KATP channelopathies in the pancreas

Integrative Physiology


Adenosine-triphosphate-sensitive potassium channels (KATP) are regulated by adenosine nucleotides, and, thereby, couple cellular metabolism with electrical activity in multiple tissues including the pancreatic β-cell. The critical involvement of KATP in insulin secretion is confirmed by the demonstration that inactivating and activating mutations in KATP underlie persistent hyperinsulinemia and neonatal diabetes mellitus, respectively, in both animal models and humans. In addition, a common variant in KATP represents a risk factor in the etiology of type 2 diabetes. This review focuses on the mechanistic basis by which KATP mutations underlie insulin secretory disorders and the implications of these findings for successful clinical intervention.


Neonatal Diabetes Hyperinsulinism Diazoxide Sulfonylurea Kir6.2 SUR1 


  1. 1.
    Aguilar-Bryan L, Nichols CG, Wechsler SW, JPt C, Boyd AE 3rd, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA (1995) Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268:423–426PubMedCrossRefGoogle Scholar
  2. 2.
    Aguilar-Bryan L, Bryan J (2008) Neonatal diabetes mellitus. Endocr Rev 29:265–291PubMedCrossRefGoogle Scholar
  3. 3.
    Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM (2009) Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc Lond B Biol Sci 364:257–267PubMedCrossRefGoogle Scholar
  4. 4.
    Aizawa T, Komatsu M, Asanuma N, Sato Y, Sharp GW (1998) Glucose action “beyond ionic events” in the pancreatic beta cell. Trends Pharmacol Sci 19:496–499PubMedCrossRefGoogle Scholar
  5. 5.
    Antcliff JF, Haider S, Proks P, Sansom MS, Ashcroft FM (2005) Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J 24:229–239PubMedCrossRefGoogle Scholar
  6. 6.
    Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312:446–448PubMedCrossRefGoogle Scholar
  7. 7.
    Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol 54:87–143PubMedCrossRefGoogle Scholar
  8. 8.
    Ashcroft FM (2005) ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 115:2047–2058PubMedCrossRefGoogle Scholar
  9. 9.
    Babenko AP, Bryan J (2003) Sur domains that associate with and gate KATP pores define a novel gatekeeper. J Biol Chem 278:41577–41580PubMedCrossRefGoogle Scholar
  10. 10.
    Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355:456–466PubMedCrossRefGoogle Scholar
  11. 11.
    Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ (2003) Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 1:E20PubMedCrossRefGoogle Scholar
  12. 12.
    Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B (1998) PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 282:1141–1144PubMedCrossRefGoogle Scholar
  13. 13.
    Bienengraeber M, Alekseev AE, Abraham MR, Carrasco AJ, Moreau C, Vivaudou M, Dzeja PP, Terzic A (2000) ATPase activity of the sulfonylurea receptor: a catalytic function for the KATP channel complex. FASEB J 14:1943–1952PubMedCrossRefGoogle Scholar
  14. 14.
    Britsch S, Krippeit-Drews P, Lang F, Gregor M, Drews G (1995) Glucagon-like peptide-1 modulates Ca2+ current but not K + ATP current in intact mouse pancreatic B-cells. Biochem Biophys Res Commun 207:33–39PubMedCrossRefGoogle Scholar
  15. 15.
    Bryan J, Vila-Carriles WH, Zhao G, Babenko AP, Aguilar-Bryan L (2004) Toward linking structure with function in ATP-sensitive K + channels. Diabetes 53(Suppl 3):S104–S112PubMedCrossRefGoogle Scholar
  16. 16.
    Bryan J, Crane A, Vila-Carriles WH, Babenko AP, Aguilar-Bryan L (2005) Insulin secretagogues, sulfonylurea receptors and K(ATP) channels. Curr Pharm Des 11:2699–2716PubMedCrossRefGoogle Scholar
  17. 17.
    Cartier EA, Conti LR, Vandenberg CA, Shyng SL (2001) Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci U S A 98:2882–2887PubMedCrossRefGoogle Scholar
  18. 18.
    Chan KW, Zhang H, Logothetis DE (2003) N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J 22:3833–3843PubMedCrossRefGoogle Scholar
  19. 19.
