Authors: Kehinde Sherifdeen Sowunmi

Abstract

Background: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, with 50–90% of cases initially misclassified as type 1 or type 2 diabetes. Genetic diagnosis enables individualized treatment.

Objective: To synthesize evidence on molecular mechanisms, clinical phenotypes, diagnostic pathways, and genotype-directed treatment for MODY and related monogenic diabetes, including HNF1B-MODY and KCNJ11/ABCC8-related permanent neonatal diabetes mellitus (PNDM).

Methods: PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science were searched from inception to 30 June 2026. Eligible publications included English-language primary studies, systematic reviews, meta-analyses, and guidelines. Small case reports, non-human studies, and unavailable full texts were excluded. One reviewer conducted study selection and data extraction. Overall, 120 primary studies and 15 secondary reviews/guidelines were included. Methodological quality was assessed using the Newcastle–Ottawa Scale, Cochrane Risk of Bias tool, and AMSTAR-2. Findings were synthesized narratively.

Results: HNF1A, GCK, and HNF4A account for most MODY diagnoses in European cohorts, although frequencies vary across populations. HNF1A- and HNF4A-MODY respond to low-dose sulfonylureas, whereas GCK-MODY generally requires no pharmacotherapy. HNF1B-MODY involves multisystem disease and generally responds poorly to sulfonylureas. KCNJ11/ABCC8-related PNDM, distinct from MODY, may respond to high-dose sulfonylureas. Autoantibody status, C-peptide preservation, and family history guide genetic testing. Evidence was predominantly observational and of moderate quality, with only one randomized trial.

Conclusion: Genetic diagnosis supports precision treatment, including sulfonylurea transition, insulin avoidance, and pregnancy-specific management. Expanding genetic testing access, particularly in resource-constrained settings, and strengthening evidence across diverse populations remain priorities.

Keywords: MODY, monogenic diabetes, HNF1A, GCK, HNF4A, HNF1B, sulfonylurea, neonatal diabetes, genetic testing, precision medicine, systematic review.