Clinical Heterogeneity in Monogenic Diabetes Caused by Mutations in the Glucokinase Gene (GCK-MODY)

OBJECTIVE To evaluate the heterogeneity in the clinical expression in a family with glucokinase mature-onset diabetes of the young (GCK-MODY). RESEARCH DESIGN AND METHODS Members (three generations) of the same family presented either with overt neonatal hyperglycemia, marked postprandial hyperglycemia, or glucosuria. Homeostasis model assessment of insulin resistance (HOMA(IR)) and insulinogenic and disposition indexes were calculated. Oral glucose tolerance test (OGTT) results in the GCK mutation carriers from this family were compared with those from other subjects with GCK mutations in the same codon (GCK(261)), with other missense and other types of GCK mutations in different codons from the European MODY Consortium database (GCK(m)). RESULTS Mutation G261R was found in the GCK gene. During the OGTT, glucose (P = 0.02) and insulin (P = 0.009) response at 2 h as well as at the 2-h glucose increment (GCK(261) versus other missense GCK mutations, P = 0.003) were significantly higher in GCK(261) than in GCK(m) carriers. CONCLUSIONS Differing from other GCK(m) carriers, the glucose and insulin response to oral glucose was significantly higher in GCK(261) carriers, indicating clinical heterogeneity in GCK-MODY.