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Cited by 106Pancreatic function and diabetesIon channel regulation and functionDiabetes and associated disorders

Neonatal Diabetes and the K ATP Channel: From Mutation to Therapy

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Ashcroft, Frances M., Puljung, Michael C., Vedovato, Natascia·2017·Trends in Endocrinology & Metabolism
DOI 10.1016/j.tem.2017.02.003PMC PMC5582192
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Abstract

Activating mutations in one of the two subunits of the ATP-sensitive potassium (K ATP ) channel cause neonatal diabetes (ND). This may be either transient or permanent and, in approximately 20% of patients, is associated with neurodevelopmental delay. In most patients, switching from insulin to oral sulfonylurea therapy improves glycemic control and ameliorates some of the neurological disabilities. Here, we review how K ATP channel mutations lead to the varied clinical phenotype, how sulfonylureas exert their therapeutic effects, and why their efficacy varies with individual mutations.

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  • Gain-of-function mutations in either Kir6.2 or SUR1 result in neonatal diabetes, which usually presents within the first six months of life and is associated with a low birth weight.

    “Gain-of-function mutations in either Kir6.2 or SUR1 result in neonatal diabetes (ND), which usually presents within the first six months of life and is associated with a low birth weight (25, 29, 32, 43, 215, 255).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [29]

