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Review article: Biomedical intelligence

Vol. 142 No. 3940 (2012)

Monogenic diabetes mellitus due to defects in insulin secretion

  • Christoph Henzen
DOI
https://doi.org/10.4414/smw.2012.13690
Cite this as:
Swiss Med Wkly. 2012;142:w13690
Published
23.09.2012

Summary

Monogenic forms of diabetes mellitus cover a heterogeneous group of diabetes which are uniformly caused by a single gene mutation and are characterised by impaired insulin secretion of the pancreatic beta cell. It is estimated that they account for up to 5% of all cases of diabetes mellitus, which are often not diagnosed or are misclassified as type 1 or 2 diabetes. However, accurate diagnosis is important because of the special implications for treatment, prognosis and family risk. The knowledge of typical clinical features such as mode of inheritance, age at diagnosis and impaired insulin secretion, as well as genetic testing establishes the diagnosis of MODY, mitochondrial diabetes and neonatal diabetes.

References

  1. Fajans SS, Graeme IB, Polonksy KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345:971–80
  2. Gardner D, Shyong Tai E. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabet Metab Syndr Obes. 2012;5:101–8.
  3. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010;53:2504–8.
  4. Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med. 2009;26:466–73.
  5. Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med. 2009;26:437–41.
  6. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT, et al. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet. 2003;362:1275–81.
  7. Ellard S, Bellanné-Chantelot C, Hattersley AT. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008;51:546–53.
  8. Shields BM, McDonald TJ, Ellard S, Campbell MJ, Hyde C, Hattersley AT. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia. 2012;55:1265–72.
  9. Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ. 2011;343:d6044
  10. Pickup J, Williams G. Textbook of diabetes. 2nd ed. 1997; Blackwell Science Ltd. Oxford UK.
  11. Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njølstad PR, Hansen T, et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia. 2002;45:427–35.
  12. Nyunt O, Wu JY, McGown IN, Harris M, Huynh T, Leong GM, et al. Investigating maturity onset diabetes of the young. Clin Biochem Rev. 2009;30:67–74.
  13. Pearson ER, Velho G, Clark P, Stride A, Shepherd M, Frayling TM, et al. β-Cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations. Diabetes 2001;50:101–7.
  14. Schnyder S, Mullis PE, Ellard S, Hattersley AT, Flück CE. Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly. 2005;135:352–6.
  15. Vionnet N, Stoffel M, Takeda J, Yasuda K, Bell GI, Zouali H, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356:721–2.
  16. Bellanné-Chantelot C, Clauin S, Chauveau D, Chauveau D, Collin P, Daumont M, et al. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005;54:3126–32.
  17. Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17:138–9.
  18. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, et al. Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nat Genet. 1997;17:384–5.
  19. 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. Nat Genet. 1999;23:323–8.
  20. Fernandez-Zapico ME, van Velkinburgh JC, Gutiérrez-Aguilar R, Neve B, Froguel P, Urrutia R, Stein R. MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells. J Biol Chem. 2009;284:36482–90.
  21. Johansson BB, Torsvik J, Bjørkhaug L, Vesterhus M, Ragvin A, Tjora E, et al. Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease. J Biol Chem. 2011;286:34593–605.
  22. Biason-Lauber A, Boehm B, Lang-Muritano M, Gauthier BR, Brun T, Wollheim CB, Schoenle EJ. Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia. 2005;48:900–6.
  23. Johansson S, Irgens H, Chudasama KK, Molnes J, Aerts J, Roque FS, et al. Exome sequencing and genetic testing for MODY. PLoS One. 2012;7:e38050. Epub 2012 May 25
  24. Zeviani M, Tiranti V, Piantadosi C. Mitochondrial disorders. Medicine. (Baltimore) 1998;77:59–72.
  25. Oçal G, Flanagan SE, Hacihamdioğlu B, Berberoğlu M, Siklar Z, Ellard S, et al. Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic beta cell. J Pediatr Endocrinol Metab. 2011;24:1019–23.
  26. D’Amato E, Lorini R. Neonatal diabetes mellitus and mutation in the HNF-1beta gene. J Clin Endocrinol Metab. 2005;90:5906–7.
  27. Thomas IH, Saini NK, Adhikari A, Lee JM, Kasa-Vubu JZ, Vazquez DM, et al. Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation. Pediatr Diabetes. 2009;10:492–6.
  28. Njolstad PR, Sovik O, Cuesta-Munoz A, Bjørkhaug L, Massa O, Barbetti F, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588–92.
  29. Russo L, Iafusco D, Brescianini S, Nocerino V, Bizzarri C, Toni S, et al. (ISPED Early Diabetes Study Group). Permanent diabetes during the first year of life: multiple gene screening in 54 patients. Diabetologia. 2011;54:1693–701.
  30. McDonald TJ, Colclough K, Brown R, Shields B, Shepherd M, Bingley P, et al. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from type 1 diabetes. Diabet Med. 2011;28:1028–33.
