A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria

Aims/hypothesis. Patients with glucokinase mutations are characterised by m ild, persistent fasting hyperglycaemia, a small increment in glucose in res ponse to an oral load and a dominant family history. These patients frequen tly present with gestational diabetes and often require insulin treatment d uring pregnancy. We assessed whether the selection of gestational diabetic subjects by clinical criteria would result in a high detection rate of gluc okinase mutations. Methods. Caucasian gestational diabetic subjects from the United Kingdom wh o had fasting hyperglycaemia in pregnancy but did not meet the diagnostic c riteria for maturity-onset diabetes of the young (MODY) were selected for d irect sequencing of the glucokinase gene if they fulfilled the following fo ur criteria; (1) persisting fasting hyperglycaemia outside pregnancy (5.5-8 mmol/l) (2) a small increment (< 4.6 mmol/l) during a 2-h oral glucose tol erance test (3) insulin treatment during at least one pregnancy but subsequ ently controlled on diet and (4) a history of Type II (non-insulin-dependen t) diabetes mellitus, gestational diabetes or fasting hyperglycaemia (> 5.5 mmol/l) in a first-degree relative. Results. Of the 15 subjects 12 (80%) with all these clinical criteria had g lucokinase gene mutations. These included four previously unreported mutati ons (N180K, R191W, Y215X and L288-1G --> A). Conclusion/interpretation. Phenotypic selection of subjects with gestationa l diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5 % ( range 0-6 %). Our study in gestational diabetes to successfully used clinic al criteria to assist in the definition of a genetic subgroup.