    Chistiakov DA, Potapov VA, Khodirev DC, Shamkhalova MS, Shestakova MV, Nosikov VV (2009) Genetic variations in the pancreatic ATP-sensitive potassium channel, beta-cell dysfunction, and susceptibility to type 2 diabetes. Acta Diabetol 46:43–49PubMedCrossRefGoogle Scholar
  20. 20.
    Clement JP IV, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J (1997) Association and stoichiometry of K(ATP) channel subunits. Neuron 18:827–838PubMedCrossRefGoogle Scholar
  21. 21.
    Cook DL, Hales CN (1984) Intracellular ATP directly blocks K + channels in pancreatic B-cells. Nature 311:271–273PubMedCrossRefGoogle Scholar
  22. 22.
    Cook DL, Satin LS, Ashford ML, Hales CN (1988) ATP-sensitive K + channels in pancreatic beta-cells. Spare-channel hypothesis. Diabetes 37:495–498PubMedCrossRefGoogle Scholar
  23. 23.
    Cosgrove KE, Shepherd RM, Fernandez EM, Natarajan A, Lindley KJ, Aynsley-Green A, Dunne MJ (2004) Genetics and pathophysiology of hyperinsulinism in infancy. Horm Res 61:270–288PubMedCrossRefGoogle Scholar
  24. 24.
    De Leon DD, Stanley CA (2007) Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab 3:57–68PubMedCrossRefGoogle Scholar
  25. 25.
    de Wet H, Rees MG, Shimomura K, Aittoniemi J, Patch AM, Flanagan SE, Ellard S, Hattersley AT, Sansom MS, Ashcroft FM (2007) Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes. Proc Natl Acad Sci U S A 104:18988–18992PubMedCrossRefGoogle Scholar
  26. 26.
    de Wet H, Proks P, Lafond M, Aittoniemi J, Sansom MS, Flanagan SE, Pearson ER, Hattersley AT, Ashcroft FM (2008) A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes. EMBO Rep 9:648–654PubMedCrossRefGoogle Scholar
  27. 27.
    Della Manna T, Battistim C, Radonsky V, Savoldelli RD, Damiani D, Kok F, Pearson ER, Ellard S, Hattersley AT, Reis AF (2008) Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene. Arq Bras Endocrinol Metabol 52:1350–1355PubMedGoogle Scholar
  28. 28.
    Detimary P, Van den Berghe G, Henquin JC (1996) Concentration dependence and time course of the effects of glucose on adenine and guanine nucleotides in mouse pancreatic islets. J Biol Chem 271:20559–20565PubMedCrossRefGoogle Scholar
  29. 29.
    Drain P, Li L, Wang J (1998) KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci U S A 95:13953–13958PubMedCrossRefGoogle Scholar
  30. 30.
    Dufer M, Haspel D, Krippeit-Drews P, Aguilar-Bryan L, Bryan J, Drews G (2004) Oscillations of membrane potential and cytosolic Ca(2+) concentration in SUR1(−/−) beta cells. Diabetologia 47:488–498PubMedCrossRefGoogle Scholar
  31. 31.
    Dunne MJ, West-Jordan JA, Abraham RJ, Edwards RH, Petersen OH (1988) The gating of nucleotide-sensitive K + channels in insulin-secreting cells can be modulated by changes in the ratio ATP4-/ADP3- and by nonhydrolyzable derivatives of both ATP and ADP. J Membr Biol 104:165–177PubMedCrossRefGoogle Scholar
  32. 32.
    Dunne MJ, Cosgrove KE, Shepherd RM, Aynsley-Green A, Lindley KJ (2004) Hyperinsulinism in infancy: from basic science to clinical disease. Physiol Rev 84:239–275PubMedCrossRefGoogle Scholar
  33. 33.
    Enkvetchakul D, Loussouarn G, Makhina E, Shyng SL, Nichols CG (2000) The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding. Biophys J 78:2334–2348PubMedCrossRefGoogle Scholar
  34. 34.
    Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT (2007) Mutations in ATP-sensitive K + channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 56:1930–1937PubMedCrossRefGoogle Scholar
  35. 35.
    Flanagan SE, Clauin S, Bellanne-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S (2009) Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 30:170–180PubMedCrossRefGoogle Scholar
  36. 36.
    Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D (2004) Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53:1360–1368PubMedCrossRefGoogle Scholar
  37. 37.
    Fournet JC, Junien C (2004) Genetics of congenital hyperinsulinism. Endocr Pathol 15:233–240PubMedCrossRefGoogle Scholar
  38. 38.
