Mechanism of action of insulin according to kDT book

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I now have comprehensive content. Let me also fetch the insulin signaling pathway diagram from Goodman & Gilman.

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.

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

Action	Effect on Blood Level
Increases glucose uptake into cells	Decreases blood glucose
Increases glycogen synthesis (glycogenesis)	-
Decreases glycogenolysis	-
Decreases gluconeogenesis	-
Increases protein synthesis	Decreases 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)

Pathway	Key Components	Result
Non-caveolar (PI3K) pathway	IRS → PI3K → PIP3 → PDK → Akt2/PKB or atypical PKC	GLUT4 translocation, glycogen synthesis, protein synthesis
Caveolar pathway	Caveolin → APS → Cbl → CrkII → C3G → TC10	GLUT4 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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