Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes

Abstract

Aims/hypothesis: The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in KCNJ11 (which encodes the inwardly rectifying potassium channel Kir6.2).

Methods: We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to KCNJ11 mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg(-1) day(-1) glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in Xenopus oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer.

Results: In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA1c from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (p = 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years, p = 0.032). There was no difference in pre-transfer HbA1c (p = 0.87), weight-for-age z scores (SD score; p = 0.12) or sex (p = 0.17).

Conclusions/interpretation: Transfer from insulin is successful for most KCNJ11 patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months.

Keywords: ATP-sensitive potassium channel; Neonatal diabetes; Sulfonylurea receptor.

Fig. 1

Sulfonylurea block of wild-type and mutant K_ATP channels. Percentage inhibition of whole-cell K_ATP channel currents in wild-type (WT) and mutant (as indicated) channels in response to 0.5 mmol/l tolbutamide. Current in the presence of tolbutamide is expressed as a percentage of that in the absence of drug [, , –14]. The numbers in parenthesis indicate the number of patients who responded to sulfonylureas (left) out of the total number (right) with the indicated mutation. White bars, all patients responded; grey bars, some patients responded; black bars, no patients responded. The vertical light grey bar indicates the level of block that separates those patients who responded from those who did not

Fig. 2

The younger the patients are (i.e. the shorter the duration of diabetes), the greater the likelihood of a successful transfer. Only KCNJ11 mutations for which some patients transfer and others do not (p.R201H, p.R201C, p.V59M, p.G334C, p.G53S, p.Q52R) are shown. White bars, successful transfer; black bars, unsuccessful transfer