Mechanism of action of insulin

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Mechanism of Action of Insulin

(Sources: Costanzo Physiology 7e, Tietz Textbook of Laboratory Medicine 7e, Goodman & Gilman's Pharmacological Basis of Therapeutics)

1. The Insulin Receptor

The insulin receptor is a heterotetrameric transmembrane glycoprotein consisting of:

Two α-subunits (MW ~135,000 Da each) - located entirely extracellularly; contain the insulin-binding site
Two β-subunits (MW ~95,000 Da each) - span the plasma membrane and extend intracellularly; contain intrinsic tyrosine kinase activity

The two α-subunits are linked to each other by disulfide bonds, and each α-subunit is connected to a β-subunit by a disulfide bond. - Costanzo Physiology 7e, p. 447

2. Step-by-Step Signaling Cascade

Step 1 - Ligand Binding & Receptor Activation Insulin binds to the α-subunits of the receptor, inducing a conformational change that activates the tyrosine kinase domains of the β-subunits.

Step 2 - Autophosphorylation The β-subunits phosphorylate themselves (autophosphorylation) on multiple tyrosine residues in the presence of ATP. This amplifies kinase activity further.

Step 3 - Phosphorylation of Intracellular Substrates The activated receptor tyrosine kinase phosphorylates several key docking proteins:

IRS proteins (IRS-1, IRS-2, IRS-3, IRS-4) - Insulin Receptor Substrate family; the most important downstream substrates
Shc (Src homology 2 domain-containing protein)
Grb2 (Growth factor receptor-bound protein 2)

The phosphorylated tyrosines on these proteins act as docking sites for intracellular signal transducers that contain SH2 (Src Homology 2) domains - ~100 amino acid sequences that specifically recognize phosphotyrosine. - Tietz 7e, p. 1721

3. Two Main Downstream Signaling Arms

Mechanism of insulin action - signaling cascade from receptor to GLUT4 translocation, glycogen synthesis, gluconeogenesis suppression, and gene transcription

FIGURE: Mechanism of insulin action (Tietz Textbook of Laboratory Medicine 7e)

A. Metabolic Arm - PI3K/Akt Pathway

This is the primary pathway for insulin's metabolic effects:

Phosphorylated IRS proteins recruit and activate PI3K (Phosphatidylinositol 3-kinase)
PI3K generates PIP3 (phosphatidylinositol 3,4,5-trisphosphate) at the membrane
PIP3 recruits and activates PDK1 (3-phosphoinositide-dependent protein kinase-1)
PDK1 phosphorylates and activates Akt (also known as PKB)
Akt then mediates the key metabolic effects:

Effect	Mechanism
GLUT4 translocation (muscle & adipose)	Akt promotes translocation of GLUT4 vesicles to plasma membrane → glucose uptake
Glycogen synthesis (liver)	Akt phosphorylates and inactivates GSK-3β → relieves inhibition of glycogen synthase
Suppression of gluconeogenesis (liver)	Akt inhibits FOXO transcription factors → reduces expression of gluconeogenic enzymes
Lipogenesis (liver)	Akt activates lipogenic pathways
Protein synthesis	Akt activates mTOR → ribosomal S6 kinase (S6K) → increased translation

B. Mitogenic Arm - Ras/MAPK Pathway

This pathway mediates insulin's growth-promoting effects:

Shc and Grb2 (bound to phosphorylated IRS or directly to the receptor) activate Ras
Ras activates Raf → MEK → ERK (MAP kinase cascade)
ERK activates S6K and nuclear transcription factors
End effects: cell growth, differentiation, and gene transcription

C. Caveolar Pathway (Alternative)

A separate pool of insulin receptors in caveolae (lipid raft microdomains) phosphorylates caveolin (CAV), APS, and Cbl. This pathway also drives GLUT4 translocation via the CrkII-C3G-TC10 signaling axis. - Goodman & Gilman's, Figure 51-4

4. Receptor Internalization and Down-regulation

After insulin-receptor binding, the complex is internalized by receptor-mediated endocytosis. The receptor is then either:

Degraded by intracellular proteases
Stored intracellularly
Recycled back to the cell membrane

Insulin down-regulates its own receptor by decreasing receptor synthesis and increasing degradation. This phenomenon is a key mechanism underlying the decreased insulin sensitivity seen in obesity and Type 2 diabetes mellitus. - Costanzo Physiology 7e, p. 447

5. Nuclear and Organelle Effects

Beyond the plasma membrane cascade, insulin also binds to elements in the nucleus, Golgi apparatus, and endoplasmic reticulum, where it directly stimulates gene transcription - an action similar to that of IGF-1 and IGF-2. - Costanzo Physiology 7e

Summary Table

Level	Key Players	Effect
Receptor	α/β tetramer, tyrosine kinase	Binding + autophosphorylation
Docking proteins	IRS-1 to 4, Shc, Grb2	Signal branching
Metabolic branch	PI3K → PDK1 → Akt	GLUT4, glycogen synthesis, anti-gluconeogenesis
Mitogenic branch	Ras → Raf → MEK → ERK	Cell growth, gene transcription
Termination	Receptor internalization, phosphatases (PTP1B)	Signal attenuation

Clinical relevance: Defects at any step in this cascade (particularly at IRS-1/2, PI3K, or Akt levels) contribute to insulin resistance in Type 2 diabetes and metabolic syndrome. PTP1B (protein tyrosine phosphatase 1B) is a key phosphatase that terminates insulin signaling and is an active drug target for insulin-sensitizing therapies.

