Our studies show that, at the time of genetic testing, 21% of patients were on insulin or OHA treatment. Patients on pharmacological treatment did not have a lower HbA1c than those off treatment; when therapy was discontinued, HbA1c did not rise. This suggests that the pharmacological treatment received by patients with GCK-MODY does not alter their glycaemia.
Our study is the largest description to date of treatment in patients with GCK-MODY, and 21% receiving pharmacological treatment is consistent with previous series . The patients on insulin treatment were usually diagnosed as children or adolescents, consistent with a misdiagnosis of type 1 diabetes. Conversely, the patients on OHAs were diagnosed later and had a higher BMI, so may have been thought to have type 2 diabetes.
Patients with GCK-MODY who are on pharmacological treatment do not have a lower HbA1c. This could either represent a lack of action or indicate that glycaemia had been less well controlled in these patients prior to treatment and was well controlled as a result of the treatment. However, the lack of change in HbA1c (95% CI: −2.97, 1.61 mmol/mol; −0.27%, 0.15%) on discontinuing treatment suggests a lack of action is the most likely explanation. In keeping with this, in pregnancies of women with GCK-MODY, the birth weight of offspring is not altered by whether or not the mother is treated with insulin .
The lack of a reduction in HbA1c by hypoglycaemic therapy is explained by patients with GCK-MODY having a glucose level that is regulated at its raised level. This is shown in OGTTs in which the glucose value rapidly falls towards the fasting level . Thus, if a small dose of exogenous insulin is given, there will be a compensatory reduction in endogenous insulin secretion without an alteration in glycaemia. The glucose level will only lower when a supra-physiological insulin dose is given. In our study, the doses of insulin and OHA were small and are unlikely to fully suppress endogenous insulin secretion.
The lack of a glycaemic response to insulin or OHAs is an example of pharmacogenetics, where the genetic subtype determines treatment response. There is evidence of pharmacogenetics for other types of monogenic diabetes. Patients with hepatocyte nuclear factor-1α/-4α (HNF1A/HNF4A)-MODY are sensitive to low doses of sulfonylureas  and those with activating KCNJ11/ABCC8 mutations causing neonatal diabetes are best treated with high-dose sulfonylureas . Stopping pharmacological treatment as a consequence of identifying a GCK mutation is the first example of a genetic subtype leading to treatment cessation.
This study was subject to limitations since it was an observational retrospective study of a relatively small number of patients. The ∼10% recruitment rate in the longitudinal treatment discontinuation study reflects that when patients are diagnosed with GCK-MODY and advised to stop treatment, they are often discharged from follow-up. The clinical characteristics of the patients included in our study are no different from those of the patients with GCK-MODY who were not followed-up (ESM Table 3). A prospective placebo-controlled randomised trial would provide the ideal study design, but would be difficult in view of the limited number of patients. This observational study is therefore important in the absence of such a trial.
In summary, we have shown that in patients with GCK-MODY, treatment does not alter glycaemic control and is unnecessary. This study provides further evidence for the role of pharmacogenetics in diabetes care.