    Gembal M, Detimary P, Gilon P, Gao ZY, Henquin JC (1993) Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K + channels in mouse B cells. J Clin Invest 91:871–880PubMedCrossRefGoogle Scholar
  39. 39.
    Gier B, Krippeit-Drews P, Sheiko T, Aguilar-Bryan L, Bryan J, Dufer M, Drews G (2009) Suppression of KATP channel activity protects murine pancreatic beta cells against oxidative stress. J Clin Invest (in press)Google Scholar
  40. 40.
    Gilon P, Shepherd RM, Henquin JC (1993) Oscillations of secretion driven by oscillations of cytoplasmic Ca2+ as evidences in single pancreatic islets. J Biol Chem 268:22265–22268PubMedGoogle Scholar
  41. 41.
    Girard CA, Shimomura K, Proks P, Absalom N, Castano L, Perez de Nanclares G, Ashcroft FM (2006) Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch 453:323–332PubMedCrossRefGoogle Scholar
  42. 42.
    Girard CA, Wunderlich FT, Shimomura K, Collins S, Kaizik S, Proks P, Abdulkader F, Clark A, Ball V, Zubcevic L, Bentley L, Clark R, Church C, Hugill A, Galvanovskis J, Cox R, Rorsman P, Bruning JC, Ashcroft FM (2009) Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes. J Clin Invest 119:80–90PubMedGoogle Scholar
  43. 43.
    Giurgea I, Bellanne-Chantelot C, Ribeiro M, Hubert L, Sempoux C, Robert JJ, Blankenstein O, Hussain K, Brunelle F, Nihoul-Fekete C, Rahier J, Jaubert F, de Lonlay P (2006) Molecular mechanisms of neonatal hyperinsulinism. Horm Res 66:289–296PubMedCrossRefGoogle Scholar
  44. 44.
    Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572PubMedCrossRefGoogle Scholar
  45. 45.
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849PubMedCrossRefGoogle Scholar
  46. 46.
    Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT (2005) Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 14:925–934PubMedCrossRefGoogle Scholar
  47. 47.
    Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ (2006) KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet 14:824–830PubMedCrossRefGoogle Scholar
  48. 48.
    Gribble FM, Tucker SJ, Ashcroft FM (1997) The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J 16:1145–1152PubMedCrossRefGoogle Scholar
  49. 49.
    Gribble FM, Proks P, Corkey BE, Ashcroft FM (1998) Mechanism of cloned ATP-sensitive potassium channel activation by oleoyl-CoA. J Biol Chem 273:26383–26387PubMedCrossRefGoogle Scholar
  50. 50.
    Gribble FM, Tucker SJ, Haug T, Ashcroft FM (1998) MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit. Proc Natl Acad Sci U S A 95:7185–7190PubMedCrossRefGoogle Scholar
  51. 51.
    Gribble FM, Loussouarn G, Tucker SJ, Zhao C, Nichols CG, Ashcroft FM (2000) A novel method for measurement of submembrane ATP concentration. J Biol Chem 275:30046–30049PubMedCrossRefGoogle Scholar
  52. 52.
    Griesemer D, Zawar C, Neumcke B (2002) Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP-sensitive potassium channels. Eur Biophys J 31:467–477PubMedCrossRefGoogle Scholar
  53. 53.
    Grimberg A, Ferry RJ Jr, Kelly A, Koo-McCoy S, Polonsky K, Glaser B, Permutt MA, Aguilar-Bryan L, Stafford D, Thornton PS, Baker L, Stanley CA (2001) Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 50:322–328PubMedCrossRefGoogle Scholar
  54. 54.
    Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rorsman P (1998) Glucagon-like peptide 1 (7–36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 47:57–65PubMedCrossRefGoogle Scholar
  55. 55.
    Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE (2009) Co-expression of the Type 2 Diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the adenosine-5′-triphosphate and sulfonylurea sensitivities of the ATP-sensitive potassium channel. Diabetes (in press)Google Scholar
  56. 56.
    Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P (1998) Missense mutations in the pancreatic islet beta cell inwardly rectifying K + hannel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 41:1511–1515PubMedCrossRefGoogle Scholar
  57. 57.
