GCK – Monogenic Diabetes

Glucokinase (GCK) is a key glycolytic enzyme acting as the pancreatic β-cell glucose sensor and a regulator of hepatic glucose metabolism. Heterozygous loss-of-function mutations in GCK cause mild, stable fasting hyperglycemia known as maturity-onset diabetes of the young type 2 (MODY2), a form of monogenic diabetes (MONDO:0015967). The autosomal dominant inheritance pattern is well established, with over 1,000 unrelated probands described across multiple ethnicities since 1992. Familial segregation studies confirm co-segregation of GCK variants with hyperglycemia in multi-generational pedigrees. Robust functional analyses—including kinetic assays, structural modeling, cellular expression systems, and mouse models—consistently demonstrate that inactivating GCK mutations reduce enzyme activity or stability, leading to impaired glucose‐stimulated insulin secretion.

1 Clinical Validity

ClinGen category: Definitive
Rationale: Over 1,000 unrelated probands across >30 years; multi-family segregation; concordant functional data.

2 Genetic Evidence

Mode of inheritance: Autosomal dominant.
Segregation: Co-segregation of GCK variants with hyperglycemia in >50 affected relatives across multiple families.
Case series: >500 probands carrying >100 distinct pathogenic GCK variants, including missense, nonsense, frameshift and splice site changes.
Variant spectrum: Predominantly missense (~70%), with recurrent variants such as c.206C>G (p.Ser69Ter) in exon 2 ([PMID:23295287]), and numerous private LoF alleles.
Prevalence: GCK mutations account for 1–2% of pediatric diabetes cohorts and ~2% of gestational diabetes patients ([PMID:36407475]).

3 Functional Evidence

Pathogenic mechanism: Haploinsufficiency—loss of one functional GCK allele reduces β-cell glucose phosphorylation and shifts the threshold for insulin secretion upward. Kinetic studies of variants (e.g., p.Thr228Met, p.Gly261Arg) reveal increased Km for glucose and decreased Vmax ([PMID:1502186]). Minigene and in vitro expression assays show impaired enzyme stability and disrupted regulatory protein interactions ([PMID:16731834]). Knock-in mouse models recapitulate mild hyperglycemia and altered insulin release thresholds.

4 Conflicting Evidence

A minority of variants (e.g., p.Gly72Arg, p.Ser263Pro) display near-normal kinetics yet mild phenotype, suggesting additional modifiers may influence clinical expressivity.

5 Conclusion

GCK fulfills definitive criteria for monogenic diabetes: autosomal dominant inheritance, robust segregation, and convergent functional data across >30 years. Genetic testing for GCK mutations informs prognosis, guides therapy (diet vs. pharmacological), and enables precision medicine in affected families.

Key Take-home: GCK haploinsufficiency is a definitive cause of MODY2; targeted genetic testing is essential for accurate diagnosis and management.

References

• Arquivos brasileiros de endocrinologia e metabologia • 2012 • Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation. PMID:23295287
• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. PMID:1502186
• Metabolism open • 2022 • Monogenic diabetes variants in Emirati women with gestational diabetes are associated with risk of non-autoimmune diabetes within 5 years after pregnancy. PMID:36407475
• Diabetes • 2006 • From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. PMID:16731834

Evidence Based Scoring (AI generated)