Синдромы с инсулинорезистентностью: инсулинорезистентность типа А, лепречаунизм, синдром Рабсона-Мендельхалла и липодистрофия

Ключевыми особенностями всех синдромов с инсулинорезистентностью являются акантокератодермия (черный акантоз), избыток андрогенов и значительно повышенные концентрации инсулина в отсутствие ожирения. Чем тяжелее инсулинорезистентность и чем раньше ее начало, тем более вероятен сахарный диабет (С).

Пациенты с синдромом Донахью (называемом еще лепречаунизмом) имеют тяжелую внутриутробную задержку в росте, полное отсутствие подкожно-жировой клетчатки при рождении, лицевой дисморфизм («эльфоподобное лицо» с большими шаровидными глазами, оттопыренными ушами и микрогнатией), вздутый живот и нарушение гомеостаза глюкозы характеризующееся гипогликемией натощак и постпрандиальной гипергликемией. Пациенты погибают обычно в первые 2 года жизни.

Пациенты с синдромом Рабсона-Менденхолла имеют дисплазию десен и зубов, быстрый рост ногтей и гирсутизм. У пациентов развивается прогрессирующий диабет с кетоацидозом, большинство доживают до подросткового возраста.

При инсулиновой резистентности типа А наблюдается преимущественно поражение лиц женского пола подросткового возраста, наблюдается тяжелая инсулинорезистентность, проявления гиперандрогении и acanthosis nigricans. Девушки могут иметь разную степень гиперандрогении – от мягкого гирсутизма до тяжелой вирилизации. Диабет или нарушенная толерантность к глюкозе является одним из наиболее поздних проявлений синдрома и может быть компенсирован метформином.

Тяжелая инсулинорезистентность с трудом поддается лечению; у большинства пациентов с таким сахарным диабетом плохой гликемический контроль и часто развиваются осложнения (С).

В число применяемых подходов входит применение препаратов, улучшающих чувствительность к инсулину, таких как метформин, но когда инсулинорезистентность имеет особенно тяжелую форму, степень их воздействия ограничена. Главным направлением лечения остается инсулинотерапия; обычно требуется использование инсулина (500 Ед) и инсулиновых помп (Е). В случае частичной липодистрофии положительный эффект может быть получен от терапии метформином, и на ранних стадиях можно обойтись без инсулина (С). При генерализованной липодистрофии может развиться тяжелая декомпенсация диабета, поэтому попытки лечения бигуанидами могут предприниматься только в научно-исследовательских учреждениях

 

 

Список использованной литературы:

1. MUSSO C, COCHRAN E, MORAN SA, SKARULIS MC, ORAL EA, TAYLOR S, et al. Clinical course of genetic diseases of the insulin receptor (type A and RabsonАMendenhall syndromes): a 30Аyear prospective. Medicine (Baltimore) 2004: 83(4): 209–22.

2. MOLLER AM, DALGAARD LT, POCIOT F, NERUP J, HANSEN T, PEDERSEN O. Mutations in the hepatocyte nuclear factorА1alpha gene in Caucasian families originally classified as having Type Idiabetes. Diabetologia 1998: 41: 1528–31.

3. LAMBERT AP, ELLARD S, ALLEN LI, GALLEN IW, GILLESPIE KM, BINGLEY PJ, et al. Identifying hepatic nuclear factor 1alpha mutations in children and young adults with a clinical diagnosis of type 1 diabetes. Diabetes Care 2003: 26(2): 333–7.

4. AFUSCO D, STAZI MA, COTICHINI R, COTELLESSA M, MARTINUCCI ME, MAZZELLA M, et al. Permanent diabetes mellitus in the first year of life. Diabetologia 2002: 45(6): 798–804.

5. TILLIL H, KOBBERLING J. AgeАcorrected empirical genetic risk estimates for firstАdegree relatives of IDDM patients. Diabetes 1987: 36(1): 93–9.

6. HATHOUT EH, SHARKEY J, RACINE M, THOMAS W, NAHAB F, ELАSHAHAWY M, et al. Diabetic autoimmu nity in infants and preАschoolers with type 1 diabetes. Pediatr Diabetes 2000: 1(3): 131–4.

