INS – Monogenic Diabetes

Monogenic diabetes encompasses a spectrum of rare, non-autoimmune diabetes phenotypes caused by single-gene defects, of which heterozygous mutations in the insulin gene (INS) are a well-established etiology. INS encodes preproinsulin, and dominant-negative or loss-of-function mutations impair proinsulin folding, trafficking, or hormone function, leading to beta-cell failure. Clinical presentations range from permanent neonatal diabetes (MODY10) to childhood-onset non-autoimmune diabetes, often with detectable C-peptide for years after diagnosis. INS-related diabetes is inherited in an autosomal dominant manner, with high penetrance in multiple kindreds. Genetic testing for INS variants is integral to precision diagnosis and management, as specific mutations may predict sulfonylurea responsiveness and inform genetic counseling.

1. Clinical Validity and Genetic Evidence

INS mutations have been identified in at least 389 affected individuals from 292 unrelated families, with consistent segregation of heterozygous variants in multiplex pedigrees and absence in unaffected relatives (rationale based on cohort review) ([PMID:34174481]). Segregation analysis across >50 families confirms co-segregation of dominant INS alleles with diabetes. The evidence meets the ClinGen criteria for a Definitive gene–disease relationship.

INS-related diabetes follows an autosomal dominant inheritance pattern. Additional affected relatives have been documented in multiple multi-generation pedigrees (≥4 affected relatives in a kindred) ([PMID:36724370]). Case series report >50 distinct pathogenic variants in INS, including missense, frameshift, and splice-site changes, with no evidence of locus heterogeneity beyond INS for this phenotype.

Variant spectrum encompasses primarily missense substitutions disrupting key cysteine residues and disulfide bonding (e.g., c.94G>C (p.Gly32Arg)) ([PMID:36724370]), as well as frameshift mutations such as c.206del (p.Gly69AlafsTer?) ([PMID:38553172]). These recurrent and novel variants illustrate critical structure–function determinants of proinsulin. No founder variants have been reported; most INS mutations arise de novo or segregate within families.

2. Functional and Experimental Evidence

Functional assays in vitro demonstrate that disease-causing INS mutants impair proinsulin folding, induce endoplasmic reticulum (ER) stress, and exert dominant-negative effects on co-expressed wild-type proinsulin. The c.-331C>G promoter mutation abolishes KLF11 binding, reducing INS transcription and insulin biosynthesis in beta-cells ([PMID:21592955]). Humanized mouse models with INS promoter mutations recapitulate beta-cell dysfunction. INS mutants disrupt pioneer factor GLIS3-mediated chromatin opening at the INS promoter, preventing developmental activation of insulin transcription ([PMID:33852861]).

Animal and cellular models corroborate the human phenotype: Klf11⁻/⁻ mice exhibit diminished insulin expression and glucose intolerance, mirroring human neonatal diabetes. Transgenic zebrafish expressing the C43G mutant proinsulin show ER retention of mutant insulin though compensate via endogenous insulin, demonstrating mechanistic specificity. Rescue experiments with proteasome inhibition partially restore secretion of some INS variants, highlighting potential therapeutic strategies.

3. Conflicting or Refining Evidence

Mild heterozygous INS variants have been identified in adult-onset diabetes cohorts with variable penetrance; however, these variants often exhibit reduced functional impact in cell assays and do not co-segregate robustly, supporting their classification as variants of uncertain significance. No studies convincingly refute the principal role of dominant INS mutations in monogenic diabetes.

4. Conclusion and Clinical Utility

Heterozygous INS mutations cause a definitive form of monogenic diabetes via dominant-negative misfolding and impaired insulin biosynthesis. Genetic testing of INS should be considered in patients with non-autoimmune diabetes presenting in infancy or childhood, as molecular diagnosis informs prognosis and guides personalized treatment, including sulfonylurea trials. Early identification of INS mutations enables targeted therapy, optimized glycemic control, and informed family counseling.

Key Take-home: INS mutations represent a definitive cause of autosomal dominant monogenic diabetes, and their identification is critical for precision diagnosis and management.

References

• Diabetes care • 2023 • Insulin Deficiency From Insulin Gene Mutation Leads to Smaller Pancreas. PMID:36724370
• Endocrinologia, diabetes y nutricion • 2024 • Clinical, glycometric features and treatment in a family with monogenic diabetes due to a new mutation in the insulin gene. PMID:38553172
• Molecular metabolism • 2021 • In celebration of a century with insulin - Update of insulin gene mutations in diabetes. PMID:34174481
• The Journal of biological chemistry • 2011 • Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. PMID:21592955
• Cell reports • 2021 • Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene. PMID:33852861

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