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All the content from Guyton is now in hand. Here is the complete answer directly from Guyton and Hall Textbook of Medical Physiology:

Mechanism of Action of Insulin

Guyton and Hall Textbook of Medical Physiology - Chapter 79

Insulin Chemistry

Human insulin (MW 5808) consists of two amino acid chains (A and B) connected by disulfide linkages. It is synthesized as preproinsulin (MW ~11,500) in the beta cells, cleaved to proinsulin (MW ~9000) in the ER, then further cleaved in the Golgi apparatus into:

Insulin (A + B chains linked by disulfide bonds)
C peptide (connecting peptide, secreted in equimolar amounts)

Insulin circulates in unbound form with a plasma half-life of ~6 minutes and is degraded primarily by insulinase in the liver. - Guyton, Ch. 79

The Insulin Receptor - Structure

Figure 79.3 - Guyton's schematic of the insulin receptor showing α/β subunits, tyrosine kinase activation, and downstream effects on glucose transport, protein synthesis, fat synthesis, glycogen synthesis, and gene expression

Fig. 79.3 - Guyton and Hall: Insulin binds to the α subunit, causing autophosphorylation of the β-subunit, which induces tyrosine kinase activity leading to a cascade of phosphorylation events.

To initiate its effects, insulin must first bind to and activate a membrane receptor protein (MW ~300,000). The receptor is a combination of four subunits held together by disulfide linkages:

Subunit	Location	Function
2 α-subunits	Entirely extracellular	Insulin-binding site
2 β-subunits	Span the membrane, protrude into cytoplasm	Contain intrinsic tyrosine kinase activity

"Insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, portions of the beta subunits protruding into the cell become autophosphorylated. Thus, the insulin receptor is an example of an enzyme-linked receptor." - Guyton, p. 963

Receptor Activation Cascade

Step 1: Insulin binds to α-subunits → conformational change

Step 2: β-subunits autophosphorylate → local tyrosine kinase is activated

Step 3: Tyrosine kinase phosphorylates multiple intracellular enzymes, especially the Insulin Receptor Substrate (IRS) proteins (IRS-1, IRS-2, IRS-3), which are expressed differently across tissues

Step 4: IRS phosphorylation activates some enzymes and inactivates others, directing intracellular metabolic machinery for carbohydrate, fat, and protein metabolism

Time-Course of Cellular Effects

Guyton uniquely organizes the downstream effects by the time of onset:

Time	Effect
Within seconds	Membranes of ~80% of body's cells markedly increase glucose uptake via GLUT4 translocation to cell membrane (mainly muscle and adipose - NOT most brain neurons). When insulin is withdrawn, GLUT4 vesicles return to cell interior within 3-5 minutes.
Seconds	Cell membrane becomes more permeable to amino acids, K⁺, and phosphate ions
10-15 minutes	Changed activity levels of intracellular metabolic enzymes via altered phosphorylation states
Hours to days	Changed rates of mRNA translation and DNA transcription in the nucleus → new protein synthesis, remodeling of cellular enzymatic machinery

"Insulin can increase the rate of transport of glucose into resting muscle cells by at least 15-fold." - Guyton, p. 964

Metabolic Effects - Three Major Systems

A. Carbohydrate Metabolism

Stimulates glucose uptake into muscle and adipose tissue
Promotes glycogen storage in muscle (up to 2-3% concentration) and liver (up to 5-6%)
Inhibits glycogenolysis (breakdown of glycogen)
Inhibits gluconeogenesis in the liver (by suppressing gluconeogenic enzymes)
During the fed state, muscles use glucose preferentially over fatty acids

B. Fat Metabolism

Acts as a fat sparer - by increasing glucose utilization, it automatically decreases fat utilization
Promotes fatty acid synthesis in the liver (excess glucose → pyruvate → acetyl-CoA → fatty acids via malonyl-CoA)
Activates lipoprotein lipase in capillary walls of adipose tissue to allow fatty acid uptake
Inhibits hormone-sensitive lipase in fat cells → prevents triglyceride hydrolysis and fatty acid release
Promotes glucose transport into fat cells → forms α-glycerol phosphate → combines with fatty acids to form and store triglycerides

"When insulin is not available, even storage of the large amounts of fatty acids transported from the liver in lipoproteins is almost blocked." - Guyton, p. 966

C. Protein Metabolism

Stimulates transport of amino acids into cells (especially valine, leucine, isoleucine, tyrosine, phenylalanine)
Increases translation of mRNA - "turns on" ribosomal machinery (acts like an on/off switch)
Increases rate of DNA transcription → more RNA → more protein synthesis
Inhibits protein catabolism - reduces lysosomal degradation of proteins
Suppresses gluconeogenesis from amino acids → conserves protein stores

"In summary, insulin promotes formation of protein and prevents degradation of proteins." - Guyton, p. 967

Insulin and Growth

Because insulin is required for protein synthesis, Guyton states it is "as essential as growth hormone for the growth of an animal." Insulin and growth hormone act synergistically to promote growth - neither alone produces normal growth in a depancreatized, hypophysectomized rat.

Key Clinical Point - Down-Regulation

Chronic hyperinsulinemia (as in obesity) leads to down-regulation of insulin receptors, reducing insulin sensitivity. This is a key mechanism in the development of Type 2 diabetes mellitus - target tissues become less responsive despite normal or elevated insulin levels.

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