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, HbA1c 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, HbA1c 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 HbA1c 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, HbA1c did not change. The mean change in HbA1c 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. HbA1c 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.

Genetics and type 2 diabetes in youth.

The rapid increase in the population prevalence of type 2 diabetes mellitus (T2DM) in youth can only be explained by changes in lifestyle. However, even when most members of a population have changed their lifestyle, only a minority of children develop diabetes, and genetic factors are important in determining which children are affected. Support for the role of genetic factors comes from epidemiological evidence that diabetes in youth is most common in high diabetes prevalence racial groups, in subjects with a strong family history, and in girls. Defining the genes predisposing to T2DM is extremely difficult as there are multiple genes involved each contributing only a small amount and lifestyle factors play a large role. Defining the molecular genetics of T2DM in youth is even harder because in addition to the low number of subjects, there is also the ethnic heterogeneity of the subjects and the lack of robust diagnostic criteria. Recently, there has been considerable progress in defining the predisposing genes for adults with T2DM using thousands of cases and controls and a collaborative genome-wide approach. Similar numbers will be needed to assess if the genes found in adults also predispose to T2DM of youth and this will require large multi-center studies. Progress to date in the molecular genetics of T2DM in youth is limited to one population, the Oji-Cree Native Canadians, where the private variant - G319S - a variant of HNF1A strongly predisposes to diabetes in children as well as in adults.