Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2005 Mar 16;42(12):893–902. doi: 10.1136/jmg.2005.030791

Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and ß cell failure

J Porter 1, T Barrett 1
PMCID: PMC1735963  PMID: 15772126

Abstract

Type 2 diabetes mellitus is caused by a combination of insulin resistance and ß cell failure. The polygenic nature of type 2 diabetes has made it difficult to study. Although many candidate genes for this condition have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have now been studied extensively, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations and explain some of the linkage seen in genome-wide scans. Monogenic disorders are also helpful in understanding both normal and disordered glucose and insulin metabolism. Three main areas of defect contribute to diabetes: defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased ß cell mass. These three pathological pathways are reviewed, focusing on rare genetic syndromes which have diabetes as a prominent feature. Apoptosis seems to be a final common pathway in both type 1 and type 2 diabetes. Study of rare forms of diabetes may help ion determining new therapeutic targets to preserve or increase ß cell mass and function.

Full Text

The Full Text of this article is available as a PDF (136.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agarwal A. K., Barnes R. I., Garg A. Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord. 2004 Feb;28(2):336–339. doi: 10.1038/sj.ijo.0802487. [DOI] [PubMed] [Google Scholar]
  2. Agarwal Anil K., Arioglu Elif, De Almeida Salome, Akkoc Nurullah, Taylor Simeon I., Bowcock Anne M., Barnes Robert I., Garg Abhimanyu. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet. 2002 Apr 22;31(1):21–23. doi: 10.1038/ng880. [DOI] [PubMed] [Google Scholar]
  3. Agarwal Anil K., Simha Vinaya, Oral Elif Arioglu, Moran Stephanie A., Gorden Phillip, O'Rahilly Stephen, Zaidi Zohra, Gurakan Figen, Arslanian Silva A., Klar Aharon. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003 Oct;88(10):4840–4847. doi: 10.1210/jc.2003-030855. [DOI] [PubMed] [Google Scholar]
  4. Aguilar-Bryan L., Clement J. P., 4th, Gonzalez G., Kunjilwar K., Babenko A., Bryan J. Toward understanding the assembly and structure of KATP channels. Physiol Rev. 1998 Jan;78(1):227–245. doi: 10.1152/physrev.1998.78.1.227. [DOI] [PubMed] [Google Scholar]
  5. Akazawa S., Sun F., Ito M., Kawasaki E., Eguchi K. Efficacy of troglitazone on body fat distribution in type 2 diabetes. Diabetes Care. 2000 Aug;23(8):1067–1071. doi: 10.2337/diacare.23.8.1067. [DOI] [PubMed] [Google Scholar]
  6. Altshuler D., Hirschhorn J. N., Klannemark M., Lindgren C. M., Vohl M. C., Nemesh J., Lane C. R., Schaffner S. F., Bolk S., Brewer C. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000 Sep;26(1):76–80. doi: 10.1038/79216. [DOI] [PubMed] [Google Scholar]
  7. Atkinson M. A., Eisenbarth G. S. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001 Jul 21;358(9277):221–229. doi: 10.1016/S0140-6736(01)05415-0. [DOI] [PubMed] [Google Scholar]
  8. Barak Y., Nelson M. C., Ong E. S., Jones Y. Z., Ruiz-Lozano P., Chien K. R., Koder A., Evans R. M. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 1999 Oct;4(4):585–595. doi: 10.1016/s1097-2765(00)80209-9. [DOI] [PubMed] [Google Scholar]
  9. Baron Dana, Assaraf Yehuda G., Cohen Nadine, Aronheim Ami. Lack of plasma membrane targeting of a G172D mutant thiamine transporter derived from Rogers syndrome family. Mol Med. 2002 Aug;8(8):462–474. [PMC free article] [PubMed] [Google Scholar]
  10. Barrett T. G., Bundey S. E., Macleod A. F. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995 Dec 2;346(8988):1458–1463. doi: 10.1016/s0140-6736(95)92473-6. [DOI] [PubMed] [Google Scholar]
  11. Barrett T. G. Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract Res Clin Endocrinol Metab. 2001 Sep;15(3):325–343. doi: 10.1053/beem.2001.0149. [DOI] [PubMed] [Google Scholar]
  12. Barroso I., Gurnell M., Crowley V. E., Agostini M., Schwabe J. W., Soos M. A., Maslen G. L., Williams T. D., Lewis H., Schafer A. J. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999 Dec 23;402(6764):880–883. doi: 10.1038/47254. [DOI] [PubMed] [Google Scholar]
