What is the mechanism of insulin?

Mechanism of Insulin Action

Insulin initiates its biological effects by binding to a cell surface glycoprotein receptor that functions as a tyrosine-specific protein kinase, triggering a cascade of intracellular phosphorylation events that ultimately regulate glucose, lipid, and protein metabolism. 1, 2

Receptor Binding and Activation

• Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular α-subunits (containing the ligand binding site) and two transmembrane β-subunits (containing the tyrosine kinase enzymatic activity). 2, 3

• Upon insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues, activating the intrinsic tyrosine kinase activity of the β-subunit. 4, 5

• This receptor activation is both necessary and sufficient for the full insulin response—studies using peroxovanadium compounds demonstrate that insulin receptor kinase (IRK) activation alone, even without insulin present, can produce complete insulin signaling. 4

Intracellular Signal Transduction

• The activated insulin receptor phosphorylates key cellular substrates, particularly insulin receptor substrate proteins (IRS-1 and others), which serve as docking proteins for downstream signaling molecules. 5, 3

• Phosphorylated IRS-1 recruits SH2-containing proteins including:

  • The p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase), which is rapidly stimulated in adipocytes and skeletal muscle 6, 3
  • Grb2 adapter proteins, which form complexes with Sos exchange factors 3

• The Grb2-Sos complex activates the Ras protein, which subsequently triggers the Raf-MAP kinase cascade, mediating growth and metabolic effects. 3

Endosomal Regulation

• Insulin receptor activation begins at the cell surface but is maintained and amplified following internalization into the endosomal system (ENS), where signaling continues and is tightly regulated. 4

• Within endosomes, insulin signaling is modulated by several mechanisms:

  • Intra-endosomal acidification promotes dissociation of insulin from the receptor 4
  • Endosomal acidic insulinase degrades internalized insulin 4
  • Insulin receptor kinase-associated phosphotyrosine phosphatases (PTPs) dephosphorylate and deactivate the receptor 4

Primary Metabolic Effects

The primary activity of insulin is regulation of glucose metabolism through multiple coordinated actions: 1

• Stimulation of peripheral glucose uptake, particularly in skeletal muscle and adipose tissue, primarily through translocation of GLUT4 glucose transporters from intracellular compartments to the cell membrane 6, 7

• Inhibition of hepatic glucose production by suppressing both glycogenolysis and gluconeogenesis 1

• Inhibition of lipolysis in adipose tissue and proteolysis in muscle 1

• Enhancement of protein synthesis across multiple tissues 1, 3

Glucose Transporter Regulation

• In all human cells, insulin governs the translocation of glucose-transporter carrier-protein molecules from the intracellular space to the cellular membrane. 6

• When insulin is present, GLUT4 transporters rapidly move to the cell surface, enabling glucose uptake—this process is impaired in insulin deficiency states. 6

Insulin Signaling Pathway Dysfunction

• Insulin resistance occurs when signal transduction systems are altered, with reduced availability of glucose transporters and diminished cellular glucose uptake despite normal or elevated insulin levels. 6

• Key mechanisms of insulin resistance include:

  • Decreased maximal insulin receptor tyrosine phosphorylation in skeletal muscle 6
  • Increased serine phosphorylation of the insulin receptor and IRS-1, which competitively inhibits tyrosine phosphorylation 6
  • Alterations at the level of the β-subunit of the insulin receptor and IRS-1 in skeletal muscle 6

Renal and Hepatic Metabolism

• The kidney clears approximately 30-80% of systemic insulin through glomerular filtration (60-65%) and peritubular uptake (35%), with subsequent degradation in proximal tubular cells. 8

• The liver performs first-pass metabolism of endogenous insulin, clearing 40-50% before it enters systemic circulation. 6

• Exogenous insulin bypasses hepatic first-pass metabolism, resulting in the kidney being responsible for up to 80% of its clearance. 6

Clinical Pitfall

A critical caveat is that in chronic kidney disease, reduced insulin clearance leads to prolonged insulin half-life and increased hypoglycemia risk, necessitating dose reductions—patients with significant creatinine elevations have a 5-fold increase in severe hypoglycemia frequency. 8