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Precision Medicine: Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes Due to KCNJ11 Mutations

  • Pediatric Type 2 and Monogenic Diabetes (O Pinhas-Hamiel, Section Editor)
  • Published:
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Abstract

Purpose of Review

The goal of this review is to provide updates on the safety and efficacy of long-term sulfonylurea use in patients with KCNJ11-related diabetes. Publications from 2004 to the present were reviewed with an emphasis on literature since 2014.

Recent Findings

Sulfonylureas, often taken at high doses, have now been utilized effectively in KCNJ11 patients for over 10 years. Mild–moderate hypoglycemia can occur, but in two studies with a combined 975 patient-years on sulfonylureas, no severe hypoglycemic events were reported. Improvements in neurodevelopment and motor function after transition to sulfonylureas continue to be described.

Summary

Sulfonylureas continue to be an effective, sustainable, and safe treatment for KCNJ11-related diabetes. Ongoing follow-up of patients in research registries will allow for deeper understanding of the facilitators and barriers to long-term sustainability. Further understanding of the effect of sulfonylurea on long-term neurodevelopmental outcomes, and the potential for adjunctive therapies, is needed.

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Abbreviations

KATP channel:

ATP-dependent potassium channel

SU:

Sulfonylurea

PNDM:

Permanent neonatal diabetes

TNDM:

Transient neonatal diabetes

DKA:

Diabetic ketoacidosis

DEND:

Developmental delay, epilepsy, and neonatal diabetes

CNS:

Central nervous system

SPECT:

Single-photon emission computed tomography

CSF:

Cerebrospinal fluid

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med. 1998;15:297–303.

    Article  CAS  Google Scholar 

  2. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389–94.

    Article  Google Scholar 

  3. Sola D, Rossi L, Schianca GPC, Maffioli P, Bigliocca M, Mella R, et al. Sulfonylureas and their use in clinical practice. Arch Med Sci. 2015;11:840–8.

  4. Proks P, Girard C, Ashcroft FM. Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet. 2005;14:2717–26.

    Article  CAS  Google Scholar 

  5. Girard CAJ, Shimomura K, Proks P, Absalom N, Castaño L, Perez de Nanclares G, et al. Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch. 2006;453:323–32.

    Article  CAS  Google Scholar 

  6. Proks 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 U S A. 2004;101:17539–44.

    Article  CAS  Google Scholar 

  7. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, et al. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet. 2005;14:925–34.

    Article  CAS  Google Scholar 

  8. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, 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;350:1838–49.

    Article  CAS  Google Scholar 

  9. Rubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatr Diabetes. 2012;13:322–5.

    Article  CAS  Google Scholar 

  10. Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes. 2010;11:203–7.

    Article  Google Scholar 

  11. Battaglia D, Lin Y-W, Brogna C, Crinò A, Grasso V, Mozzi AF, et al. Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation. Pediatr Diabetes. 2012;13:656–60.

    Article  Google Scholar 

  12. Day JO, Flanagan SE, Shepherd MH, Patrick AW, Abid N, torrens L, et al. Hyperglycaemia-related complications at the time of diagnosis can cause permanent neurological disability in children with neonatal diabetes. Diabet Med. 2017;34:1000–4.

    Article  CAS  Google Scholar 

  13. • Letourneau LR, Carmody D, Wroblewski K, Denson AM, Sanyoura M, Naylor RN, et al. Diabetes presentation in infancy: high risk of diabetic ketoacidosis. Diabetes Care. 2017;40:e147–8 This paper examined medical records from 88 infancy-onset diabetes cases and found that a staggering 66% presented in DKA at the time of diagnosis. This supports the need for systematic and early identification of all forms of infancy-onset diabetes.

    Article  Google Scholar 

  14. Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006;49:1190–7.

    Article  CAS  Google Scholar 

  15. •• Bowman P, Sulen Å, Barbetti F, Beltrand J, Svalastoga P, Codner E, 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;6:637–46 This impressive paper is the longest follow-up study of patients with KCNJ11 mutations. Overall, this work suggests that sulfonylurea therapy is sustainable, effective, and safe.