  13. Bernard-Kargar C., Ktorza A. Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes. 2001 Feb;50 (Suppl 1):S30–S35. doi: 10.2337/diabetes.50.2007.s30. [DOI] [PubMed] [Google Scholar]
  14. Biason-Lauber Anna, Lang-Muritano Mariarosaria, Vaccaro Tindara, Schoenle Eugen J. Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes. 2002 Jul;51(7):2301–2305. doi: 10.2337/diabetes.51.7.2301. [DOI] [PubMed] [Google Scholar]
  15. Bin-Abbas Bassam, Al-Mulhim Abdulmohsen, Al-Ashwal Abdullah. Wolcott-Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet. 2002 Aug 1;111(2):187–190. doi: 10.1002/ajmg.10495. [DOI] [PubMed] [Google Scholar]
  16. Boros László G., Steinkamp Mara P., Fleming Judith C., Lee Wai-Nang Paul, Cascante Marta, Neufeld Ellis J. Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA). Blood. 2003 Jul 31;102(10):3556–3561. doi: 10.1182/blood-2003-05-1537. [DOI] [PubMed] [Google Scholar]
  17. Brickwood S., Bonthron D. T., Al-Gazali L. I., Piper K., Hearn T., Wilson D. I., Hanley N. A. Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet. 2003 Sep;40(9):685–689. doi: 10.1136/jmg.40.9.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Brosh R. M., Jr, Karmakar P., Sommers J. A., Yang Q., Wang X. W., Spillare E. A., Harris C. C., Bohr V. A. p53 Modulates the exonuclease activity of Werner syndrome protein. J Biol Chem. 2001 Jun 26;276(37):35093–35102. doi: 10.1074/jbc.M103332200. [DOI] [PubMed] [Google Scholar]
  19. Butler Alexandra E., Janson Juliette, Bonner-Weir Susan, Ritzel Robert, Rizza Robert A., Butler Peter C. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003 Jan;52(1):102–110. doi: 10.2337/diabetes.52.1.102. [DOI] [PubMed] [Google Scholar]
  20. Campuzano V., Montermini L., Lutz Y., Cova L., Hindelang C., Jiralerspong S., Trottier Y., Kish S. J., Faucheux B., Trouillas P. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997 Oct;6(11):1771–1780. doi: 10.1093/hmg/6.11.1771. [DOI] [PubMed] [Google Scholar]
  21. Campuzano V., Montermini L., Moltò M. D., Pianese L., Cossée M., Cavalcanti F., Monros E., Rodius F., Duclos F., Monticelli A. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996 Mar 8;271(5254):1423–1427. doi: 10.1126/science.271.5254.1423. [DOI] [PubMed] [Google Scholar]
  22. Chen Lishan, Oshima Junko. Werner Syndrome. J Biomed Biotechnol. 2002;2(2):46–54. doi: 10.1155/S1110724302201011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Cock Terrie-Anne, Houten Sander M., Auwerx Johan. Peroxisome proliferator-activated receptor-gamma: too much of a good thing causes harm. EMBO Rep. 2004 Feb;5(2):142–147. doi: 10.1038/sj.embor.7400082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Cuesta-Muñoz Antonio L., Huopio Hanna, Otonkoski Timo, Gomez-Zumaquero Juan M., Näntö-Salonen Kirsti, Rahier Jacques, López-Enriquez Soledad, García-Gimeno Maria A., Sanz Pascual, Soriguer Federico C. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes. 2004 Aug;53(8):2164–2168. doi: 10.2337/diabetes.53.8.2164. [DOI] [PubMed] [Google Scholar]
  25. Deeb S. S., Fajas L., Nemoto M., Pihlajamäki J., Mykkänen L., Kuusisto J., Laakso M., Fujimoto W., Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998 Nov;20(3):284–287. doi: 10.1038/3099. [DOI] [PubMed] [Google Scholar]
  26. Delépine M., Nicolino M., Barrett T., Golamaully M., Lathrop G. M., Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000 Aug;25(4):406–409. doi: 10.1038/78085. [DOI] [PubMed] [Google Scholar]
  27. Diaz G. A., Banikazemi M., Oishi K., Desnick R. J., Gelb B. D. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet. 1999 Jul;22(3):309–312. doi: 10.1038/10385. [DOI] [PubMed] [Google Scholar]
  28. Dor Yuval, Brown Juliana, Martinez Olga I., Melton Douglas A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 2004 May 6;429(6987):41–46. doi: 10.1038/nature02520. [DOI] [PubMed] [Google Scholar]
