Human short-acting insulin preparations
In modern medical practice, recombinant human insulin preparations serve as the primary benchmark for safety and biocompatibility.
- A prominent representative is Actrapid HM, which is a solution of biosynthetic human insulin.
- Pharmaceutical formulations include vials (at a concentration of 40 or 100 IU/mL) and specialized cartridges designed for pen injectors (e.g., NovoPen).
- Pharmacokinetic profile: the drug begins to act 30 minutes after administration, reaches its maximum peak in 1–3 hours, and the total duration of its effect is about 8 hours.
Ultra-short-acting insulins and analogues
Regular unmodified insulin in solution and at the injection site tends to form large aggregates—dimers and hexamers. This physical property significantly slows down the absorption of the active substance into the systemic circulation.
To overcome this drawback, insulin analogues were developed—chemically modified molecules that prevent aggregate formation and remain in monomeric form.
- Representatives: insulin lispro, insulin aspart, and insulin glulisine.
- Lispro characteristics: in the B-chain of the molecule, an inversion of the amino acid sequence occurs at positions 28 and 29 (amino acids proline and lysine swap places, forming a lysine-proline sequence instead of proline-lysine).
- Advantages: absorption occurs twice as fast (the effect begins after 15 minutes), and the total duration does not exceed 3 hours. This allows the drug to be administered immediately before a meal for reliable control of postprandial hypoglycemia and a reduction in the risk of delayed coma.
Drug interactions in insulin therapy
The effectiveness of insulin administration directly depends on the patient's concurrent pharmacotherapy, which requires strict medical supervision.
- Potentiation of the hypoglycemic effect (increased risk of dangerous hypoglycemia) is caused by $\beta$-blockers (which additionally mask the symptoms of falling blood sugar), sulfonamides, anabolic steroids, and MAO inhibitors.
- Attenuation of the hypoglycemic effect (risk of hyperglycemia) is observed with the combined use of thiazide diuretics, thyroid hormones, heparin, and glucocorticoids, which have a pronounced counter-regulatory action.
Contraindications
The use of insulin preparations has strict medical limitations and contraindications in the following pathological conditions:
- Developing or existing hypoglycemia.
- Acute diseases of the hepatobiliary system (liver) and pancreas.
- Decompensated heart defects.
Briefly: answers to topical questions
What chemical modifications distinguish insulin aspart and glulisine from human insulin?
Insulin aspart and insulin glulisine are created using a chemical modification principle similar to that of insulin lispro, although the exact amino acid substitutions for them are not specified in the sources.
- Prevention of aggregation — structural changes prevent the formation of dimers and hexamers.
- As a result of chemical modification, these preparations remain in monomeric form, which ensures their faster absorption compared to regular human insulin.
What is the mechanism of action of insulin at the cellular level?
The mechanism of action of insulin is based on the activation of specific membrane receptors with tyrosine kinase activity.
- Binding — the hormone interacts with the extracellular $\alpha$-subunits of the receptor.
- Activation — approximation and autophosphorylation of the transmembrane $\beta$-subunits at tyrosine residues occur.
- Cascade of reactions — the insulin receptor substrate (IRS-1) is phosphorylated, which binds to PI3-kinase, leading to the formation of $PIP_3$ and activation of protein kinase B.
- Effects — the complex enters the cytoplasm via endocytosis. Translocation of GLUT-4 transporters to the membrane for glucose uptake, activation of glycolysis and glycogen synthase enzymes, and inhibition of glycogenolysis occur.
What are the possible side effects of insulin therapy, besides hypoglycemia?
In addition to hypoglycemia, insulin therapy can cause local and immune adverse reactions.
- Allergic reactions — may occur in response to the drug itself (especially when using animal insulins due to the presence of protein impurities such as proinsulin or C-peptide).
- Lipodystrophies — local disruption of adipose tissue at injection sites (post-injection lipodystrophy), resulting from repeated administrations of the drug into the same area.
What are the acceptable routes of administration for short- and ultra-short-acting insulins?
Short- and ultra-short-acting (rapid) insulins are administered exclusively via parenteral routes.
- Subcutaneous administration — the main route for systematic treatment and control of postprandial glycemia (drugs are administered before meals).
- Intravenous administration — acceptable for short- and ultra-short-acting preparations in the management of emergency conditions (e.g., diabetic coma).
- Intramuscular administration — mentioned as one of the possible parenteral routes for insulin preparations.
Oral administration is impossible due to the destruction of the hormone by gastrointestinal tract enzymes.
In what emergency conditions is intravenous administration of short-acting insulin indicated?
Intravenous administration of short-acting insulin is indicated for a number of life-threatening conditions to rapidly achieve a therapeutic effect.
- Diabetic ketoacidosis (DKA) — for emergency correction of hyperglycemia and metabolic acidosis.
- Diabetic coma — for prompt management of acute decompensation of carbohydrate metabolism.
- Severe hyperkalemia — in chronic kidney disease, insulin is administered intravenously as a bolus (in combination with beta-2 agonist inhalations) for rapid reduction of blood potassium levels and management of life-threatening arrhythmias.
Lispro is «lis-pro» in reverse: lysine and proline swap places at positions 28 and 29 so that insulin does not stick together into hexamers and acts instantly!
Class and exam questions
What is the main pharmacokinetic difference between insulin lispro and regular human insulin?
Due to chemical modification, insulin lispro does not form dimers and hexamers. It exists in monomeric form, which is why it is absorbed twice as fast (starts working after 15 minutes) and has a short duration of action up to 3 hours.
Which drug classes enhance the hypoglycemic effect of insulin?
Potentiation of the hypoglycemic effect is caused by sulfonamides, anabolic steroids, MAO inhibitors, as well as $\beta$-blockers, which can additionally mask the symptoms of hypoglycemia.
What are the main dosage forms and pharmacokinetics of Actrapid HM?
Actrapid HM is available in vials of 40 or 100 IU/mL, as well as in cartridges for pen injectors. Its onset of action occurs in 30 minutes, peak in 1–3 hours, and total duration is about 8 hours.
What else to study on this topic
- Intermediate- and long-acting human insulin preparations (Isophane Insulin HM, Monotard HM, Ultratard HM)
- The specific mechanism of action of insulin glargine and its isoelectric point
- Porcine insulin preparations (Actrapid MC, isophane insulin, Lente SPP)
- Specifics of intravenous neutral insulin administration in the management of diabetic coma
- Comparison of pharmacokinetic profiles of amorphous and crystalline zinc insulin
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