  16. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503–13.

    Article  CAS  Google Scholar 

  17. Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, et al. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet. 2006;14:824–30.

    Article  CAS  Google Scholar 

  18. Busiah K, Drunat S, Vaivre-Douret L, Bonnefond A, Simon A, Flechtner I, et al. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected]. Lancet Diabetes Endocrinol. 2013;1:199–207.

    Article  CAS  Google Scholar 

  19. • Carmody D, Pastore AN, Landmeier KA, Letourneau LR, Martin R, Hwang JL, et al. Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls. Diabet Med. 2016;33:1380–6 Sibling controls and children affected with KCNJ11 diabetes were analyzed in this study, which uncovered that even patients with ‘mild’ KCNJ11 mutations may still have developmental struggles compared to their healthy siblings.

    Article  CAS  Google Scholar 

  20. Bowman P, Hattersley AT, Knight BA, Broadbridge E, Pettit L, Reville M, et al. Neuropsychological impairments in children with KCNJ11 neonatal diabetes. Diabet Med. 2017;34:1171–3.

    Article  CAS  Google Scholar 

  21. • Bowman P, Broadbridge E, Knight BA, Pettit L, Flanagan SE, Reville M, et al. Psychiatric morbidity in children with KCNJ11neonatal diabetes. Diabet Med. 2016;33:1387–91 Six out of ten KCNJ11 participants were noted to have a psychiatric disorder (most commonly autism, anxiety, or ADHD) in this study, which was the first to specifically examine psychiatric morbidity.

    Article  CAS  Google Scholar 

  22. Landmeier KA, Lanning M, Carmody D, Greeley SAW, Msall ME. ADHD, learning difficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes. Pediatr Diabetes. 2017;18:518–23.

    Article  CAS  Google Scholar 

  23. • Bowman P, day J, torrens L, shepherd M, knight B, ford T, et al. Cognitive, neurological, and behavioral features in adults with KCNJ11 neonatal diabetes. Diabetes Care. 2019;42:215–24 The majority of adults with KCNJ11 mutations from this study (7/8) had abnormal neurological examinations, including difficulties such as impaired attention and reduced IQ.

    Article  Google Scholar 

  24. Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–77.

    Article  CAS  Google Scholar 

  25. Bremer AA, Ranadive S, Lustig RH. Outpatient transition of an infant with permanent neonatal diabetes due to a KCNJ11 activating mutation from subcutaneous insulin to oral glyburide. Pediatr Diabetes. 2008;9:236–9.

    Article  CAS  Google Scholar 

  26. • Babiker T, Vedovato N, Patel K, Thomas N, Finn R, Männikkö R, et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia. 2016;59:1162–6 Babiker and colleagues analyzed data from 127 participants with KCNJ11 mutations and found that 88% were able to transfer fully onto SU and reach target HbA1c levels. They noted that participants who had a shorter duration of diabetes prior to SU transfer were more likely to have a successful transfer, highlighting the need for early initiation of SU.

    Article  CAS  Google Scholar 

  27. Thurber BW, Carmody D, Tadie EC, Pastore AN, Dickens JT, Wroblewski KE, et al. Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes. Diabetologia. 2015;58:1430–5.

    Article  CAS  Google Scholar 

  28. Sagen JV, Ræder H, Hathout E, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004;53:2713–8.

    Article  CAS  Google Scholar 

  29. Tonini G, Bizzarri C, Bonfanti R, Vanelli M, Cerutti F, Faleschini E, et al. Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene. Diabetologia. 2006;49:2210–3.

    Article  CAS  Google Scholar 

  30. Iafusco D, Bizzarri C, Cadario F, Pesavento R, Tonini G, Tumini S, et al. No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes. Diabetologia. 2011;54:2736–8.