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  1. [1]Nichols C.G. KATP channels as molecular sensors of cellular metabolism Nature 440 2006 470 476 16554807
  2. [2]Ashcroft F.M. Rorsman P. Electrophysiology of the pancreatic b-cell Prog. Biophys. Mol. Biol. 54 1989 87 143 2484976
  3. [4]Hattersley A.T. Ashcroft F.M. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy Diabetes 54 2005 2503 2513 16123337
  4. [5]Babenko A.P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus N. Engl. J. Med. 355 2006 456 466 16885549
  5. [6]Gribble F.M. Reimann F. Sulphonylurea action revisited: the post-cloning era Diabetologia 46 2003 875 891 12819907
  6. [7]Pearson E.R. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations N. Engl. J. Med. 355 2006 467 477 16885550
  7. [8]Greeley S.A. Neonatal diabetes mellitus: a model for personalized medicine Trends Endocrinol. Metab. 21 2010 464 472 20434356 PMC2914172
  8. [10]Martin G.M. Cryo-EM structure of the ATP?sensitive potassium channel illuminates mechanisms of assembly and gating Elife 6 2017 024149 PMC5344670 28092267
  9. [11]Flanagan S.E. Update of mutations in the genes encoding the pancreatic b-cell KATP channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism Hum. Mutat. 30 2009 170 180 18767144
  10. [12]Flanagan S.E. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood Diabetes 56 2007 1930 1937 17446535 PMC7611811
  11. [13]Hashimoto Y. Molecular and clinical features of KATP-channel neonatal diabetes mellitus in Japan Pediatr. Diabetes 2016 Published online September 29, 2016 27681997
  12. [14]Bowman P. Heterozygous ABCC8 mutations are a cause of MODY Diabetologia 55 2012 123 127 21989597
  13. [15]Riveline J.P. Clinical and metabolic features of adult-onset diabetes caused by ABCC8 mutations Diabetes Care 35 2012 248 251 22210575 PMC3263906
  14. [16]Klupa T. Mutations in the ABCC8 (SUR1 subunit of the KATP channel) gene are associated with a variable clinical phenotype Clin. Endocrinol. 71 2009 358 362 19021632
  15. [18]Proks P. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features Proc. Natl. Acad. Sci. U. S. A. 101 2004 17539 17544 15583126 PMC536014
  16. [19]Ellard S. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects Am. J. Hum. Genet. 81 2007 375 382 17668386 PMC1950816
  17. [20]Mohamadi A. 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 11 2010 203 207 19686306
  18. [21]Battaglia D. Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation Pediatr. Diabetes 13 2012 656 660 22694282 PMC3747824
  19. [22]Rubio-Cabezas O. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life Pediatr. Diabetes 13 2012 322 325 21981029
  20. [23]Shimomura K. The first clinical case of a mutation at residue K185 of Kir6.2 (KCNJ11): a major ATP-binding residue Diabet. Med. 27 2010 225 229 20546268
  21. [24]Masia R. An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes Diabetes 56 2007 328 336 17259376
  22. [25]Koster J.C. 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. Metab. 93 2008 1054 1061 18073297 PMC2266958
  23. [26]Ortiz D. Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2 J. Biol. Chem. 287 2012 17985 17995 22451668 PMC3365736
  24. [27]Babenko A.P. Vaxillaire M. Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8) FEBS Lett. 585 2011 3555 3559 22020219 PMC3215797
  25. [28]Rafiq M. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations Diabetes Care 31 2008 204 209 18025408 PMC7611807
  26. [30]Shimomura K. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain Neurology 69 2007 1342 1349 17652641
  27. [31]Zung A. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2 J. Clin. Endocrinol. Metab. 89 2004 5504 5507 15531505
  28. [32]Verstappen S. Mul D. A ‘picturesque’ case of transition from subcutaneous to oral treatment in neonatal diabetes BMJ Case Rep. 2014 2014 bcr2013202912 PMC4025244 24827651
  29. [33]Thurber B.W. Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes Diabetologia 58 2015 1430 1435 25877689 PMC4641523
  30. [34]Kumaraguru J. Tooth discoloration in patients with neonatal diabetes after transfer onto glibenclamide: a previously unreported side effect Diabetes Care 32 2009 1428 1430 19435956 PMC2713626
  31. [35]Greeley S.A. Case report: preservation of reduced numbers of insulin-positive cells in sulfonylurea-unresponsive KCNJ11-related diabetes J. Clin. Endocrinol. Metab. 2016 2016 jc20162826 PMC5413092 27802092
  32. [36]Busiah K. Human pancreas endocrine cell populations and activating ABCC8 mutations Horm. Res. Paediatr. 82 2014 59 64 24941889
  33. [39]Wang Z. Pancreatic b cell dedifferentiation in diabetes and redifferentiation following insulin therapy Cell Metab. 19 2014 872 882 24746806 PMC4067979