7. BORG H, MARCUS C, SJOBLAD S, FERNLUND P, SUNDKVIST G. Insulin autoantibodies are of less value compared with islet antibodies in the clinical diagnosis of autoimmune type 1 diabetes in children older than 3 yr of age. Pediatr Diabetes 2002: 3(3): 149–54.

8. SABBAH E, SAVOLA K, KULMALA P, VEIJOLA R, VAHASALO P, KARJALAINEN J, et al. DiabetesАassociated autoantibodies in relation to clinical charА acteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. J Clin Endocrinol Metab 1999: 84(5): 1534–9.

9. GUNGOR N, HANNON T, LIBMAN I, BACHA F, ARSLANIAN S. Type 2 diabetes mellitus in youth: the complete picture to date. Pediatr Clin North Am 2005: 52(6): 1579–609.

10. EHTISHAM S, BARRETT TG, SHAW NJ. Type 2 diabetes mellitus in UK children–an emerging problem. Diabet Med 2000: 17(12): 867–71.

11. EHTISHAM S, HATTERSLEY AT, DUNGER DB, BARRETT TG. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child 2004: 89(6): 526–9.

12. American Diabetes Association. Type 2 diabetes in Children and Adolescents. Diabetes Care 2000: 23: 381–9. 13. SLINGERLAND AS, HATTERSLEY AT. Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann Med 2005: 37(3): 186–95.

14. POLAK M, SHIELD J. Neonatal and veryАearlyАonset diabetes mellitus. Semin Neonatol 2004: 9(1): 59–65.

15. TEMPLE IK, GARDNER RJ, MACKAY DJ, BARBER JC, ROBINSON DO, SHIELD JP. Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 2000: 49(8): 1359–66.

16. GARDNER RJ, MACKAY DJ, MUNGALL AJ, POLY CHRONAKOS C, SIEBERT R, SHIELD JP, et al. An imprinted locus associated with transient neonatal dia betes mellitus. Hum Mol Genet 2000: 9(4): 589–96.

17. GLOYN AL, PEARSON ER, ANTCLIFF JF, PROKS P, BRU INING GJ, SLINGERLAND AS, et al. Activating mutations in the gene encoding the ATPАsensitive potassiumАchannel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004: 350(18): 1838–49.

18. HATTERSLEY AT, ASHCROFT FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005: 54(9): 2503–13.

19. NJOLSTAD P, SOVIK O, CUESTAАMUNOZ A, BJORKHAUG L, MASSA O, BARBETTI F, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. NEJM 2001: 344: 1588–1592.

20. NJOLSTAD PR, SAGEN JV, BJORKHAUG L, ODILI S, SHEHADEH N, BAKRY D, et al. Permanent neonatal diabetes mellitus due to glucokinase deficienА cyАan inborn error of glucoseАinsulin signalling pathway. Diabetes 2003: 52(11): 2854–2860

. 21. MACKAY DJ, COUPE AM, SHIELD JP, STORR JN, TEMPLE IK, ROBINSON DO. Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus. Hum Genet 2002: 110(2): 139–44.

22. GLOYN AL, REIMANN F, GIRARD C, EDGHILL EL, PROKS P, PEARSON ER, et al. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 2005.

23. INAGAKI N, GONOI T, IV JPC. Reconstitution of IK ATP: an inward rectifier subunit plus the sulphonylurea receptor. Science 1995: 270: 1166–1170.

24. SAGEN JV, RAEDER H, HATHOUT E, SHEHADEH N, GUDMUNDSSON K, BAEVRE H, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 2004: 53(10): 2713–8.

25. CODNER E, FLANAGAN S, ELLARD S, GARCIA H, HATTERSLEY AT. HighАDose Glibenclamide Can Replace Insulin Therapy Despite Transitory Diarrhea in EarlyАOnset Diabetes Caused by a Novel R201L Kir6.2 Mutation. Diabetes Care 2005: 28(3): 758–9.

26. MASSA O, IAFUSCO D, D’AMATO E, GLOYN AL, HAT TERSLEY AT, PASQUINO B, et al. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005: 25(1): 22–7.

