Insulin Signaling Mechanisms in Metabolic Disorders

Insulin orchestrates systemic glucose homoeostasis by engaging a cell-surface tyrosine kinase receptor and activating a network of intracellular pathways. Upon insulin binding, the insulin receptor (IR) undergoes autophosphorylation and recruits adaptor proteins, chiefly the insulin receptor substrates (IRS), which in turn activate the phosphatidylinositol-3-kinase (PI3K)–AKT cascade. This axis promotes translocation of the glucose transporter GLUT4 to the plasma membrane, facilitating glucose uptake in muscle and adipose tissue, and suppresses hepatic gluconeogenesis. In metabolic disorders such as type 2 diabetes, obesity and nonalcoholic fatty liver disease, defects arise at multiple nodes: IR downregulation, serine phosphorylation of IRS proteins, impaired PI3K–AKT signalling, endoplasmic reticulum stress, mitochondrial dysfunction and chronic inflammation. Ectopic lipid accumulation and intracellular Ca2+ overload further perturb kinase activation and membrane trafficking. Recent insights have revealed non-canonical, kinase-independent IR pathways that modulate cellular senescence and matrix remodelling, as well as ubiquitin-mediated receptor turnover that influences basal insulin responsiveness. Epigenetic modifications and sex-specific gene expression patterns add additional layers of regulation, highlighting the complexity of insulin signalling in health and disease and guiding the rational design of targeted therapies.

Research from Nature Portfolio

Recent studies have uncovered a second, ligand- and kinase-independent pathway of the insulin receptor that controls cellular senescence, extracellular matrix remodelling and apoptotic sensitivity in metabolic tissues. Tailored receptor mutations revealed distinct intracellular domains capable of modulating phosphorylation networks without insulin binding, thereby affecting cell-cycle regulators and immune-related genes. Another investigation identified an E3 ubiquitin ligase that sets the basal level of insulin receptor on the cell surface by ubiquitination-mediated degradation. Loss-of-function of this ligase enhances hepatic insulin responsiveness, while overexpression reduces receptor abundance, pointing to a new mechanism for receptor downregulation in obesity-associated insulin resistance.

Insulin Signaling Mechanisms in Metabolic Disorders publication trend

The graph below shows the total number of articles in insulin signaling mechanisms in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Insulin receptor (IR): A cell-surface tyrosine kinase that mediates insulin binding and initiates downstream signalling.

Insulin receptor substrate (IRS): Cytoplasmic adaptor proteins that transduce signals from IR to pathways such as PI3K–AKT.

PI3K–AKT pathway: A key cascade regulating glucose uptake, growth and metabolism following IR activation.

GLUT4: An insulin-responsive glucose transporter whose translocation to the plasma membrane is essential for glucose uptake in muscle and adipose tissue.

Ubiquitin ligase: An enzyme that tags proteins with ubiquitin, marking them for degradation by the proteasome.

Store-operated Ca2+ entry (SOC): A mechanism by which endoplasmic reticulum Ca2+ depletion triggers Ca2+ influx through plasma-membrane channels, affecting insulin signalling.

Epigenetics: Heritable changes in gene expression not involving alterations to the DNA sequence, often through DNA methylation or histone modification.

DNA methylation: An epigenetic modification where methyl groups added to DNA regulate gene transcription.

References

1. Insulin Signaling and the Regulation of Glucose Transport. Molecular Medicine (2004).
2. Insulin Signal Transduction Perturbations in Insulin Resistance. International Journal of Molecular Sciences (2021).
3. Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis. Nature Communications (2023).
4. MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nature Communications (2016).
5. Candesartan, an angiotensin-II receptor blocker, ameliorates insulin resistance and hepatosteatosis by reducing intracellular calcium overload and lipid accumulation. Experimental & Molecular Medicine (2023).
6. Interactions between insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts. Journal of Clinical Investigation (2024).