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Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment
Author(s) -
Misra S.,
Vedovato N.,
Cliff E.,
De Franco E.,
Hattersley A. T.,
Ashcroft F. M.,
Oliver N. S.
Publication year - 2018
Publication title -
diabetic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.474
H-Index - 145
eISSN - 1464-5491
pISSN - 0742-3071
DOI - 10.1111/dme.13758
Subject(s) - glibenclamide , medicine , sulfonylurea , tolbutamide , insulin , diabetes mellitus , endocrinology , kir6.2 , type 2 diabetes , biology , biochemistry , protein subunit , gene
Abstract Background Permanent neonatal diabetes caused by mutations in the KCNJ 11 gene may be managed with high‐dose sulfonylureas. Complete transfer to sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ 11 mutation, in whom combination therapy led to clinically meaningful improvements. Case A 22‐year‐old woman was found to have a KCNJ 11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin‐pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose‐titration with C‐peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block ( n = 6) with 0.5 mM tolbutamide]. C‐peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose‐titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels sustainably, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once‐daily long‐acting insulin was still required to maintain glycaemia. This resulted in improved HbA 1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. Conclusion In people with KCNJ 11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy.