Abstract | AIMS/HYPOTHESIS: Mutations of the glucokinase gene cause hyperglycaemia or hypoglycaemia. A quantitative understanding of these defects of glucose homeostasis linked to the glucokinase gene was lacking. Therefore a database of kinetic variables of wild-type and 20 missense mutants of glucokinase was developed and used in mathematical modelling to predict the thresholds for glucose-stimulated insulin release. METHODS: RESULTS: Large changes, varying greatly between mutants were found in nearly all variables. Glucokinase flux at threshold for glucose-stimulated insulin release was about 25 % of total phosphorylating potential in the normal beta-cell and this was used to predict thresholds for the mutant heterozygotes. Clinical data for maturity onset diabetes of the young type linked to the glucokinase gene and familial hyperinsulinaemic hypoglycaemia linked to the glucokinase gene and the glucokinase kinetic data of this study were used to test the model. The model predicts fasting blood glucose between 3 and 7 mmol/l in these cases. CONCLUSION/INTERPRETATION: A kinetics database of wild-type and 20 mutants of glucokinase was developed. Many kinetic differences were found for the mutants. The mathematical model to calculate the threshold for glucose-stimulated insulin release predicts fasting blood glucose between 3 and 7 mmol/l in subjects with glucokinase gene mutations. [Diabetologia 42: 1175-1186]
|
Authors | E A Davis, A Cuesta-Muñoz, M Raoul, C Buettger, I Sweet, M Moates, M A Magnuson, F M Matschinsky |
Journal | Diabetologia
(Diabetologia)
Vol. 42
Issue 10
Pg. 1175-86
(Oct 1999)
ISSN: 0012-186X [Print] Germany |
PMID | 10525657
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- Adaptor Proteins, Signal Transducing
- Blood Glucose
- Carrier Proteins
- GCKR protein, human
- Insulin
- Proteins
- Recombinant Fusion Proteins
- glucokinase regulatory protein
- Adenosine Triphosphate
- Glutathione Transferase
- Glucokinase
- Glucose
|
Topics |
- Adaptor Proteins, Signal Transducing
- Adenosine Triphosphate
(metabolism)
- Blood Glucose
(metabolism)
- Carrier Proteins
- Enzyme Activation
(drug effects, genetics)
- Enzyme Stability
- Glucokinase
(antagonists & inhibitors, genetics, metabolism)
- Glucose
(pharmacology, physiology)
- Glutathione Transferase
(genetics)
- Homeostasis
- Humans
- Hyperglycemia
(blood, genetics)
- Hypoglycemia
(blood, genetics)
- Insulin
(blood)
- Models, Biological
- Mutation
- Proteins
(pharmacology)
- Recombinant Fusion Proteins
(genetics, isolation & purification, metabolism)
- Syndrome
|