A clinical mutation in glucokinase causing maturity‐onset diabetes in the young type 2 increases enzyme activity

• Published in: FEBS letters Vol. 597; no. 11; pp. 1469 - 1478
• Main Authors: Aránguiz, Oscar, Rivera, Rodrigo, Durruty, Pilar, Seelenfreund, Daniela, Báez, Mauricio
• Format: Journal Article
• Language: English
• Published: England 01.06.2023
• Subjects: Diabetes Mellitus, Type 2 - genetics; glucokinase; Glucokinase - genetics; Glucose; Hill coefficient; Humans; kinetic parameters; MODY2; Mutation; kinetic parameters; mutation; Hill coefficient; MODY2; glucokinase
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.14561

Glucokinase (GCK) is the pancreatic β‐cell glucose sensor, and its kinetics are key to that purpose. A slow transition step, displayed as non‐hyperbolic kinetics, and a low affinity for glucose characterize GCK. Mutations in GCK associated with maturity‐onset diabetes of the young type 2 (MODY2) previously described reduce the functionality of the human pancreatic β‐cell, leading to diabetic clinical phenotypes. We present a kinetic characterization of the G448D mutation identified in a MODY2 patient, which is one of the first mutations to exhibit increased functionality. This mutant displays increased activity, high affinity for both Mg2+‐ATP and glucose, hyperbolic kinetics and increased phosphorylation potential. Hyperbolic kinetics and assays in the presence of glycerol indicate that G448D lacks the slow transition step crucial for the pancreatic β‐cell glucose sensor function. Maturity‐onset diabetes of the young type 2 (MODY2) is caused by mutations in glucokinase (GCK) that alter pancreatic β cell glucose‐induced insulin release (GSIR). Previously described mutations reduce functionality, disrupting the glucose sensor function. We describe the G448D GCK mutant which has increased functionality. Altered GSIR might be due to changes in the reaction mechanism.