Precision medicine in KCNJ11 permanent neonatal diabetes
Authors: Siri Atma W Greeley, Lisa R Letourneau, Louis H Philipson
Journal: The Lancet Diabetes & Endocrinology (2018)

One of the most important advances towards personalised genetic medicine for diabetes was the discovery that nearly half of neonatal diabetes is caused by de-novo (usually) or inherited mutations in the subunits of the pancreatic β-cell ATP-sensitive potassium (KATP) channel.1Gloyn AL Pearson ER Antcliff JF et al.Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.N Engl J Med. 2004; 350: 1838-1849Crossref PubMed Scopus (975) Google Scholar These activating mutations in the KCNJ11 and ABCC8 genes shift the probability of the KATP channels to have an open configuration, causing plasma membrane hyperpolarisation, thereby inhibiting insulin secretion, and causing permanent or transient neonatal diabetes. With most of these mutations, channel function can be restored by blockade with sulfonylurea tablets. This simple and low-cost treatment allows most patients to achieve substantially improved glycaemic control—with minimal hypoglycaemia—compared with insulin injections.2Greeley SAW John PM Winn AN et al.The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes.Diabetes Care. 2011; 34: 622-627Crossref PubMed Scopus (70) Google Scholar, 3Proks P Antcliff JF Lippiat J Gloyn AL Hattersley AT Ashcroft FM Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.Proc Natl Acad Sci USA. 2004; 101: 17539-17544Crossref PubMed Scopus (209) Google Scholar Identification and appropriate treatment of these individuals with sulfonylureas is also remarkably cost-effective over their lifetime.2Greeley SAW John PM Winn AN et al.The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes.Diabetes Care. 2011; 34: 622-627Crossref PubMed Scopus (70) Google Scholar In many cases, the KATP subunit mutations also cause a spectrum of sometimes severe neurological defects that often (but not always) correlate with the open probability of the mutant channels and the ability of sulfonylurea drugs to block the channel.3Proks P Antcliff JF Lippiat J Gloyn AL Hattersley AT Ashcroft FM Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.Proc Natl Acad Sci USA. 2004; 101: 17539-17544Crossref PubMed Scopus (209) Google Scholar Despite this profoundly insightful set of discoveries, some concern has remained about the safety and durability of sulfonylurea treatment in these patients, which often requires higher than approved doses and is given off-label in most countries when used in children. In The Lancet Diabetes & Endocrinology, Pamela Bowman and colleagues4Bowman P Sulen A Barbetti F et al.Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.Lancet Diabetes Endocrinol. 2018; (published online June 1.)http://dx.doi.org/10.1016/S2213-8587(18)30106-2Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar report findings from long-term follow-up of an international cohort of patients with neonatal diabetes due to KCNJ11 mutations who were switched from insulin to sulfonylurea treatment. After about 10 years of follow-up, 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Very good glycaemic control was maintained for patients for whom paired data were available on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64), with median HbA1c 6·4% at most recent follow-up, compared with 5·9% at 1 year and 8·1% before transfer to sulfonylurea therapy. There were no reports of severe hypoglycaemia in 809 patient-years of follow-up for the whole cohort. We agree that these positive long-term findings confirm this approach to be one of the best examples of precision genetic medicine in all medical practice. In type 2 diabetes, sulfonylurea drugs are associated with hypoglycaemia and failure to durably maintain improvements in glucose control, and have also been associated with increased all-cause mortality and cardiovascular events in adults with type 2 diabetes.5Riddle MC Modern sulfonylureas: dangerous or wrongly accused?.Diabetes Care. 2017; 40: 629-631Crossref PubMed Scopus (22) Google Scholar, 6Azoulay L Suissa S Sulfonylureas and the risks of cardiovascular events and death: a methodological meta-regression analysis of the observational studies.Diabetes Care. 2017; 40: 706-714Crossref PubMed Scopus (122) Google Scholar Additional concerns exist about the use of glibenclamide specifically in type 2 diabetes.7Tuccori M Wu JW Yin H Majdan A Azoulay L The use of glyburide compared with other sulfonylureas and the risk of cancer in patients with type 2 diabetes.Diabetes Care. 2015; 38: 2083-2089Crossref PubMed Scopus (21) Google Scholar These concerns might contribute to reluctance among some clinicians to pursue sulfonylurea therapy in patients known to have KCNJ11 or ABCC8 mutations causing neonatal diabetes. However, compared with adults with type 2 diabetes, most individuals with KATP mutation-related diabetes are children or young adults who are non-obese and insulin sensitive, without confounding or contributory histories of coronary artery disease, hyperlipidaemia, hypertension, and renal insufficiency, among other issues more common in type 2 diabetes. The evidence that HbA1c is improved by sulfonylurea treatment more than with insulin is robust,8Pearson ER Flechtner I Njølstad PR et al.Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.N Engl J Med. 2006; 355: 467-477Crossref PubMed Scopus (788) Google Scholar, 9Thurber BW Carmody D Tadie EC et al.Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes.Diabetologia. 2015; 58: 1430-1435Crossref PubMed Scopus (57) Google Scholar and the results of Bowman and colleagues' study,4Bowman P Sulen A Barbetti F et al.Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.Lancet Diabetes Endocrinol. 2018; (published online June 1.)http://dx.doi.org/10.1016/S2213-8587(18)30106-2Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar together with previous research,10Lanning MS Carmody D Szczerbiński Ł Letourneau LR Naylor RN Greeley SAW Hypoglycemia in sulfonylurea-treated KCNJ11-neonatal diabetes: mild-moderate symptomatic episodes occur infrequently but none involving unconsciousness or seizures.Pediatr Diabetes. 2017; 49: 405Google Scholar show that hypoglycaemia is mild and other side-effects of high-dose sulfonylureas are not clinically significant. Some evidence exists that sulfonylurea therapy might have a beneficial effect on the neurological features seen in patients with more severe mutations, but treatment might need to start at an early age and the benefit might be small.11Shah RP Spruyt K Kragie BC Greeley SAW Msall ME Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas.Diabetes Care. 2012; 35: 2086-2088Crossref PubMed Scopus (62) Google Scholar Bowman and colleagues report that,4Bowman P Sulen A Barbetti F et al.Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.Lancet Diabetes Endocrinol. 2018; (published online June 1.)http://dx.doi.org/10.1016/S2213-8587(18)30106-2Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar despite some initial improvement in some patients, neurological features persisted in their international cohort of long-term sulfonylurea-treated patients. Bowman and colleagues' findings4Bowman P Sulen A Barbetti F et al.Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.Lancet Diabetes Endocrinol. 2018; (published online June 1.)http://dx.doi.org/10.1016/S2213-8587(18)30106-2Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar show that during more than 10 years of treatment there was no loss of the effect of sulfonylurea therapy on insulin secretion; rather, there was a small but detectable continued lowering of the dose (expressed as dose per kg bodyweight) necessary to maintain normal glycaemia. Why this might be the case is unclear, but several possibilities exist. It could be that there is continued improvement of the capacity of β cells for glucose-stimulated insulin secretion during sulfonylurea treatment, or that sulfonylureas, often hydrophobic in nature, can accumulate in tissues over time. This theory might also explain why we have heard anecdotally from patients that occasional doses can be missed without a prompt rise in blood sugar. In individuals showing signs of developmental delay and neurological dysfunction due to KATP mutations, there might only be a modest effect on improving the neurological features with sulfonylurea drugs.11Shah RP Spruyt K Kragie BC Greeley SAW Msall ME Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas.Diabetes Care. 2012; 35: 2086-2088Crossref PubMed Scopus (62) Google Scholar, 12Mlynarski W Tarasov AI Gach A et al.Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11.Nat Clin Pract Neurol. 2007; 3: 640-645Crossref PubMed Scopus (92) Google Scholar, 13Fendler W Pietrzak I Brereton MF et al.Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion.Diabetes Care. 2013; 36: 2311-2316Crossref PubMed Scopus (27) Google Scholar, 14Busiah K Drunat S Vaivre-Douret L et al.Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study.Lancet Diabetes Endocrinol. 2013; 1: 199-207Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar CNS effects are clearly variable in their response and might depend on getting the drug to affected individuals as early as possible,9Thurber BW Carmody D Tadie EC et al.Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes.Diabetologia. 2015; 58: 1430-1435Crossref PubMed Scopus (57) Google Scholar and in a way that overcomes the low concentration of sulfonylurea in the CNS itself.15Lahmann C Kramer HB Ashcroft FM Systemic administration of glibenclamide fails to achieve therapeutic levels in the brain and cerebrospinal fluid of rodents.PLoS One. 2015; 10: e0134476Crossref PubMed Scopus (56) Google Scholar Overall, Bowman and colleagues' findings4Bowman P Sulen A Barbetti F et al.Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study.Lancet Diabetes Endocrinol. 2018; (published online June 1.)http://dx.doi.org/10.1016/S2213-8587(18)30106-2Summary Full Text Full Text PDF PubMed Scopus (93) Google Scholar illustrating the durability of sulfonylurea therapy without substantial off-target effects will be of general interest, not only to those following advances in this field, but as an exemplar of precision medicine. These results also suggest that there are important differences between sulfonylurea therapy in type 2 diabetes and neonatal KATP-related diabetes, the mechanisms of which remain to be fully elucidated. We declare no competing interests. Our work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health (grant numbers R01 DK104942 and K23 DK094866). Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort studyHigh-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years. Full-Text PDF Open Access