    Hardy OT, Hernandez-Pampaloni M, Saffer JR, Scheuermann JS, Ernst LM, Freifelder R, Zhuang H, MacMullen C, Becker S, Adzick NS, Divgi C, Alavi A, Stanley CA (2007) Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab 92:4706–4711PubMedCrossRefGoogle Scholar
  58. 58.
    Henquin JC (1998) A minimum of fuel is necessary for tolbutamide to mimic the effects of glucose on electrical activity in pancreatic beta-cells. Endocrinology 139:993–998PubMedCrossRefGoogle Scholar
  59. 59.
    Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760PubMedCrossRefGoogle Scholar
  60. 60.
    Huopio H, Reimann F, Ashfield R, Komulainen J, Lenko HL, Rahier J, Vauhkonen I, Kere J, Laakso M, Ashcroft F, Otonkoski T (2000) Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 106:897–906PubMedCrossRefGoogle Scholar
  61. 61.
    Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M (2003) A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 361:301–307PubMedCrossRefGoogle Scholar
  62. 62.
    Inagaki N, Gonoi T, JPt C, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–1170PubMedCrossRefGoogle Scholar
  63. 63.
    John SA, Weiss JN, Xie LH, Ribalet B (2003) Molecular mechanism for ATP-dependent closure of the K + channel Kir6.2. J Physiol 552:23–34PubMedCrossRefGoogle Scholar
  64. 64.
    Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B (2000) Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49:1325–1333PubMedCrossRefGoogle Scholar
  65. 65.
    Kennedy HJ, Pouli AE, Ainscow EK, Jouaville LS, Rizzuto R, Rutter GA (1999) Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem 274:13281–13291PubMedCrossRefGoogle Scholar
  66. 66.
    Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG (2000) Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 100:645–654PubMedCrossRefGoogle Scholar
  67. 67.
    Koster JC, Knopp A, Flagg TP, Markova KP, Sha Q, Enkvetchakul D, Betsuyaku T, Yamada KA, Nichols CG (2001) Tolerance for ATP-insensitive K(ATP) channels in transgenic mice. Circ Res 89:1022–1029PubMedCrossRefGoogle Scholar
  68. 68.
    Koster JC, Remedi MS, Flagg TP, Johnson JD, Markova KP, Marshall BA, Nichols CG (2002) Hyperinsulinism induced by targeted suppression of beta cell KATP channels. Proc Natl Acad Sci U S A 99:16992–16997PubMedCrossRefGoogle Scholar
  69. 69.
    Koster JC, Permutt MA, Nichols CG (2005) Diabetes and insulin secretion: the ATP-sensitive K + channel (K ATP) connection. Diabetes 54:3065–3072PubMedCrossRefGoogle Scholar
  70. 70.
    Koster JC, Remedi MS, Dao C, Nichols CG (2005) ATP and sulfonylurea sensitivity of mutant ATP-sensitive K + channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes 54:2645–2654PubMedCrossRefGoogle Scholar
  71. 71.
    Koster JC, Remedi MS, Masia R, Patton B, Tong A, Nichols CG (2006) Expression of ATP-insensitive KATP channels in pancreatic beta-cells underlies a spectrum of diabetic phenotypes. Diabetes 55:2957–2964PubMedCrossRefGoogle Scholar
  72. 72.
    Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Barbetti F (2008) 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 93:1054–1061PubMedCrossRefGoogle Scholar
  73. 73.
    Larsson O, Deeney JT, Branstrom R, Berggren PO, Corkey BE (1996) Activation of the ATP-sensitive K + channel by long chain acyl-CoA. A role in modulation of pancreatic beta-cell glucose sensitivity. J Biol Chem 271:10623–10626PubMedCrossRefGoogle Scholar
  74. 74.
    Markworth E, Schwanstecher C, Schwanstecher M (2000) ATP4- mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites. Diabetes 49:1413–1418PubMedCrossRefGoogle Scholar
  75. 75.
    Masia R, Enkvetchakul D, Nichols CG (2005) Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. J Mol Cell Cardiol 39:491–501PubMedCrossRefGoogle Scholar
  76. 76.
    Masia R, De Leon DD, MacMullen C, McKnight H, Stanley CA, Nichols CG (2007) A mutation in the TMD0–L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes 56:1357–1362PubMedCrossRefGoogle Scholar
  77. 77.
    Masia R, Koster JC, Tumini S, Chiarelli F, Colombo C, Nichols CG, Barbetti F (2007) An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Diabetes 56:328–336PubMedCrossRefGoogle Scholar
  78. 78.
    Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC (1998) UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med 15:297–303PubMedCrossRefGoogle Scholar
  79. 79.
    Mikhailov MV, Campbell JD, de Wet H, Shimomura K, Zadek B, Collins RF, Sansom MS, Ford RC, Ashcroft FM (2005) 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. EMBO J 24:4166–4175PubMedCrossRefGoogle Scholar
  80. 80.
    Miki T, Tashiro F, Iwanaga T, Nagashima K, Yoshitomi H, Aihara H, Nitta Y, Gonoi T, Inagaki N, Miyazaki J, Seino S (1997) Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel. Proc Natl Acad Sci U S A 94:11969–11973PubMedCrossRefGoogle Scholar
  81. 81.
    Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S (1998) Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci U S A 95:10402–10406PubMedCrossRefGoogle Scholar
  82. 82.
    Mlynarski W, Tarasov AI, Gach A, Girard CA, Pietrzak I, Zubcevic L, Kusmierek J, Klupa T, Malecki MT, Ashcroft FM (2007) Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. Nat Clin Pract Neurol 3:640–645PubMedCrossRefGoogle Scholar
  83. 83.
    Moreau C, Jacquet H, Prost AL, D’Hahan N, Vivaudou M (2000) The molecular basis of the specificity of action of K(ATP) channel openers. EMBO J 19:6644–6651PubMedCrossRefGoogle Scholar
  84. 84.
    Moreau C, Prost AL, Derand R, Vivaudou M (2005) SUR, ABC proteins targeted by KATP channel openers. J Mol Cell Cardiol 38:951–963PubMedCrossRefGoogle Scholar
  85. 85.
    Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, Stanley CA, Thornton PS, JPt C, Bryan J, Aguilar-Bryan L, Permutt MA (1996) Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5:1813–1822PubMedCrossRefGoogle Scholar
  86. 86.
    Nichols CG, Shyng SL, Nestorowicz A, Glaser B, JPt C, Gonzalez G, Aguilar-Bryan L, Permutt MA, Bryan J (1996) Adenosine diphosphate as an intracellular regulator of insulin secretion. Science 272:1785–1787PubMedCrossRefGoogle Scholar
  87. 87.
    Nichols CG (2006) KATP channels as molecular sensors of cellular metabolism. Nature 440:470–476PubMedCrossRefGoogle Scholar
  88. 88.
    Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O (2003) The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 52:573–577PubMedCrossRefGoogle Scholar
  89. 89.
    Nugent DA, Smith DM, Jones HB (2008) A review of islet of Langerhans degeneration in rodent models of type 2 diabetes. Toxicol Pathol 36:529–551PubMedCrossRefGoogle Scholar
  90. 90.
    Oyama K, Minami K, Ishizaki K, Fuse M, Miki T, Seino S (2006) Spontaneous recovery from hyperglycemia by regeneration of pancreatic beta-cells in Kir6.2G132S transgenic mice. Diabetes 55:1930–1938PubMedCrossRefGoogle Scholar
  91. 91.
    Partridge CJ, Beech DJ, Sivaprasadarao A (2001) Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J Biol Chem 276:35947–35952PubMedCrossRefGoogle Scholar
  92. 92.
    Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S (2007) Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab 9(Suppl 2):28–39PubMedCrossRefGoogle Scholar
  93. 93.
    Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355:467–477PubMedCrossRefGoogle Scholar
  94. 94.
    Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT (2007) Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4:e118PubMedCrossRefGoogle Scholar
  95. 95.
    Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C, Thornton P, Ganguly A, Shyng SL, Stanley CA (2008) Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 118:2877–2886PubMedCrossRefGoogle Scholar
  96. 96.
    Polak M, Cave H (2007) Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis 2:12PubMedCrossRefGoogle Scholar
  97. 97.
    Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM (2004) Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A 101:17539–17544PubMedCrossRefGoogle Scholar
  98. 98.
    Proks P, Girard C, Ashcroft FM (2005) Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP. Hum Mol Genet 14:2717–2726PubMedCrossRefGoogle Scholar
  99. 99.
    Proks P, Shimomura K, Craig TJ, Girard CA, Ashcroft FM (2007) Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Hum Mol Genet 16:2011–2019PubMedCrossRefGoogle Scholar
  100. 100.