  29. Dupont S., Dubois D., Vionnet N., Boitard C., Caillat-Zucman S., Timsit J., Froguel P. No association between the Friedreich's ataxia gene and NIDDM in the French population. Diabetes. 1998 Oct;47(10):1654–1656. doi: 10.2337/diabetes.47.10.1654. [DOI] [PubMed] [Google Scholar]
  30. Dürr A., Cossee M., Agid Y., Campuzano V., Mignard C., Penet C., Mandel J. L., Brice A., Koenig M. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med. 1996 Oct 17;335(16):1169–1175. doi: 10.1056/NEJM199610173351601. [DOI] [PubMed] [Google Scholar]
  31. Fleming J. C., Tartaglini E., Steinkamp M. P., Schorderet D. F., Cohen N., Neufeld E. J. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 1999 Jul;22(3):305–308. doi: 10.1038/10379. [DOI] [PubMed] [Google Scholar]
  32. Frayling T. M., Evans J. C., Bulman M. P., Pearson E., Allen L., Owen K., Bingham C., Hannemann M., Shepherd M., Ellard S. beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes. 2001 Feb;50 (Suppl 1):S94–100. doi: 10.2337/diabetes.50.2007.s94. [DOI] [PubMed] [Google Scholar]
  33. Fu Mao, Kazlauskaite Rasa, Baracho Maria de Fátima Paiva, Santos Maria Goretti Do Nascimento, Brandão-Neto José, Villares Sandra, Celi Francesco S., Wajchenberg Bernardo L., Shuldiner Alan R. Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects. J Clin Endocrinol Metab. 2004 Jun;89(6):2916–2922. doi: 10.1210/jc.2003-030485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Gavrilova Oksana, Haluzik Martin, Matsusue Kimihiko, Cutson Jaime J., Johnson Lisa, Dietz Kelly R., Nicol Christopher J., Vinson Charles, Gonzalez Frank J., Reitman Marc L. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem. 2003 Jun 11;278(36):34268–34276. doi: 10.1074/jbc.M300043200. [DOI] [PubMed] [Google Scholar]
  35. Glaser B., Kesavan P., Heyman M., Davis E., Cuesta A., Buchs A., Stanley C. A., Thornton P. S., Permutt M. A., Matschinsky F. M. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998 Jan 22;338(4):226–230. doi: 10.1056/NEJM199801223380404. [DOI] [PubMed] [Google Scholar]
  36. Gloyn Anna L., Cummings Elizabeth A., Edghill Emma L., Harries Lorna W., Scott Rachel, Costa Teresa, Temple I. Karen, Hattersley Andrew T., Ellard Sian. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab. 2004 Aug;89(8):3932–3935. doi: 10.1210/jc.2004-0568. [DOI] [PubMed] [Google Scholar]
  37. Gloyn Anna L. Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat. 2003 Nov;22(5):353–362. doi: 10.1002/humu.10277. [DOI] [PubMed] [Google Scholar]
  38. Gloyn Anna L., Pearson Ewan R., Antcliff Jennifer F., Proks Peter, Bruining G. Jan, Slingerland Annabelle S., Howard Neville, Srinivasan Shubha, Silva José M. C. L., Molnes Janne. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004 Apr 29;350(18):1838–1849. doi: 10.1056/NEJMoa032922. [DOI] [PubMed] [Google Scholar]
  39. Gloyn Anna L. The search for type 2 diabetes genes. Ageing Res Rev. 2003 Apr;2(2):111–127. doi: 10.1016/s1568-1637(02)00061-2. [DOI] [PubMed] [Google Scholar]
  40. Grandori Carla, Wu Kou-Juey, Fernandez Paula, Ngouenet Celine, Grim Jonathan, Clurman Bruce E., Moser Michael J., Oshima Junko, Russell David W., Swisshelm Karen. Werner syndrome protein limits MYC-induced cellular senescence. Genes Dev. 2003 Jul 1;17(13):1569–1574. doi: 10.1101/gad.1100303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Harding Heather P., Ron David. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002 Dec;51 (Suppl 3):S455–S461. doi: 10.2337/diabetes.51.2007.s455. [DOI] [PubMed] [Google Scholar]
  42. Hattersley A. T., Turner R. C., Permutt M. A., Patel P., Tanizawa Y., Chiu K. C., O'Rahilly S., Watkins P. J., Wainscoat J. S. Linkage of type 2 diabetes to the glucokinase gene. Lancet. 1992 May 30;339(8805):1307–1310. doi: 10.1016/0140-6736(92)91958-b. [DOI] [PubMed] [Google Scholar]
  43. Hebinck J., Hardt C., Schöls L., Vorgerd M., Briedigkeit L., Kahn C. R., Ristow M. Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans. Diabetes. 2000 Sep;49(9):1604–1607. doi: 10.2337/diabetes.49.9.1604. [DOI] [PubMed] [Google Scholar]
  44. Hegele Robert A., Cao Henian, Frankowski Christy, Mathews Suresh T., Leff Todd. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002 Dec;51(12):3586–3590. doi: 10.2337/diabetes.51.12.3586. [DOI] [PubMed] [Google Scholar]