    Article  CAS  Google Scholar 

  31. Beltrand J, Elie C, Busiah K, Fournier E, Boddaert N, Bahi-Buisson N, et al. Sulfonylurea therapy benefits neurological and psychomotor functions in patients with neonatal diabetes owing to potassium channel mutations. Diabetes Care. 2015;38:2033–41.

    Article  CAS  Google Scholar 

  32. Støy J, Greeley SAW, Paz VP, Ye H, Pastore AN, Skowron KB, et al. Diagnosis and treatment of neonatal diabetes: an United States experience†. Pediatr Diabetes. 2008;9:450–9.

    Article  Google Scholar 

  33. Greeley SAW, Zielinski MC, Poudel A, Ye H, Berry S, Taxy JB, et al. Preservation of reduced numbers of insulin-positive cells in sulfonylurea-unresponsive KCNJ11-related diabetes. J Clin Endocrinol Metabol. 2017;102:1–5.

  34. Russo C, Salina A, Aloi C, Iafusco D, Lorini R, d'Annunzio G. Mother and daughter carrying the same KCNJ11 mutation but with a different response to switching from insulin to sulfonylurea. Diabetes Res Clin Pract. 2011;94:e50–2.

    Article  CAS  Google Scholar 

  35. Sastre J, Luque A, del Val F, Aragonés A, López J. Long-term efficacy of glibenclamide and sitagliptin therapy in adult patients with KCNJ11 permanent diabetes. Diabetes Care. 2014;37:e55–6.

    Article  CAS  Google Scholar 

  36. Malecki MT, Skupien J, Klupa T, Wanic K, Mlynarski W, Gach A, et al. Transfer to sulphonylurea therapy in adult subjects with permanent neonatal diabetes due to KCNJ11-activating [corrected] mutations: evidence for improvement in insulin sensitivity. Diabetes Care. 2007;30:147–9.

  37. Brereton MF, Iberl M, Shimomura K, Zhang Q, Adriaenssens AE, Proks P, et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat Commun. 2014;5:4639.

  38. Brereton MF, Rohm M, Shimomura K, Holland C, Tornovsky-Babeay S, Dadon D, et al. Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells. Nat Commun. 2016;7:13496.

  39. Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia. 2006;49:2559–63.

    Article  CAS  Google Scholar 

  40. Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Barbetti F. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metabol. 2008;93:1054–61.

    Article  CAS  Google Scholar 

  41. Slingerland AS, Hurkx W, Noordam K, Flanagan SE, Jukema JW, Meiners LC, et al. Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation. Diabet Med. 2008;25:277–81.

    Article  CAS  Google Scholar 

  42. Gurgel LC, Crispim F, Noffs MHS, Belzunces E, Rahal MA, Moises RS. Sulfonylrea treatment in permanent neonatal diabetes due to G53D mutation in the KCNJ11 gene: improvement in glycemic control and neurological function. Diabetes Care. 2007;30:e108–8.

    Article  Google Scholar 

  43. Shah 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;35:2086–8.

    Article  CAS  Google Scholar 

  44. Fendler W, Pietrzak I, Brereton MF, Lahmann C, Gadzicki M, Bienkiewicz M, et al. Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion. Diabetes Care. 2013;36:2311–6.

    Article  CAS  Google Scholar 

  45. Mlynarski W, Tarasov AI, Gach A, Girard CA, Pietrzak I, Zubcevic L, et al. Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. Nat Clin Pract Neurol. 2007;3:640–5.

    Article  CAS  Google Scholar 

  46. Lahmann 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:e0134476.

    Article  Google Scholar 

  47. •• Lanning 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;19:393–7 Frequency of hypoglycemia was analyzed in 30 participants with KCNJ11-related diabetes. Mild-moderate hypoglycemia was reported, although infrequently, and no episodes of hypoglycemia were noted to be severe.

    Article  Google Scholar 

  48. Mazze RS, Strock E, Wesley D, Borgman S, Morgan B, Bergenstal R, et al. Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis. Diabetes Technol Ther. 2008;10:149–59.

