ABCC8 – Diabetes Mellitus

ABCC8 encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic β-cell ATP‐sensitive potassium (KATP) channel. Loss‐ or gain‐of‐function variants perturb channel gating, leading to dysregulated insulin secretion and diverse diabetic phenotypes, including monogenic neonatal diabetes, maturity-onset diabetes of the young (MODY), and adult‐onset type 2 diabetes. Numerous case series describe both autosomal recessive and dominant inheritance, with heterozygous SUR1 activating mutations causing neonatal diabetes and inactivating mutations linked to diabetes progression after congenital hyperinsulinism.

1 Assess Clinical Validity

Overall association strength is Strong, supported by at least 87 probands with ABCC8-related nonneonatal diabetes carrying 71 distinct variants and multi-family segregation, with consistent functional characterization across studies ([PMID:34631896]).

2 Genetic Evidence

Inheritance mode is Autosomal dominant, with additional reports of recessive neonatal forms. Segregation analysis documents 13 affected relatives across pedigrees with co-segregating ABCC8 variants. Case series report 71 unique ABCC8 variants in diabetes probands, including missense and frameshift alleles. A recurrent variant, c.886G>A (p.Gly296Arg), has been identified in multiple unrelated families, associated with sulfonylurea-responsive diabetes.

3 Functional / Experimental Evidence

Mechanism involves altered SUR1 gating: activating alleles reduce ATP inhibition and enhance MgADP stimulation, while inactivating mutations impair channel trafficking or nucleotide binding. For example, the p.Arg1420Cys mutation disrupts cooperative nucleotide binding at NBF2 and diminishes MgADP activation, underscoring haploinsufficiency mechanisms ([PMID:10615958]). Patch‐clamp and 86Rb⁺ efflux assays across variants demonstrate concordant functional defects correlating with clinical phenotype.

4 Conflicting Evidence

Some common ABCC8 polymorphisms show no association with type 2 diabetes in population cohorts, indicating phenotypic specificity of rare pathogenic alleles.

5 Integration & Conclusion

ABCC8 variants exert graded effects on KATP channel function, with genotype–phenotype correlations informing therapeutic response to sulfonylureas and predicting diabetes risk. Both activating and inactivating mutations illustrate the continuum from hyperinsulinism to diabetes. Further large cohort studies will refine penetrance estimates and variant pathogenicity.

Key Take-home: ABCC8 mutation screening guides precision diagnosis and sulfonylurea therapy across monogenic and pediatric diabetes presentations.

References

• Journal of diabetes research • 2021 • Clinical and Genetic Characteristics of ABCC8 Nonneonatal Diabetes Mellitus: A Systematic Review PMID:34631896
• The Journal of clinical endocrinology and metabolism • 2000 • Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1 PMID:10615958

Evidence Based Scoring (AI generated)