27. HATTERSLEY AT. Molecular genetics goes to the diabetes clinic. Clin Med 2005: 5(5): 476–81.

28. ZUNG A, GLASER B, NIMRI R, ZADIK Z. Glibenclamide Treatment in Permanent Neonatal Diabetes Mellitus due to an Activating Mutation in Kir6.2. J Clin Endocrinol Metab 2004: 89(11): 5504–7.

29. 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. Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New England Journal of Medicine 2006: 355(5): 467–77.

30. PROKS P, ARNOLD AL, BRUINING J, GIRARD C, FLANA GAN SE, LARKIN B, COLCLOUGH K, HATTERSLEY AT, ASHCROFT FM, ELLARD S. A heterozyА gous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Human Molecular Genetics 2006: 15(11): 1793–800.

31. BABENKO AP, POLAK M, CAVE H, BUSIAH K, CZERNICHOW P, SCHARFMANN R, BRYAN J, AGUILAR BRYAN L, VAXILLAIRE M, FROGUEL P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. New England Journal of Medicine 2006: 355(5): 456–66.

32. IYER S, KORADA M, RAINBOW L, KIRK J, BROWN RM, SHAW N, et al. WolcottАRallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paediatr 2004: 93(9): 1195–201.

33. SENEE V, VATTEM KM, DELEPINE M, RAINBOW LA, HATON C, LECOQ A, et al. WolcottАRallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004: 53(7): 1876–83.

34. DELEPINE M, NICOLINO M, BARRETT T, GOLAMAULLY M, LATHROP GM, JULIER C. EIF2AK3, encoding translation initiation factor 2Аalpha is mutated in patients with WolcottАRallison syndrome. Nat Genet 2000: 25(4): 406–9. 35. STOY J, EDGHILL EL, FLANAGAN SE, YE H, PAZ VP, PLUZHNIKOV A, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007: 104: 15040–4.

36. STRIDE A, HATTERSLEY AT. Different genes, different diabetes: lessons from maturityАonset diabetes of the young. Ann Med 2002: 34(3): 207–16.

37. STRIDE A, VAXILLAIRE M, TUOMI T, BARBETTI F, NJOLSTAD PR, HANSEN T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 2002: 45(3): 427–35.

38. PEARSON ER, LIDDELL WG, SHEPHERD M, CORRALL RJ, HATTERSLEY AT. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor 1 alpha gene mutations: evidence for pharmacogenetics in diabetes. Diab Med 2000: 17: 543–5.

39. PEARSON ER, STARKEY BJ, POWELL RJ, GRIBBLE FM, CLARK PM, HATTERSLEY AT. Genetic aetiology of hyperglycaemia determines response to treatment in diabetes. Lancet 2003: 362(9392): 1275–1281.

40. BYRNE MM, STURIS J, MENZEL S, YAMAGATA K, FAJANS SS, DRONSFIELD MJ, et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on Chromosome 12. Diabetes 1996: 45: 1503–1510.

41. ISOMAA B, HENRICSSON M, LEHTO M, FORSBLOM C, KARANKO S, SARELIN L, et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 1998: 41(4): 467–73.

42. PEARSON ER, STARKEY BJ, POWELL RJ, GRIBBLE FM, CLARK PM, HATTERSLEY AT. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003: 362(9392): 1275–81.

43. SHEPHERD M, PEARSON ER, HOUGHTON J, SALT G, ELLARD S, HATTERSLEY AT. No deterioration in glycemic control in HNFА1alpha maturityАonset diabetes of the young following transfer from longАterm insulin to sulphonylureas. Diabetes Care 2003: 26(11): 3191–2.

44. TUOMI T, HONKANEN EH, ISOMAA B, SARELIN L, GROOP LC. Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturityАonset diabetes of the young type 3. Diabetes Care 2006: 29(2): 189–94.

45. PEARSON ER, PRUHOVA S, TACK CJ, JOHANSEN A, CASTLEDEN HA, LUMB PJ, et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 2005: 48(5): 878–85.

46. FAJANS SS, BROWN MB. Administration of sulfony lureas can increase glucoseАinduced insulin secretion for decades in patients with maturityАonset diabetes of the young. Diabetes Care 1993: 16(9): 1254–61.