  45. Hevener Andrea L., He Weimin, Barak Yaacov, Le Jamie, Bandyopadhyay Gautam, Olson Peter, Wilkes Jason, Evans Ronald M., Olefsky Jerrold. Muscle-specific Pparg deletion causes insulin resistance. Nat Med. 2003 Nov 16;9(12):1491–1497. doi: 10.1038/nm956. [DOI] [PubMed] [Google Scholar]
  46. Hone J., Accili D., Psiachou H., Alghband-Zadeh J., Mitton S., Wertheimer E., Sinclair L., Taylor S. I. Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism. Hum Mutat. 1995;6(1):17–22. doi: 10.1002/humu.1380060105. [DOI] [PubMed] [Google Scholar]
  47. Inoue H., Tanizawa Y., Wasson J., Behn P., Kalidas K., Bernal-Mizrachi E., Mueckler M., Marshall H., Donis-Keller H., Crock P. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143–148. doi: 10.1038/2441. [DOI] [PubMed] [Google Scholar]
  48. Ishihara Hisamitsu, Takeda Satoshi, Tamura Akira, Takahashi Rui, Yamaguchi Suguru, Takei Daisuke, Yamada Takahiro, Inoue Hiroshi, Soga Hiroyuki, Katagiri Hideki. Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet. 2004 Mar 31;13(11):1159–1170. doi: 10.1093/hmg/ddh125. [DOI] [PubMed] [Google Scholar]
  49. Kamath-Loeb A. S., Johansson E., Burgers P. M., Loeb L. A. Functional interaction between the Werner Syndrome protein and DNA polymerase delta. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4603–4608. doi: 10.1073/pnas.97.9.4603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kamath-Loeb A. S., Loeb L. A., Johansson E., Burgers P. M., Fry M. Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. J Biol Chem. 2001 Feb 8;276(19):16439–16446. doi: 10.1074/jbc.M100253200. [DOI] [PubMed] [Google Scholar]
  51. Kamiya M., Judson H., Okazaki Y., Kusakabe M., Muramatsu M., Takada S., Takagi N., Arima T., Wake N., Kamimura K. The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes. Hum Mol Genet. 2000 Feb 12;9(3):453–460. doi: 10.1093/hmg/9.3.453. [DOI] [PubMed] [Google Scholar]
  52. Kelly I. E., Han T. S., Walsh K., Lean M. E. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care. 1999 Feb;22(2):288–293. doi: 10.2337/diacare.22.2.288. [DOI] [PubMed] [Google Scholar]
  53. Kelly M. A., Mijovic C. H., Barnett A. H. Genetics of type 1 diabetes. Best Pract Res Clin Endocrinol Metab. 2001 Sep;15(3):279–291. doi: 10.1053/beem.2001.0146. [DOI] [PubMed] [Google Scholar]
  54. Khanim F., Kirk J., Latif F., Barrett T. G. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Hum Mutat. 2001 May;17(5):357–367. doi: 10.1002/humu.1110. [DOI] [PubMed] [Google Scholar]
  55. Kharroubi Ilham, Ladrière Laurence, Cardozo Alessandra K., Dogusan Zeynep, Cnop Miriam, Eizirik Décio L. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004 Aug 5;145(11):5087–5096. doi: 10.1210/en.2004-0478. [DOI] [PubMed] [Google Scholar]
  56. Kim H. I., Kim J. W., Kim S. H., Cha J. Y., Kim K. S., Ahn Y. H. Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. Diabetes. 2000 Sep;49(9):1517–1524. doi: 10.2337/diabetes.49.9.1517. [DOI] [PubMed] [Google Scholar]
  57. Kim Ha-Il, Ahn Yong-Ho. Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells. Diabetes. 2004 Feb;53 (Suppl 1):S60–S65. doi: 10.2337/diabetes.53.2007.s60. [DOI] [PubMed] [Google Scholar]
  58. Kim Ha-il, Cha Ji-Young, Kim So-Youn, Kim Jae-woo, Roh Kyung Jin, Seong Je-Kyung, Lee Nam Taek, Choi Kang-Yell, Kim Kyung-Sup, Ahn Yong-ho. Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells. Diabetes. 2002 Mar;51(3):676–685. doi: 10.2337/diabetes.51.3.676. [DOI] [PubMed] [Google Scholar]
  59. Koutnikova Hana, Cock Terrie-Anne, Watanabe Mitsuhiro, Houten Sander M., Champy Marie-France, Dierich Andreé, Auwerx Johan. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. Proc Natl Acad Sci U S A. 2003 Nov 5;100(24):14457–14462. doi: 10.1073/pnas.2336090100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Labay V., Raz T., Baron D., Mandel H., Williams H., Barrett T., Szargel R., McDonald L., Shalata A., Nosaka K. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet. 1999 Jul;22(3):300–304. doi: 10.1038/10372. [DOI] [PubMed] [Google Scholar]