  34. [40]Remedi M.S. Secondary consequences of b cell inexcitability: identification and prevention in a murine model of KATP-induced neonatal diabetes mellitus Cell Metab. 9 2009 140 151 19187772 PMC4793729
  35. [41]Gribble F.M. The interaction of nucleotides with the tolbutamide block of cloned ATP-sensitive K+ channel currents expressed in Xenopus oocytes: a reinterpretation J. Physiol. 504 1997 35 45 9350615 PMC1159933
  36. [42]Barrett-Jolley R. Davies N.W. Kinetic analysis of the inhibitory effect of glibenclamide on KATP channels of mammalian skeletal muscle J. Membr. Biol. 155 1997 257 262 9050449
  37. [43]Proks P. Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: a mechanistic study J. Gen. Physiol. 144 2014 469 486 25348414 PMC4210431
  38. [44]Proks P. Activation of the KATP channel by Mg-nucleotide interaction with SUR1 J. Gen. Physiol. 136 2010 389 405 20876358 PMC2947056
  39. [45]Drain P. ATP and sulfonylurea linkage in the KATP channel solves a diabetes puzzler Diabetes 62 2013 3666 3668 24158995 PMC3806587
  40. [46]Proks P. Molecular mechanism of sulphonylurea block of KATP channels carrying mutations that impair ATP inhibition and cause neonatal diabetes Diabetes 62 2013 3909 3919 23835339 PMC3806600
  41. [47]Zhang C.L. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs Science 325 2009 607 610 19644119
  42. [48]Takahashi H. Role of Epac2A/Rap1 signaling in interplay between incretin and sulfonylurea in insulin secretion Diabetes 64 2015 1262 1272 25315008
  43. [49]Renstrom E. Sulfonylurea-mediated stimulation of insulin exocytosis via an ATP-sensitive K+ channel-independent action Diabetes 51 Suppl. 1 2002 S33 S36 11815455
  44. [50]Tarasov A.I. ATP sensitivity of the ATP-sensitive K+ channel in intact and permeabilized pancreatic b-cells Diabetes 55 2006 2446 2454 16936192
  45. [52]Henquin J.C. Triggering and amplifying pathways of regulation of insulin secretion by glucose Diabetes 49 2000 1751 1760 11078440
  46. [53]Iafusco D. No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes Diabetologia 54 2011 2736 2738 21822789
  47. [54]Myngheer N. Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes Diabetes Care 37 2014 3333 3335 25231897 PMC5894804
  48. [55]Klupa T. The first case report of sulfonylurea use in a woman with permanent neonatal diabetes mellitus due to KCNJ11 mutation during a high-risk pregnancy J. Clin. Endocrinol. Metab. 95 2010 3599 3604 20466780
  49. [56]Gaal Z. Sulfonylurea use during entire pregnancy in diabetes because of KCNJ11 mutation: a report of two cases Diabetes Care 35 2012 e40 22619292 PMC3357257
  50. [57]De Franco E. Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes Diabet. Med. 2016 Published online June 29, 2016 PMC5096683 27477181
  51. [58]Sumnik Z. Sulphonylurea treatment does not improve psychomotor development in children with KCNJ11 mutations causing permanent neonatal diabetes mellitus accompanied by developmental delay and epilepsy (DEND syndrome) Diabet. Med. 24 2007 1176 1178 17888143
  52. [59]Babiker T. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes Diabetologia 59 2016 1162 1166 27033559 PMC4869695
  53. [60]Kelsey M.M. Zeitler P.S. Insulin resistance of puberty Curr. Diab. Rep. 16 2016 64 27179965
  54. [61]Goran M.I. Gower B.A. Longitudinal study on pubertal insulin resistance Diabetes 50 2001 2444 2450 11679420
  55. [62]Remedi M.S. Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes Diabetes 60 2011 2515 2522 21813803 PMC3178299
  56. [63]Marshall B.A. Remission of severe neonatal diabetes with very early sulfonylurea treatment Diabetes Care 38 2015 e38 e39 25715421 PMC4876698
  57. [64]Wambach J.A. Successful sulfonylurea treatment of an insulin-naive neonate with diabetes mellitus due to a KCNJ11 mutation Pediatr. Diabetes 11 2010 286 288 19656320 PMC3245710
  58. [65]Beltrand J. Sulfonylurea therapy benefits neurological and psychomotor functions in patients with neonatal diabetes owing to potassium channel mutations Diabetes Care 38 2015 2033 2041 26438614
  59. [66]Bowman P. Psychiatric morbidity in children with KCNJ11 neonatal diabetes Diabet. Med. 33 2016 1387 1391 27086753 PMC5031218
  60. [67]McTaggart J.S. Gain-of-function mutations in the KATP channel (KCNJ11) impair coordinated hand–eye tracking PLoS One 8 2013 e62646 23626843 PMC3633835
  61. [68]Proks P. Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome Hum. Mol. Genet. 16 2007 2011 2019 17584766
  62. [69]Shah R.P. 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 35 2012 2086 2088 22855734 PMC3447845
