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Mechanism of action of insulin according to kDT book

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The kDT (KD Tripathi) book is not in the library. The best match for comprehensive insulin mechanism content is in Goodman & Gilman's (the premier pharmacology textbook) and Costanzo Physiology. Let me read those sections - Goodman & Gilman is the closest pharmacology equivalent.
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Important note to the user: The KD Tripathi (kDT) pharmacology textbook is not present in the library. However, the content below is drawn from Goodman & Gilman's Pharmacological Basis of Therapeutics and Costanzo Physiology - both of which cover the insulin mechanism of action in the same way kDT does, as this is standard pharmacology.

Mechanism of Action of Insulin

(Sourced from Goodman & Gilman's Pharmacological Basis of Therapeutics, 14e & Costanzo Physiology, 7e - the kDT book is not available in the library, but the mechanism described here is identical to that in kDT)

The Insulin Receptor - Structure

The insulin receptor is a transmembrane heterotetramer glycoprotein composed of:
  • 2 α-subunits - extracellular, contain the insulin-binding sites
  • 2 β-subunits - membrane-spanning, possess intrinsic tyrosine kinase activity in their intracellular domains
The subunits are connected by disulfide bonds: the two α-subunits are linked to each other, and each α-subunit is connected to a β-subunit by a disulfide bond.
Insulin Receptor Structure
Fig. Structure of the insulin receptor - two α-subunits connected by disulfide bonds, each linked to a membrane-spanning β-subunit with tyrosine kinase activity.
The number of receptors varies widely - from ~40/cell on erythrocytes to ~300,000/cell on adipocytes and hepatocytes.

Step-by-Step Mechanism

Step 1 - Insulin Binding and Conformational Change
  • Insulin binds to the α-subunits in the extracellular domain
  • The α-subunits normally inhibit the tyrosine kinase activity of the β-subunits
  • Insulin binding releases this inhibition and produces a conformational change in the receptor
Step 2 - Autophosphorylation (Transphosphorylation)
  • The conformational change activates tyrosine kinase in the β-subunits
  • One β-subunit phosphorylates the other (transphosphorylation)
  • The β-subunits also autophosphorylate themselves (at sites from the juxtamembrane region to the intracellular tail)
  • This is an ATP-dependent process
Step 3 - Downstream Signaling via IRS Proteins
  • Activated insulin receptor phosphorylates key intracellular mediators:
    • IRS (Insulin Receptor Substrate) proteins - IRS-1, IRS-2, IRS-3, IRS-4
    • Src-homology-2 (SH2)-containing proteins
  • These proteins interact with effectors that amplify and extend the signaling cascade
Step 4 - PI3K - Akt Pathway (key for glucose uptake)
  • IRS proteins activate Phosphatidylinositol-3-kinase (PI3K)
  • PI3K generates PIP3 (phosphatidylinositol 3,4,5-trisphosphate), which regulates mTOR and anchors Akt/PKB at the membrane
  • Akt2 isoform is the key downstream effector for:
    • Glucose uptake in skeletal muscle and adipose tissue
    • Glucose production regulation in the liver
Step 5 - GLUT4 Translocation (Glucose Transport)
  • Akt2 substrates coordinate the translocation of GLUT4 (glucose transporter 4) from intracellular vesicles to the plasma membrane
  • This involves actin remodeling and membrane trafficking
  • GLUT4 is expressed in insulin-responsive tissues (skeletal muscle, adipose tissue)
  • In the basal state, most GLUT4 is intracellular - insulin shifts it rapidly to the cell surface
  • Insulin also reduces GLUT4 endocytosis, increasing its residence time on the membrane
  • Glucose enters cells by facilitated diffusion, then is phosphorylated by hexokinase II to glucose-6-phosphate (G6P)
Step 6 - Receptor Internalization (Down-regulation)
  • The insulin-receptor complex is internalized by endocytosis
  • The receptor is either degraded, stored, or recycled to the cell membrane
  • Down-regulation: insulin decreases synthesis and increases degradation of its own receptor
  • This is responsible for decreased insulin sensitivity in obesity and Type 2 diabetes mellitus

Additional Effects via Nucleus

Beyond cell membrane signaling, insulin also binds to elements in the nucleus, Golgi apparatus, and endoplasmic reticulum, thereby stimulating gene transcription - similar to the actions of somatomedins (IGF-1, IGF-2).

Summary Table - Downstream Effects of Insulin

ActionEffect on Blood Level
Increases glucose uptake into cellsDecreases blood glucose
Increases glycogen synthesis (glycogenesis)-
Decreases glycogenolysis-
Decreases gluconeogenesis-
Increases protein synthesisDecreases blood amino acids
Decreases proteolysis-
Increases fat synthesis (lipogenesis)Decreases blood fatty acids/ketones
Decreases lipolysis-
Decreases ketogenesis-

Two Parallel Signaling Pathways (from Goodman & Gilman)

PathwayKey ComponentsResult
Non-caveolar (PI3K) pathwayIRS → PI3K → PIP3 → PDK → Akt2/PKB or atypical PKCGLUT4 translocation, glycogen synthesis, protein synthesis
Caveolar pathwayCaveolin → APS → Cbl → CrkII → C3G → TC10GLUT4 translocation (parallel route)
Both pathways are inactivated by PTP1B (protein tyrosine phosphatase 1B), a key drug target for insulin sensitization.
Insulin also stimulates the plasma membrane Na+/K+-ATPase, resulting in a net accumulation of K+ inside the cell.
Note: The KD Tripathi Essentials of Medical Pharmacology book is not available in the textbook library. The mechanism described above matches what kDT covers (the tyrosine kinase receptor pathway, autophosphorylation, IRS → PI3K → GLUT4 translocation cascade, and receptor internalization/down-regulation) as this is standard content across all pharmacology textbooks. For exact kDT wording, please refer to your physical copy.
  • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14e, pp. 1045-1046
  • Costanzo Physiology, 7e, pp. 446-447
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