  61. Lebel M., Cardiff R. D., Leder P. Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase. Cancer Res. 2001 Mar 1;61(5):1816–1819. [PubMed] [Google Scholar]
  62. Lodi R., Cooper J. M., Bradley J. L., Manners D., Styles P., Taylor D. J., Schapira A. H. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11492–11495. doi: 10.1073/pnas.96.20.11492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Longo Nicola, Wang Yuhuan, Smith Shelley A., Langley Sharon D., DiMeglio Linda A., Giannella-Neto Daniel. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002 Jun 1;11(12):1465–1475. doi: 10.1093/hmg/11.12.1465. [DOI] [PubMed] [Google Scholar]
  64. Ma Dan, Shield Julian P. H., Dean Wendy, Leclerc Isabelle, Knauf Claude, Burcelin R R. éMy, Rutter Guy A., Kelsey Gavin. Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. J Clin Invest. 2004 Aug;114(3):339–348. doi: 10.1172/JCI19876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Ma Kun, Vattem Krishna M., Wek Ronald C. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J Biol Chem. 2002 Mar 20;277(21):18728–18735. doi: 10.1074/jbc.M200903200. [DOI] [PubMed] [Google Scholar]
  66. Maedler Kathrin, Sergeev Pavel, Ris Frédéric, Oberholzer José, Joller-Jemelka Helen I., Spinas Giatgen A., Kaiser Nurit, Halban Philippe A., Donath Marc Y. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002 Sep;110(6):851–860. doi: 10.1172/JCI15318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Magré J., Delépine M., Khallouf E., Gedde-Dahl T., Jr, Van Maldergem L., Sobel E., Papp J., Meier M., Mégarbané A., Bachy A. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001 Aug;28(4):365–370. doi: 10.1038/ng585. [DOI] [PubMed] [Google Scholar]
  68. Mandrup-Poulsen Thomas. Apoptotic signal transduction pathways in diabetes. Biochem Pharmacol. 2003 Oct 15;66(8):1433–1440. doi: 10.1016/s0006-2952(03)00494-5. [DOI] [PubMed] [Google Scholar]
  69. McCabe D. J., Ryan F., Moore D. P., McQuaid S., King M. D., Kelly A., Daly K., Barton D. E., Murphy R. P. Typical Friedreich's ataxia without GAA expansions and GAA expansion without typical Friedreich's ataxia. J Neurol. 2000 May;247(5):346–355. doi: 10.1007/s004150050601. [DOI] [PubMed] [Google Scholar]
  70. Melis Roberta, Pruett Paul B., Wang Yuhuan, Longo Nicola. Gene expression in human cells with mutant insulin receptors. Biochem Biophys Res Commun. 2003 Aug 8;307(4):1013–1020. doi: 10.1016/s0006-291x(03)01293-2. [DOI] [PubMed] [Google Scholar]
  71. Mercado Maria M., McLenithan John C., Silver Kristi D., Shuldiner Alan R. Genetics of insulin resistance. Curr Diab Rep. 2002 Feb;2(1):83–95. doi: 10.1007/s11892-002-0063-9. [DOI] [PubMed] [Google Scholar]
  72. Miles P. D., Barak Y., He W., Evans R. M., Olefsky J. M. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest. 2000 Feb;105(3):287–292. doi: 10.1172/JCI8538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Minton Jayne A. L., Hattersley Andrew T., Owen Katharine, McCarthy Mark I., Walker Mark, Latif Farida, Barrett Timothy, Frayling Timothy M. Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations. Diabetes. 2002 Apr;51(4):1287–1290. doi: 10.2337/diabetes.51.4.1287. [DOI] [PubMed] [Google Scholar]
  74. Mohamed-Ali V., Pinkney J. H., Coppack S. W. Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord. 1998 Dec;22(12):1145–1158. doi: 10.1038/sj.ijo.0800770. [DOI] [PubMed] [Google Scholar]
  75. Monrós E., Moltó M. D., Martínez F., Cañizares J., Blanca J., Vílchez J. J., Prieto F., de Frutos R., Palau F. Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Am J Hum Genet. 1997 Jul;61(1):101–110. doi: 10.1086/513887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Mori Y., Murakawa Y., Okada K., Horikoshi H., Yokoyama J., Tajima N., Ikeda Y. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care. 1999 Jun;22(6):908–912. doi: 10.2337/diacare.22.6.908. [DOI] [PubMed] [Google Scholar]
  77. Njølstad P. R., Søvik O., Cuesta-Muñoz A., Bjørkhaug L., Massa O., Barbetti F., Undlien D. E., Shiota C., Magnuson M. A., Molven A. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001 May 24;344(21):1588–1592. doi: 10.1056/NEJM200105243442104. [DOI] [PubMed] [Google Scholar]