    Article  CAS  Google Scholar 

  49. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Variation of interstitial glucose measurements assessed by continuous glucose monitors in healthy, nondiabetic individuals. Diabetes Care. 2010;33:1297–9.

    Article  Google Scholar 

  50. Misra S, Vedovato N, Cliff E, De Franco E, Hattersley AT, Ashcroft FM, et al. Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment. Diabet Med. 2018;35:1291–6.

    Article  Google Scholar 

  51. Stanik J, Dankovcikova A, Barak L, Skopkova M, Palko M, Divinec J, et al. Sulfonylurea vs insulin therapy in individuals with sulfonylurea-sensitive permanent neonatal diabetes mellitus, attributable to a KCNJ11 mutation, and poor glycaemic control. Diabet Med. 2018;35:386–91.

    Article  CAS  Google Scholar 

  52. Babiker T, Shepherd MH, Hattersley AT. Continue with long term sulfonylureas in patients with mutations in the KCNJ11 gene when there is evidence of response even if insulin treatment is still required. Diabetes Res Clin Pract. 2013;100:e63.

    Article  CAS  Google Scholar 

  53. Carmody D, Bell CD, Hwang JL, Dickens JT, Sima DI, Felipe DL, et al. Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metabol. 2014;99:E2709–14.

    Article  CAS  Google Scholar 

  54. • Li X, Xu A, Sheng H, Ting TH, Mao X, Huang X, et al. Early transition from insulin to sulfonylureas in neonatal diabetes and follow-up: experience from China. Pediatr Diabetes. 2018;19:251–8 Li and colleagues report on their experience trialing SU before genetic testing results were available in 16 cases with neonatal diabetes in China.

    Article  Google Scholar 

  55. Kumaraguru J, Flanagan SE, Greeley SAW, Nuboer R, Støy J, Philipson LH, et al. Tooth discoloration in patients with neonatal diabetes after transfer onto glibenclamide: a previously unreported side effect. Diabetes Care. 2009;32:1428–30.

    Article  CAS  Google Scholar 

  56. Roumie CL, Min JY, D'Agostino McGowan L, Presley C, Grijalva CG, Hackstadt AJ, Hung AM, Greevy RA, Elasy T, Griffin MR (2017) Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J Am Heart Assoc 6:696.

  57. Vendramini MF, Gurgel LC, Moisés RS. Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene. Arq Bras Endocrinol Metabol. 2010;54:682–4.

    Article  Google Scholar 

  58. Klupa T, Skupien J, Mirkiewicz-Sieradzka B, Gach A, Noczynska A, Szalecki M, et al. Diabetic retinopathy in permanent neonatal diabetes due to Kir6.2 gene mutations: the results of a minimum 2-year follow-up after the transfer from insulin to sulphonylurea. Diabet Med. 2009;26:663–4.

    Article  CAS  Google Scholar 

  59. Klupa T, Skupien J, Mirkiewicz-Sieradzka B, Gach A, Noczynska A, Zubkiewicz-Kucharska A, et al. Efficacy and safety of sulfonylurea use in permanent neonatal diabetes due to KCNJ11 gene mutations: 34-month median follow-up. Diabetes Technol Ther. 2010;12:387–91.

    Article  CAS  Google Scholar 

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Acknowledgments

We would like to acknowledge the international group of scientists and families who contribute to monogenic diabetes research. We would especially like to thank the families who participate in the Monogenic Diabetes Registry at the University of Chicago, and the healthcare teams providing care for them.

Funding

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [grant numbers R01 DK104942, P30 DK020595, and K23 DK094866], the CTSA [grant number UL1 TR002389], as well as by grants from the American Diabetes Association [grant numbers 1-11-CT-41 and 1-17-JDF-008], and gifts from the Kovler Family Foundation.

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Correspondence to Siri Atma W. Greeley.

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Letourneau, L.R., Greeley, S.A.W. Precision Medicine: Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes Due to KCNJ11 Mutations. Curr Diab Rep 19, 52 (2019). https://doi.org/10.1007/s11892-019-1175-9

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