the addition of zinc or protamine). They are administered only subcutaneously or intramuscularly. Only rapid-acting drugs are permitted to be administered intravenously.
What else to study on this topic
- The role of C-peptide in the diagnostics of the incretory function of the pancreas
- Degrees of purification of animal insulins: monocomponent and monpeak preparations
- Pathogenesis of diabetic ketoacidosis and diabetic angiopathies
- Influence of the autonomic nervous system on the secretion of the islets of Langerhans
- Differences between absolute and relative insulin deficiency
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