  78. Njølstad Pål R., Sagen Jørn V., Bjørkhaug Lise, Odili Stella, Shehadeh Naim, Bakry Doua, Sarici S. Umit, Alpay Faruk, Molnes Janne, Molven Anders. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes. 2003 Nov;52(11):2854–2860. doi: 10.2337/diabetes.52.11.2854. [DOI] [PubMed] [Google Scholar]
  79. Norris Andrew W., Chen Lihong, Fisher Simon J., Szanto Ildiko, Ristow Michael, Jozsi Alison C., Hirshman Michael F., Rosen Evan D., Goodyear Laurie J., Gonzalez Frank J. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest. 2003 Aug;112(4):608–618. doi: 10.1172/JCI17305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Opresko Patricia L., Cheng Wen-Hsing, von Kobbe Cayetano, Harrigan Jeanine A., Bohr Vilhelm A. Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process. Carcinogenesis. 2003 May;24(5):791–802. doi: 10.1093/carcin/bgg034. [DOI] [PubMed] [Google Scholar]
  81. Oshima J. The Werner syndrome protein: an update. Bioessays. 2000 Oct;22(10):894–901. doi: 10.1002/1521-1878(200010)22:10<894::AID-BIES4>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  82. Osman Abdullah A., Saito Mitsuyoshi, Makepeace Carol, Permutt M. Alan, Schlesinger Paul, Mueckler Mike. Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem. 2003 Oct 3;278(52):52755–52762. doi: 10.1074/jbc.M310331200. [DOI] [PubMed] [Google Scholar]
  83. Owen K., Hattersley A. T. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Pract Res Clin Endocrinol Metab. 2001 Sep;15(3):309–323. doi: 10.1053/beem.2001.0148. [DOI] [PubMed] [Google Scholar]
  84. Owen Katharine R., Stride Amanda, Ellard Sian, Hattersley Andrew T. Etiological investigation of diabetes in young adults presenting with apparent type 2 diabetes. Diabetes Care. 2003 Jul;26(7):2088–2093. doi: 10.2337/diacare.26.7.2088. [DOI] [PubMed] [Google Scholar]
  85. Ozdemir Mehmet Akif, Akcakus Mustafa, Kurtoglu Selim, Gunes Tamer, Torun Yasemin Altuner. TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature. Pediatr Diabetes. 2002 Dec;3(4):205–209. doi: 10.1034/j.1399-5448.2002.30407.x. [DOI] [PubMed] [Google Scholar]
  86. Pearson Ewan R., Starkey Bryan J., Powell Roy J., Gribble Fiona M., Clark Penny M., Hattersley Andrew T. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet. 2003 Oct 18;362(9392):1275–1281. doi: 10.1016/S0140-6736(03)14571-0. [DOI] [PubMed] [Google Scholar]
  87. Porter F. S., Rogers L. E., Sidbury J. B., Jr Thiamine-responsive megaloblastic anemia. J Pediatr. 1969 Apr;74(4):494–504. doi: 10.1016/s0022-3476(69)80031-4. [DOI] [PubMed] [Google Scholar]
  88. Reginato M. J., Bailey S. T., Krakow S. L., Minami C., Ishii S., Tanaka H., Lazar M. A. A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor gamma-activating properties. J Biol Chem. 1998 Dec 4;273(49):32679–32684. doi: 10.1074/jbc.273.49.32679. [DOI] [PubMed] [Google Scholar]
  89. Ristow M., Giannakidou E., Hebinck J., Busch K., Vorgerd M., Kotzka J., Knebel B., Mueller-Berghaus J., Epplen C., Pfeiffer A. An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene. Diabetes. 1998 May;47(5):851–854. doi: 10.2337/diabetes.47.5.851. [DOI] [PubMed] [Google Scholar]
  90. Ristow M., Müller-Wieland D., Pfeiffer A., Krone W., Kahn C. R. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998 Oct 1;339(14):953–959. doi: 10.1056/NEJM199810013391403. [DOI] [PubMed] [Google Scholar]
  91. Ristow Michael, Mulder Hindrik, Pomplun Doreen, Schulz Tim J., Müller-Schmehl Katrin, Krause Anja, Fex Malin, Puccio Helene, Müller Jörg, Isken Frank. Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J Clin Invest. 2003 Aug;112(4):527–534. doi: 10.1172/JCI18107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Rocchi S., Picard F., Vamecq J., Gelman L., Potier N., Zeyer D., Dubuquoy L., Bac P., Champy M. F., Plunket K. D. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol Cell. 2001 Oct;8(4):737–747. doi: 10.1016/s1097-2765(01)00353-7. [DOI] [PubMed] [Google Scholar]
  93. Rosen E. D., Sarraf P., Troy A. E., Bradwin G., Moore K., Milstone D. S., Spiegelman B. M., Mortensen R. M. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999 Oct;4(4):611–617. doi: 10.1016/s1097-2765(00)80211-7. [DOI] [PubMed] [Google Scholar]
