Genetic Mechanisms of Insulin Resistance Syndromes

Inherited insulin resistance syndromes arise predominantly from mutations in the insulin receptor (INSR) gene, though variants in downstream signalling components and regulatory loci also contribute. Defects in INSR disrupt receptor tyrosine kinase activity, impairing phosphorylation of insulin receptor substrates and attenuating the PI3K–AKT pathway that governs glucose uptake and lipid metabolism. Severe biallelic mutations give rise to Donohue syndrome and Rabson–Mendenhall syndrome, characterised by profound growth retardation, hyperinsulinaemia and early mortality. Milder, often dominant, missense mutations underlie type A insulin resistance syndrome, which presents during puberty with hyperandrogenism, acanthosis nigricans and dysregulated glycaemia. Recent genome-wide studies have identified common polymorphisms in insulin-signalling genes that modulate risk of age-related insulin resistance and type 2 diabetes, highlighting shared pathways between rare monogenic syndromes and common metabolic disorders. Advances in next-generation sequencing, functional assays and cell-model systems have refined our understanding of receptor folding, endosomal trafficking and the role of accessory proteins. This body of work forms the basis for early genetic diagnosis, prognostic stratification and the development of targeted therapies, including recombinant insulin-like growth factor I and allosteric modulators of INSR function.

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Genetic Mechanisms of Insulin Resistance Syndromes publication trend

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

Technical terms

Insulin receptor (INSR) gene: Encodes a transmembrane tyrosine kinase critical for mediating insulin-stimulated glucose and lipid metabolism.

Missense mutation: A single nucleotide change that results in substitution of one amino acid for another in the protein sequence, potentially altering function.

Compound heterozygous mutation: Presence of two different pathogenic alleles at the same gene locus, one inherited from each parent, causing a recessive disorder.

Hyperinsulinaemia: Elevated circulating levels of insulin, typically arising from receptor resistance and compensatory β-cell hypersecretion.

Acanthosis nigricans: Skin thickening and hyperpigmentation often observed in insulin resistance, reflecting epidermal proliferation driven by insulin-like growth factors.

References

1. A Novel Mutation in the INSR Gene Causes Severe Insulin Resistance and Rabson–Mendenhall Syndrome in a Paraguayan Patient. International Journal of Molecular Sciences (2024).
2. Unusual Glycemic Presentations in a Child with a Novel Heterozygous Intragenic INSR Deletion. Hormone Research in Paediatrics (2020).
3. Case Report: A Chinese Family of Type A Insulin Resistance Syndrome With Diabetes Mellitus, With a Novel Heterozygous Missense Mutation of the Insulin Receptor Gene. Frontiers in Endocrinology (2022).