    Remedi MS, Nichols CG (2008) Chronic antidiabetic sulfonylureas in vivo: reversible effects on mouse pancreatic beta-cells. PLoS Med 5:e206PubMedCrossRefGoogle Scholar
  101. 101.
    Remedi MS, Kurata HT, Scott A, Wunderlich FT, Rother E, Kleinridders A, Tong A, Bruning JC, Koster JC, Nichols CG (2009) Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus. Cell Metab 9:140–151PubMedCrossRefGoogle Scholar
  102. 102.
    Riedel MJ, Boora P, Steckley D, de Vries G, Light PE (2003) Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes? Diabetes 52:2630–2635PubMedCrossRefGoogle Scholar
  103. 103.
    Riedel MJ, Steckley DC, Light PE (2005) Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. Hum Genet 116:133–145PubMedCrossRefGoogle Scholar
  104. 104.
    Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR (2004) Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718PubMedCrossRefGoogle Scholar
  105. 105.
    Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM (1996) Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia 39:1233–1236PubMedCrossRefGoogle Scholar
  106. 106.
    Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336PubMedCrossRefGoogle Scholar
  107. 107.
    Schulze DU, Dufer M, Wieringa B, Krippeit-Drews P, Drews G (2007) An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells. Diabetologia 50:2126–2134PubMedCrossRefGoogle Scholar
  108. 108.
    Schwanstecher C, Meyer U, Schwanstecher M (2002) K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels. Diabetes 51:875–879PubMedCrossRefGoogle Scholar
  109. 109.
    Schwanstecher C, Schwanstecher M (2002) Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51(Suppl 3):S358–S362PubMedCrossRefGoogle Scholar
  110. 110.
    Seghers V, Nakazaki M, DeMayo F, Aguilar-Bryan L, Bryan J (2000) Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem 275:9270–9277PubMedCrossRefGoogle Scholar
  111. 111.
    Shimomura K, Girard CA, Proks P, Nazim J, Lippiat JD, Cerutti F, Lorini R, Ellard S, Hattersley AT, Barbetti F, Ashcroft FM (2006) Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects. Diabetes 55:1705–1712PubMedCrossRefGoogle Scholar
  112. 112.
    Shimomura K, Horster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft F, Ebinger F (2007) A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 69:1342–1349PubMedCrossRefGoogle Scholar
  113. 113.
    Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren PO, Magnuson MA (2002) Sulfonylurea receptor type 1 knockout mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem 277:37176–37183PubMedCrossRefGoogle Scholar
  114. 114.
    Shyng S, Nichols CG (1997) Octameric stoichiometry of the KATP channel complex. J Gen Physiol 110:655–664PubMedCrossRefGoogle Scholar
  115. 115.
    Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG (1998) Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 47:1145–1151PubMedCrossRefGoogle Scholar
  116. 116.
    Shyng SL, Cukras CA, Harwood J, Nichols CG (2000) Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels. J Gen Physiol 116:599–608PubMedCrossRefGoogle Scholar
  117. 117.
    Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, DeFronzo RA (1984) Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33:838–845PubMedCrossRefGoogle Scholar
  118. 118.
    Slingerland AS (2006) Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient. Rev Endocr Metab Disord 7:171–185PubMedCrossRefGoogle Scholar
  119. 119.
    Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ (2006) 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 49:2559–2563PubMedCrossRefGoogle Scholar
  120. 120.
    Stanojevic V, Habener JF, Holz GG, Leech CA (2008) Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells. Biochem Biophys Res Commun 368:614–619PubMedCrossRefGoogle Scholar
  121. 121.
    Sumnik Z, Kolouskova S, Wales JK, Komarek V, Cinek O (2007) 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 24:1176–1178PubMedCrossRefGoogle Scholar
  122. 122.
    Tammaro P, Girard C, Molnes J, Njolstad PR, Ashcroft FM (2005) Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions. EMBO J 24:2318–2330PubMedCrossRefGoogle Scholar
  123. 123.
    Tammaro P, Proks P, Ashcroft FM (2006) Functional effects of naturally occurring KCNJ11 mutations causing neonatal diabetes on cloned cardiac KATP channels. J Physiol 571:3–14PubMedCrossRefGoogle Scholar
  124. 124.