  94. Rosen Evan D., Kulkarni Rohit N., Sarraf Pasha, Ozcan Umut, Okada Terumasa, Hsu Chung-Hsin, Eisenman Daniel, Magnuson Mark A., Gonzalez Frank J., Kahn C. Ronald. Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. Mol Cell Biol. 2003 Oct;23(20):7222–7229. doi: 10.1128/MCB.23.20.7222-7229.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Sagen Jørn V., Raeder Helge, Hathout Eba, Shehadeh Naim, Gudmundsson Kolbeinn, Baevre Halvor, Abuelo Dianne, Phornphutkul Chanika, Molnes Janne, Bell Graeme I. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004 Oct;53(10):2713–2718. doi: 10.2337/diabetes.53.10.2713. [DOI] [PubMed] [Google Scholar]
  96. Sakamoto N., Ohshima K., Montermini L., Pandolfo M., Wells R. D. Sticky DNA, a self-associated complex formed at long GAA*TTC repeats in intron 1 of the frataxin gene, inhibits transcription. J Biol Chem. 2001 May 4;276(29):27171–27177. doi: 10.1074/jbc.M101879200. [DOI] [PubMed] [Google Scholar]
  97. Sakuraba H., Mizukami H., Yagihashi N., Wada R., Hanyu C., Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia. 2002 Jan;45(1):85–96. doi: 10.1007/s125-002-8248-z. [DOI] [PubMed] [Google Scholar]
  98. Savage David B., Tan Garry D., Acerini Carlo L., Jebb Susan A., Agostini Maura, Gurnell Mark, Williams Rachel L., Umpleby A. Margot, Thomas E. Louise, Bell Jimmy D. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes. 2003 Apr;52(4):910–917. doi: 10.2337/diabetes.52.4.910. [DOI] [PubMed] [Google Scholar]
  99. Shaw J., Lichter P., Driesel A. J., Williamson R., Chamberlain S. Regional localisation of the Friedreich ataxia locus to human chromosome 9q13----q21.1. Cytogenet Cell Genet. 1990;53(4):221–224. doi: 10.1159/000132936. [DOI] [PubMed] [Google Scholar]
  100. Shepherd Maggie, Pearson Ewan R., Houghton Jane, Salt Gill, Ellard Sian, Hattersley Andrew T. No deterioration in glycemic control in HNF-1alpha maturity-onset diabetes of the young following transfer from long-term insulin to sulphonylureas. Diabetes Care. 2003 Nov;26(11):3191–3192. doi: 10.2337/diacare.26.11.3191-a. [DOI] [PubMed] [Google Scholar]
  101. Song Qilin, Singleton Charles K. Mitochondria from cultured cells derived from normal and thiamine-responsive megaloblastic anemia individuals efficiently import thiamine diphosphate. BMC Biochem. 2002 Apr 25;3:8–8. doi: 10.1186/1471-2091-3-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Spillare E. A., Robles A. I., Wang X. W., Shen J. C., Yu C. E., Schellenberg G. D., Harris C. C. p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev. 1999 Jun 1;13(11):1355–1360. doi: 10.1101/gad.13.11.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Stanley Charles A. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab. 2004 Apr;81 (Suppl 1):S45–S51. doi: 10.1016/j.ymgme.2003.10.013. [DOI] [PubMed] [Google Scholar]
  104. Strom T. M., Hörtnagel K., Hofmann S., Gekeler F., Scharfe C., Rabl W., Gerbitz K. D., Meitinger T. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998 Dec;7(13):2021–2028. doi: 10.1093/hmg/7.13.2021. [DOI] [PubMed] [Google Scholar]
  105. Subramanian Veedamali S., Marchant Jonathan S., Parker Ian, Said Hamid M. Cell biology of the human thiamine transporter-1 (hTHTR1). Intracellular trafficking and membrane targeting mechanisms. J Biol Chem. 2002 Nov 25;278(6):3976–3984. doi: 10.1074/jbc.M210717200. [DOI] [PubMed] [Google Scholar]
  106. Suter S. L., Nolan J. J., Wallace P., Gumbiner B., Olefsky J. M. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care. 1992 Feb;15(2):193–203. doi: 10.2337/diacare.15.2.193. [DOI] [PubMed] [Google Scholar]
  107. Tan G., Chen L. S., Lonnerdal B., Gellera C., Taroni F. A., Cortopassi G. A. Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum Mol Genet. 2001 Sep 15;10(19):2099–2107. doi: 10.1093/hmg/10.19.2099. [DOI] [PubMed] [Google Scholar]
  108. Taylor S. I., Kadowaki T., Kadowaki H., Accili D., Cama A., McKeon C. Mutations in insulin-receptor gene in insulin-resistant patients. Diabetes Care. 1990 Mar;13(3):257–279. doi: 10.2337/diacare.13.3.257. [DOI] [PubMed] [Google Scholar]
