Dataset Information

The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.

ABSTRACT:

Context

Mutations in the Kir6.2 subunit (KCNJ11) of the ATP-sensitive potassium channel (KATP) underlie neonatal diabetes mellitus. In severe cases, Kir6.2 mutations underlie developmental delay, epilepsy, and neonatal diabetes (DEND). All Kir6.2 mutations examined decrease the ATP inhibition of KATP, which is predicted to suppress electrical activity in neurons (peripheral and central), muscle, and pancreas. Inhibitory sulfonylureas (SUs) have been used successfully to treat diabetes in patients with activating Kir6.2 mutations. There are two reports of improved neurological features in SU-treated DEND patients but no report of such improvement in adulthood.

Objective

The objective of the study was to determine the molecular basis of intermediate DEND in a 27-yr-old patient with a KCNJ11 mutation (G53D) and the patient's response to SU therapy.

Design

The G53D patient was transferred from insulin to gliclazide and then to glibenclamide over a 160-d period. Motor function was assessed throughout. Electrophysiology assessed the effect of the G53D mutation on KATP activity.

Results

The G53D patient demonstrated improved glycemic control and motor coordination with SU treatment, although glibenclamide was more effective than gliclazide. Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. G53D channels coexpressed with SUR1 (the pancreatic and neuronal isoform) exhibit high-affinity block by gliclazide but are insensitive to block when coexpressed with SUR2A (the skeletal muscle isoform). High-affinity block by glibenclamide is present in G53D channels coexpressed with either SUR1 or SUR2A.

Conclusion

The results demonstrate that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle KATP.

SUBMITTER: Koster JC

PROVIDER: S-EPMC2266958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims/hypothesisThe 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).MethodsWe 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.ResultsIn 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/interpretationTransfer 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.