    Tammaro P, Flanagan SE, Zadek B, Srinivasan S, Woodhead H, Hameed S, Klimes I, Hattersley AT, Ellard S, Ashcroft FM (2008) A Kir6.2 mutation causing severe functional effects in vitro produces neonatal diabetes without the expected neurological complications. Diabetologia 51:802–810PubMedCrossRefGoogle Scholar
  125. 125.
    Tanabe K, Tucker SJ, Matsuo M, Proks P, Ashcroft FM, Seino S, Amachi T, Ueda K (1999) Direct photoaffinity labeling of the Kir6.2 subunit of the ATP-sensitive K + channel by 8-azido-ATP. J Biol Chem 274:3931–3933PubMedCrossRefGoogle Scholar
  126. 126.
    Tarasov AI, Nicolson TJ, Riveline JP, Taneja TK, Baldwin SA, Baldwin JM, Charpentier G, Gautier JF, Froguel P, Vaxillaire M, Rutter GA (2008) A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K + channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults. Diabetes 57:1595–1604PubMedCrossRefGoogle Scholar
  127. 127.
    Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J (1995) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268:426–429PubMedCrossRefGoogle Scholar
  128. 128.
    Tonini G, Bizzarri C, Bonfanti R, Vanelli M, Cerutti F, Faleschini E, Meschi F, Prisco F, Ciacco E, Cappa M, Torelli C, Cauvin V, Tumini S, Iafusco D, Barbetti F (2006) 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 49:2210–2213PubMedCrossRefGoogle Scholar
  129. 129.
    Trapp S, Haider S, Jones P, Sansom MS, Ashcroft FM (2003) Identification of residues contributing to the ATP binding site of Kir6.2. EMBO J 22:2903–2912PubMedCrossRefGoogle Scholar
  130. 130.
    Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K + channel in mouse pancreatic beta-cells. Pflugers Arch 407:493–499PubMedCrossRefGoogle Scholar
  131. 131.
    Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft FM (1997) Truncation of Kir6.2 produces ATP-sensitive K + channels in the absence of the sulphonylurea receptor. Nature 387:179–183PubMedCrossRefGoogle Scholar
  132. 132.
    Tucker SJ, Gribble FM, Proks P, Trapp S, Ryder TJ, Haug T, Reimann F, Ashcroft FM (1998) Molecular determinants of KATP channel inhibition by ATP. EMBO J 17:3290–3296PubMedCrossRefGoogle Scholar
  133. 133.
    Villareal DT, Koster JC, Robertson H, Akrouh A, Miyake K, Bell GI, Patterson BW, Nichols CG, Polonsky KS (2009) 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 58:1869–1878PubMedCrossRefGoogle Scholar
  134. 134.
    Wambach JA, Marshall BA, Koster JC, White NH, Nichols CG (2009) Successful sulfonylurea treatment of an insulin-naive neonate with diabetes mellitus due to a KCNJ11 mutation. Pediatr Diabetes (in press)Google Scholar
  135. 135.
    Yan FF, Casey J, Shyng SL (2006) Sulfonylureas correct trafficking defects of disease-causing ATP-sensitive potassium channels by binding to the channel complex. J Biol Chem 281:33403–33413PubMedCrossRefGoogle Scholar
  136. 136.
    Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y, Hosokawa M, Yamada Y, Inagaki N, Nakahata T (2005) The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab 90:3174–3178PubMedCrossRefGoogle Scholar
  137. 137.
    Zawar C, Plant TD, Schirra C, Konnerth A, Neumcke B (1999) Cell-type specific expression of ATP-sensitive potassium channels in the rat hippocampus. J Physiol 514(Pt 2):327–341PubMedGoogle Scholar
  138. 138.
    Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, McCarthy MI, Hattersley AT (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341PubMedCrossRefGoogle Scholar
  139. 139.
    Zingman LV, Alekseev AE, Bienengraeber M, Hodgson D, Karger AB, Dzeja PP, Terzic A (2001) Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K + conductance. Neuron 31:233–245PubMedCrossRefGoogle Scholar
  140. 140.
    Zingman LV, Hodgson DM, Bienengraeber M, Karger AB, Kathmann EC, Alekseev AE, Terzic A (2002) Tandem function of nucleotide binding domains confers competence to sulfonylurea receptor in gating ATP-sensitive K + channels. J Biol Chem 277:14206–14210PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Cell Biology and PhysiologyWashington University School of MedicineSt. LouisUSA

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