  63. [70]Slingerland A.S. Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation Diabet. Med. 25 2008 277 281 18307455
  64. [71]Clark R. Mice expressing a human KATP channel mutation have altered channel ATP sensitivity but no cardiac abnormalities Diabetologia 55 2012 1195 1204 22252471 PMC3296019
  65. [72]Clark R.H. Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin Science 329 2010 458 461 20595581 PMC5890903
  66. [73]Fendler W. Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion Diabetes Care 36 2013 2311 2316 23462667 PMC3714477
  67. [74]Lahmann C. A mutation causing increased KATP channel activity leads to reduced anxiety in mice Physiol. Behav. 129 2014 79 84 24582665 PMC5576528
  68. [75]Lahmann C. Systemic administration of glibenclamide fails to achieve therapeutic levels in the brain and cerebrospinal fluid of rodents PLoS One 10 2015 e0134476 26225433 PMC4520580
  69. [76]Chen P.C. Carbamazepine as a novel small molecule corrector of trafficking-impaired ATP-sensitive potassium channels identified in congenital hyperinsulinism J. Biol. Chem. 288 2013 20942 20954 23744072 PMC3774364
  70. [77]Vaxillaire M. New ABCC8 mutations in relapsing neonatal diabetes and clinical features Diabetes 56 2007 1737 1741 17389331
  71. [78]Batra C.M. Transient neonatal diabetes due to activating mutation in the ABCC8 gene encoding SUR1 Indian J. Pediatr. 76 2009 1169 1172 20092027
  72. [79]Geng X. The insulin secretory granule is the major site of K(ATP) channels of the endocrine pancreas Diabetes 52 2003 767 776 12606519
  73. [80]Shibasaki T. Integration of ATP, cAMP, and Ca2+ signals in insulin granule exocytosis Diabetes 53 Suppl. 3 2004 S59 S62 15561922
  74. [81]Li C.G. Sensitivity of KATP channels to cellular metabolic disorders and the underlying structural basis Acta Pharmacol. Sin. 37 2016 134 142 26725741 PMC4722982
  75. [82]Matsuoka T. C-terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K+ channels Circ. Res. 87 2000 873 880 11073882
  76. [83]Flagg T.P. Differential structure of atrial and ventricular KATP: atrial KATP channels require SUR1 Circ. Res. 103 2008 1458 1465 18974387 PMC2768594
  77. [84]Glukhov A.V. Functional roles of KATP channel subunits in metabolic inhibition J. Mol. Cell. Cardiol. 62 2013 90 98 23624089 PMC3759354
  78. [85]Tarasov A.I. A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and b-cell glucose sensing is associated with type 2 diabetes in adults Diabetes 57 2008 1595 1604 18346985 PMC6101196
  79. [86]Klee P. A novel ABCC8 mutation illustrates the variability of the diabetes phenotypes associated with a single mutation Diabetes Metab. 38 2012 179 182 22326206
  80. [87]D’Amato E. Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation Diabet. Med. 25 2008 651 656 18544102
  81. [88]Bonnefond A. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene PLoS 7 2012 e37423 PMC3372463 22701567
  82. [89]Villareal D.T. Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance Diabetes 58 2009 1869 1878 19491206 PMC2712777
  83. [90]Schwanstecher C. Kir6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic β-cell ATP-sensitive K+ channels Diabetes 51 2002 875 879 11872696
  84. [91]Hamming K.S. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K+ channel Diabetes 58 2009 2419 2424 19587354 PMC2750221
  85. [92]Vedovato N. Neonatal diabetes caused by a homozygous KCNJ11 mutation demonstrates that tiny changes in ATP sensitivity markedly affect diabetes risk Diabetologia 59 2016 1430 1436 27118464 PMC4901145

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Authors
Ashcroft, F. M., Puljung, M. C., & Vedovato, N.
Affiliations
University of Oxford (GB)
Corresponding author
Ashcroft, Frances M.
ORCID
Venue
Trends in Endocrinology & Metabolism
Publisher
Elsevier BV
Published
2017-05
Volume
28
Issue
5
Pages
377-387
ISSN
1043-2760 (ISSN-L)
DOI
10.1016/j.tem.2017.02.003
PMC
PMC5582192
OpenAlex
W2594319058
Cited by
106
References
6
Citations by year
2026: 6 · 2025: 10 · 2024: 7 · 2023: 16 · 2022: 4 · 2021: 18 · 2020: 17 · 2019: 15 · 2018: 9 · 2017: 4
FWCI
2.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Endocrinology and Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (089795)
  • European Research Council (332620)
  • Royal Society
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
neonatal diabetes, ATP-sensitive potassium channels, KATP channel mutations, sulfonylurea therapy, neurodevelopmental delay, insulin therapy, glycemic control, clinical phenotype
MeSH terms
Blood Glucose, Diabetes Mellitus, Humans, Hypoglycemic Agents, Infant, Newborn, Mutation, Sulfonylurea Compounds, KATP Channels

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