  109. Taylor S. I., Samuels B., Roth J., Kasuga M., Hedo J. A., Gorden P., Brasel D. E., Pokora T., Engel R. R. Decreased insulin binding in cultured lymphocytes from two patients with extreme insulin resistance. J Clin Endocrinol Metab. 1982 May;54(5):919–930. doi: 10.1210/jcem-54-5-919. [DOI] [PubMed] [Google Scholar]
  110. Temple I. K., Gardner R. J., Mackay D. J., Barber J. C., Robinson D. O., Shield J. P. Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes. 2000 Aug;49(8):1359–1366. doi: 10.2337/diabetes.49.8.1359. [DOI] [PubMed] [Google Scholar]
  111. Thomas P. M., Cote G. J., Wohllk N., Haddad B., Mathew P. M., Rabl W., Aguilar-Bryan L., Gagel R. F., Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science. 1995 Apr 21;268(5209):426–429. doi: 10.1126/science.7716548. [DOI] [PubMed] [Google Scholar]
  112. Thomas P., Ye Y., Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet. 1996 Nov;5(11):1809–1812. doi: 10.1093/hmg/5.11.1809. [DOI] [PubMed] [Google Scholar]
  113. Tritos N. A., Mantzoros C. S. Clinical review 97: Syndromes of severe insulin resistance. J Clin Endocrinol Metab. 1998 Sep;83(9):3025–3030. doi: 10.1210/jcem.83.9.5143. [DOI] [PubMed] [Google Scholar]
  114. Van Maldergem L., Magré J., Khallouf T. E., Gedde-Dahl T., Jr, Delépine M., Trygstad O., Seemanova E., Stephenson T., Albott C. S., Bonnici F. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet. 2002 Oct;39(10):722–733. doi: 10.1136/jmg.39.10.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Vaxillaire M., Benmezroua Y., Durand E., Vasseur F., Froguel P. No evidence for diabetes-associated mutations of PEK/EIF2AK3 gene in French patients with early-onset type II diabetes. Diabetologia. 2001 Jun;44(6):786–786. doi: 10.1007/s001250051690. [DOI] [PubMed] [Google Scholar]
  116. Vionnet N., Stoffel M., Takeda J., Yasuda K., Bell G. I., Zouali H., Lesage S., Velho G., Iris F., Passa P. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992 Apr 23;356(6371):721–722. doi: 10.1038/356721a0. [DOI] [PubMed] [Google Scholar]
  117. Wobser Hella, Düssmann Heiko, Kögel Donat, Wang Haiyan, Reimertz Claus, Wollheim Claes B., Byrne Maria M., Prehn Jochen H. M. Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. J Biol Chem. 2001 Nov 27;277(8):6413–6421. doi: 10.1074/jbc.M108390200. [DOI] [PubMed] [Google Scholar]
  118. Wong A., Yang J., Cavadini P., Gellera C., Lonnerdal B., Taroni F., Cortopassi G. The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999 Mar;8(3):425–430. doi: 10.1093/hmg/8.3.425. [DOI] [PubMed] [Google Scholar]
  119. Yamada K., Ikegami H., Yoneda H., Miki T., Ogihara T. All patients with Werner's syndrome are insulin resistant, but only those who also have impaired insulin secretion develop overt diabetes. Diabetes Care. 1999 Dec;22(12):2094–2095. doi: 10.2337/diacare.22.12.2094. [DOI] [PubMed] [Google Scholar]
  120. Yamauchi T., Kamon J., Waki H., Murakami K., Motojima K., Komeda K., Ide T., Kubota N., Terauchi Y., Tobe K. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem. 2001 Aug 31;276(44):41245–41254. doi: 10.1074/jbc.M103241200. [DOI] [PubMed] [Google Scholar]
  121. Yamauchi T., Waki H., Kamon J., Murakami K., Motojima K., Komeda K., Miki H., Kubota N., Terauchi Y., Tsuchida A. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. J Clin Invest. 2001 Oct;108(7):1001–1013. doi: 10.1172/JCI12864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Yu C. E., Oshima J., Fu Y. H., Wijsman E. M., Hisama F., Alisch R., Matthews S., Nakura J., Miki T., Ouais S. Positional cloning of the Werner's syndrome gene. Science. 1996 Apr 12;272(5259):258–262. doi: 10.1126/science.272.5259.258. [DOI] [PubMed] [Google Scholar]
  123. t Hart L. M., Ruige J. B., Dekker J. M., Stehouwer C. D., Maassen J. A., Heine R. J. Altered beta-cell characteristics in impaired glucose tolerant carriers of a GAA trinucleotide repeat polymorphism in the frataxin gene. Diabetes. 1999 Apr;48(4):924–926. doi: 10.2337/diabetes.48.4.924. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES