title: Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.
abstract: 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).
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Tarig
authors.initials: T
authors.lastname: Babiker
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Natascia
authors.initials: N
authors.lastname: Vedovato
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Thomas
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Roisin
authors.initials: R
authors.lastname: Finn
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.|UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK.
authors.forename: Roope
authors.initials: R
authors.lastname: Männikkö
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.|Department of Diabetes and Endocrinology, Royal Sussex County Hospital, Brighton and Sussex University Hospitals, Brighton, UK.
authors.forename: Ali J
authors.initials: AJ
authors.lastname: Chakera
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Maggie H
authors.initials: MH
authors.lastname: Shepherd
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. frances.ashcroft@dpag.ox.ac.uk.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.affiliation: Department of Diabetes and Endocrinology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK. A.T.Hattersley@exeter.ac.uk.|Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK. A.T.Hattersley@exeter.ac.uk.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000188:drug therapy; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012189:Retrospective Studies; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D000099161:Kcnj11 Channel
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; D000099161:Kcnj11 Channel
keywords: ATP-sensitive potassium channel; Neonatal diabetes; Sulfonylurea receptor