47. STOFFERS DA, FERRER J, CLARKE WL, HABENER JF. EarlyАonset typeАII diabetes mellitus (MODY4) linked to IPF1. Nature Genetics 1997: 17: 138– 139.

48. MALECKI MT, JHALA US, ANTONELLIS A, FIELDS L, DORIA A, ORBAN T, et al. Mutations in NEUROD1 are associated with the development of Type 2 diabetes mellitus. Nature Genetics 1999: 23(3): 323–328.

49. KRISTINSSON SY, THOROLFSDOTTIR ET, TALSETH B, STEINGRIMSSON E, THORSSON AV, HELGASON T, et al. MODY in Iceland is associated with mutations in HNF 1alpha and a novel mutation in NeuroD1. Diabetologia 2001: 44(11): 2098–103.

50. RAEDER H, JOHANSSON S, HOLM PI, HALDORSEN IS, MAS E, SBARRA V, et al. Mutations in the CEL VNTR cause a syndrome of diabetes and panА creatic exocrine dysfunction. Nat Genet 2006: 38(1): 54–62.

51. VELHO G, BLANCHE H, VAXILLAIRE M, BELLANNE CHANTELOT C, PARDINI VC, TIMSIT J, et al. Identifica tion of 14 new glucokinase mutations and description of the clinical profile of 42 MODYА2 families. Diabetologia 1997: 40: 217–224.

52. BARRETT TG, BUNDEY SE, MACLEOD AF. Neurode generation and diabetes: UK nationwide study of Wol fram (DIDMOAD) syndrome. The Lancet 1995: 346: 1458–1463.

53. STROM TM, HORTNAGEL K, HOFMANN S, GEKELER F, SCHARFE C, RABL W, et al. 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: 7(13): 2021–8.

54. INOUE H, TANIZAWA Y, WASSON J, BEHN P, KALIDAS K, BERNALАMIZRACHI E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 1998: 20(2): 143–8.

55. HARDY C, KHANIM F, TORRES R, SCOTTАBROWN M, SELLER A, POULTON J, et al. Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1. Am.J.Hum.Genet. 199965: 1279–1290. 56. LABAY V, RAZ T, BARON D, MANDEL H, WILLIAMS H, BARRETT T, et al. Mutations in SLC19A2 cause thiamineАresponsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 1999: 22(3): 300–4.

57. OZDEMIR MA, AKCAKUS M, KURTOGLU S, GUNES T, TORUN YA. TRMA syndrome (thiamineАresponsive megaloblastic anemia): a case report and review of the literature. Pediatr Diabetes 2002: 3(4): 205–9.

58. BINGHAM C, HATTERSLEY AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factorА1{beta}. Nephrol Dial TransА plant 2004: 19(11): 2703–2708.

59. BELLANNEАCHANTELOT C, CLAUIN S, CHAUVEAU D, COLLIN P, DAUMONT M, DOUILLARD C, et al. Large genomic rearrangements in the hepatocyte nuclear factorА1beta (TCF2) gene are the most frequent cause of maturityАonset diabetes of the young type 5. Diabetes 2005: 54(11): 3126–32.

60. PEARSON ER, BADMAN MK, LOCKWOOD CR, CLARK PM, ELLARD S, BINGHAM C, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor 1alpha and А1beta mutations. Diabetes Care 2004: 27(5): 1102–7.

61. BELLANNEАCHANTELOT C, CHAUVEAU D, GAUTIER JF, DUBOISАLAFORGUE D, CLAUIN S, BEAUFILS S, et al. Clinical spectrum associated with hepaА tocyte nuclear factorА1beta mutations. Ann Intern Med 2004: 140(7): 510–7.

62. VAN DEN OUWELAND JM, LEMKES HH, RUITENBEEK W, SANDKUIJL LA, DE VIJLDER MF, STRUYVENBERG PA, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genetics 1992: 1(5): 368–71.

63. OWEN KR, DONOHOE M, ELLARD S, HATTERSLEY AT. Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene. Diabet Med 2003: 20(10): 823–7.

64. PETERSEN KF, ORAL EA, DUFOUR S, BEFROY D, ARIYAN C, YU C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002: 109(10): 1345–50.