Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia

AIMS/HYPOTHESIS: Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control. METHODS: Treatment details were ascertained for 799 patients with heterozygous GCK mutations. In a separate, longitudinal study, HbA(1c) was obtained for 16 consecutive patients receiving insulin (n = 10) or oral hypoglycaemic agents (OHAs) (n = 6) whilst on treatment, and again having discontinued treatment following a genetic diagnosis of GCK-MODY. For comparison, HbA(1c) before and after genetic testing was studied in a control group (n = 18) not receiving pharmacological therapy. RESULTS: At referral for genetic testing, 168/799 (21%) of patients were on pharmacological treatment (13.5% OHAs, 7.5% insulin). There was no difference in the HbA(1c) of these patients compared with those receiving no treatment(median [IQR]: 48 [43, 51] vs 46 [43, 50] mmol/mol, respectively; 6.5% [6.1%, 6.8%] vs 6.4% [6.1%, 6.7%]; p = 0.11). Following discontinuation of pharmacological treatment in 16 patients, HbA(1c) did not change. The mean change in HbA(1c) was −0.68 mmol/mol (95% CI: −2.97, 1.61) (−0.06% [95% CI: −0.27, 0.15]). CONCLUSIONS/INTERPRETATION: Prior to a genetic diagnosis, 21% of patients were on pharmacological treatment. HbA(1c) was no higher than in untreated patients and did not change when therapy was discontinued, suggesting no impact on glycaemia. The lack of response to pharmacological therapy is likely to reflect the regulated hyperglycaemia seen in these patients owing to their glucose sensing defect and is an example of pharmacogenetics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-013-3075-x) contains peer reviewed but unedited supplementary material, which is available to authorised users.