Endocrine Abstracts

JOINT1149

Introduction: Heterozygous inactivating variants in GCK cause GCK-related hyperglycaemia (GCK-MODY), presenting with lifelong mild fasting hyperglycaemia. While different GCK variants have substantially variable functional effects on glucokinase activity In vitro, no specific variant has been linked to a distinct human phenotype. We hypothesized that the differences in enzyme activity might translate into variant-specific effects on fasting glucose in humans. This study aimed to assess how each GCK variant influences fasting plasma glucose and identify other factors that further modulate glucose levels.

Methods: We investigated GCK variants classified as pathogenic or likely pathogenic, identified in at least three carriers and two non-carrier relatives in the FINNMODY/Botnia study. We analysed how these variants and other factors influence fasting plasma glucose (FPG) and, in a subgroup, 2-hour plasma glucose (2PG) during an OGTT.

Results: The preliminary analyses of ten GCK variants (60 carriers, 37 non-carriers) suggested that each variant had a distinct effect on FPG (effect 1. 09-3. 03 mmol/l, FPG range 5. 1-10. 1 mmol/l) and 2PG (data for 8 variants, effect 1. 09-8. 36 mmol/l, 2PG range 4. 4-19. 4 mmol/l). Among the carriers, FPG was strongly correlated with 2PG (P = 0. 00039) and fasting insulin (P = 3. 35e-05). HbA1c correlated more strongly with FPG than with 2PG. Surprisingly, metabolic factors such as BMI or lipids showed no significant correlation with FPG or 2PG.

Interpretation: Each GCK variant demonstrated a distinctive effect on plasma glucose. Beyond the GCK variant, individual factors might further modify glucose levels. To assess this, we are performing GWAS genotyping to calculate a polygenic risk score for type 2 diabetes.