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Long-term follow-up of glycemic and neurological outcomes in an international series of patients with sulfonylurea-treated ABCC8 permanent neonatal diabetes

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posted on 12.11.2020, 01:54 by Pamela Bowman, Frances Mathews, Fabrizio Barbetti, Maggie H. Shepherd, Janine Sanchez, Barbara Piccini, Jacques Beltrand, Lisa R. Letourneau-Freiberg, Michel Polak, Siri Atma W. Greeley, Eamon Rawlins, Tarig Babiker, Nicholas J. Thomas, Elisa De Franco, Sian Ellard, Sarah E. Flanagan, Andrew T. Hattersley, the Neonatal Diabetes International Collaborative Group
Objective

ABCC8 mutations cause neonatal diabetes that can be transient (TNDM) or less commonly permanent (PNDM); ~90% individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of permanent and transient forms of ABCC8-NDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM.
Research Design and Methods

We studied all 24 individuals with ABCC8-PNDM diagnosed in the UK, Italy, France or USA known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analysed using non-parametric statistical methods.
Results

Long-term data were obtained for 21/24 individuals (median follow-up 10.0 (4.1-13.2) years). 18/21 remained on sulfonylureas without insulin at most recent follow-up. Glycemic control improved on sulfonylureas (pre-sulfonylurea vs 1-year post-transfer HbA1c 7.2% vs 5.7%, p=0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, p=0.04), n=16. Relatively high doses were used (1-year vs 10-year dose 0.37 vs 0.25mg/kg/day glyburide, p=0.50), without any severe hypoglycemia. Neurological features were reported in 13/21 individuals: these improved following sulfonylurea transfer in 7/13. The commonest features were learning difficulties (52%), developmental delay (48%), and ADHD (38%).
Conclusions

Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.

Funding

PB has a Sir George Alberti Clinical Research Training Fellowship funded by Diabetes UK (Grant Number 16/0005407). ATH is supported by a Wellcome Trust Senior Investigator award (Grant number 098395/Z/12/Z). SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 105636/Z/14/Z). EDF has a RD Lawrence Fellowship funded by Diabetes UK (19/005971). MHS is a National Institute for Health Research (NIHR) Senior Nurse and Midwife Research Leader (NIHR4-SNMRL058) and is also supported by the Exeter NIHR Clinical Research Facility at the University of Exeter. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care. NJT is funded by a Wellcome Trust funded GW4 PhD. The University of Chicago Monogenic Diabetes Registry is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104942 and P30DK020595).

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