Molecular structure
Chemically, insulin is a polypeptide. The mature active hormone molecule consists of two polypeptide chains:
- Chain A: comprises 21 amino acid residues.
- Chain B: consists of 30 amino acid residues.
The spatial structure of the hormone is stabilized by three disulfide bonds. Two of them are interchain bonds (they firmly connect chain A to chain B). The third bond is an intrachain bond, forming a loop within chain A itself.
Stages of biosynthesis and secretion
Insulin formation is a complex, multi-step process taking place in the pancreatic $\beta$-cells:
- Translation and preproinsulin formation. Synthesis of the polypeptide chain begins on polyribosomes attached to the rough endoplasmic reticulum (ER). At this stage, an inactive precursor with a signal peptide is formed.
- Proinsulin formation. Within the ER lumen, the signal peptide is cleaved off, and the molecule folds with the formation of disulfide bonds. This yields proinsulin.
- Processing in the Golgi apparatus. Proinsulin is transported to the Golgi apparatus. There, specific proteases excise the connecting region—the C-peptide.
- Packaging. Mature insulin (chains A and B) and the C-peptide are packaged into secretory granules.
- Exocytosis. Upon stimulation, the granule contents are released into the extracellular space.
Regulation of production and metabolism
The primary stimulus for insulin secretion is an elevated blood glucose concentration (hyperglycemia). Additional stimuli include amino acids (especially arginine and lysine), fatty acids, and ketone bodies. Hormone production is inhibited by epinephrine, somatostatin, and certain gastrointestinal peptides.
After performing its function, the hormone degrades rapidly. Its half-life is only 3–10 minutes. Cleavage is catalyzed by the enzyme insulinase, which is localized predominantly in the liver and to a lesser extent in the kidneys.
Mechanism of action and metabolic effects
The insulin signal is transmitted via a specific tyrosine kinase receptor on the membrane of target cells (liver, muscles, adipose tissue). Hormone binding triggers the phosphorylation of intracellular substrate proteins (IRS), which activates the PI3K/Akt and MAPK cascades.
As a result, anabolism is activated in tissues:
- Glucose transport into cells increases due to the translocation of GLUT4 transporters to the membrane.
- Glycolysis and glycogen synthesis are stimulated.
- Lipogenesis (fat formation) and protein synthesis are enhanced.
Clinical significance of C-peptide
C-peptide is secreted into the bloodstream in a strict equimolar ratio with insulin (1:1). However, its half-life is significantly longer—about 30 minutes.
In laboratory diagnostics, C-peptide levels are used to assess the pancreas's own (endogenous) insulin secretion. This is especially important if the patient is already receiving exogenous insulin injections (pharmaceutical preparations do not contain C-peptide, so the analysis will show only what the body itself has produced).
Briefly: answers to topical questions
What key regulatory enzymes of glycolysis and glycogen synthesis does insulin activate?
Insulin activates the following key enzymes of glycolysis and glycogen synthesis via covalent modification (dephosphorylation) and induction of synthesis:
- Glucokinase — activated through the induction of enzyme synthesis.
- Phosphofructokinase-1 — activated by fructose-2,6-bisphosphate, the concentration of which is increased by insulin.
- Pyruvate kinase — activated by dephosphorylation and via the induction of synthesis.
- Glycogen synthase — transitions into the active form via dephosphorylation.
How to remember insulin disulfide bonds: "Two bridges between the shores, one on the shore." Two interchain bridges connect chains A and B, while one intrachain bridge is located entirely within chain A.
Class and exam questions
Which chains make up the active insulin molecule?
The mature hormone consists of two polypeptide chains: chain A (21 amino acids) and chain B (30 amino acids). They are connected by disulfide bonds.
Why does a deficiency of insulin occur in type 1 diabetes mellitus?
Type 1 diabetes mellitus involves autoimmune destruction of the $\beta$-cells in the islets of Langerhans, making hormone synthesis impossible.
What inhibits insulin secretion?
Insulin production is inhibited by epinephrine, somatostatin, and certain gastrointestinal peptides.
What else to study on this topic
- Comparative characteristics of counter-regulatory hormones (glucagon, cortisol, adrenaline, growth hormone, iodothyronines)
- Intracellular signaling cascades: PI3K/Akt and MAPK pathways
- Genetic defects in insulin biosynthesis
- Mechanisms of $\beta$-cell exhaustion during prolonged hyperglycemia (Type 2 diabetes)
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