  31. Frayling TM, Bulman MP, Appleton M, Hattersley AT, Ellard S. A rapid screening method for hepatocyte nuclear factor 1 alpha frameshift mutations; prevalence in maturity-onset diabetes of the young and late-onset non-insulin dependent diabetes. Hum Genet. 1997;101:351–4.
  32. Stride A, Ellard S, Clark P, Shakespeare L, Salzmann M, Shepherd M, et al. Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers. Diabetes Care. 2005;28:1751–6.
  33. Fajans SS, Brown MB. Administration of sulfonylureas can increase glucose-induced insulin secretion for decades in patients with maturity-onset diabetes of the young. Diabetes Care. 1993;16:1254–61.
  34. Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care. 2002;25:2287–91.
  35. Isomaa B, Henricsson M, Lehto M, Forsblom C, Karanko S, Sarelin L, et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia. 1998;41:467–73.
  36. Steele AM, Shields BM, Shepherd M, Ellard S, Hattersley AT, Pearson ER. Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med. 2010;27:157–61.
  37. Prisco F, Iafusco D, Franzese A, Sulli N, Barbetti F. MODY2 presenting as neonatal hyperglycaemia: a need to reshape the definition of “neonatal diabetes”? Diabetologia. 2000;43:1331–2.
  38. Martin D, Bellanné-Chantelot C, Deschamps I, Froguel P, Robert JJ, Velho G. Long-term follow-up of oral glucose tolerance test-derived glucose tolerance and insulin secretion and insulin sensitivity indexes in subjects with glucokinase mutations (MODY2) Diabetes Care. 2008;31:1321–3.
  39. Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet. 1999;8:2001–8.
  40. Bellanné-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;6140:510–7.
  41. Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, et al. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol. 2006;17:497–503.
  42. Raile K, Klopocki E, Holder M, Wessel T, Galler A, Deiss D, et al. Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young. J Clin Endocrinol Metab. 2009;94:2658–64.
  43. Bellanné-Chantelot C, Lévy DJ, Carette C, Saint-Martin C, Riveline JP, Larger E, et al. (French Monogenic Diabetes Study Group). Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. J Clin Endocrinol Metab. 2011;96:1346–51.
  44. Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59:2326–31.
  45. Chavali S, Mahajan A, Tabassum R, Dwivedi OP, Chauhan G, Ghosh S, et al. Association of variants in genes involved in pancreatic β-cell development and function with type 2 diabetes in North Indians. J Hum Genet. 2011;56:695–700.
  46. Raile K, O’Connell M, Galler A, Werther G, Kühnen P, Krude H, et al. Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals. Eur J Endocrinol. 2011;165:255–60.
  47. Bowman P, Flanagan SE, Edghill EL, Damhuis A, Shepherd MH, Paisey R, et al. Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia. 2012;55:123–7.
  48. Thanabalasingham G, Shah N, Vaxillaire M, Hansen T, Tuomi T, Gašperíková D, et al. A large multicentre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia. 2011;54:2801–10.
  49. Haldorsen IS, Raeder H, Vesterhus M, Molven A, Njolstad PR. The role of pancreatic imaging in monogenic diabetes mellitus. Nat Rev Endocrinol. 2012;8:148–59.
  50. Vesterhus M, Haldorsen IS, Raeder H, Molven A, Njølstad PR. Reduced pancreatic volume in hepatocyte nuclear factor 1A-maturity-onset diabetes of the young. J Clin Endocrinol Metab. 2008;93:3505–9.
  51. de Andrade PB, Rubi B, Frigerio F, van den Ouweland JM, Maassen JA, Maechler P. Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function. Diabetologia. 2006;49:1816–26.
  52. Nagata H, Kumahara K, Tomemori T, Arimoto Y, Isoyama K, Yoshida K, et al. Frequency and clinical features of patients with sensorineural hearing loss associated with the A3243G mutation of the mitochondrial DNA in otorhinolaryngic clinics. J Hum Genet. 2001;46:595–9.
  53. Laloi-Michelin M, Meas T, Ambonville C, Bellanné-Chantelot C, Beaufils S, Massin P, et al. Mitochondrial Diabetes French Study Group. The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes. J Clin Endocrinol Metab. 2009;94:3025–30.
  54. Lynn S, Borthwick GM, Charnley RM, Walker M, Turnbull DM. Heteroplasmic ratio of the A3243G mitochondrial DNA mutation in single pancreatic beta cells. Diabetologia. 2003;46:296–9.
  55. Maassen JA, ’T Hart LM, Van Essen E, Heine RJ, Nijpels G, Jahangir Tafrechi RS, et al. Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes. 2004;53:103–9.
  56. Domenech E, Gomez-Zaera M, Nunes V. Wolfram/DIDMOAD syndrome, a heterogenic and molecularly complex neurodegenerative disease. Pediatr Endocrinol Rev. 2006;3:249–57.
  57. Laloi-Michelin M, Virally M, Jardel C, Meas T, Ingster-Moati I, Lombès A, et al. Kearns Sayre syndrome: an unusual form of mitochondrial diabetes. Diabetes Metab. 2006;32:182–6.
  58. Rubio-Cabezas O, Klupa T, Malecki MT. CEED3 Consortium. Permanent neonatal diabetes mellitus – the importance of diabetes differential diagnosis in neonates and infants. Eur J Clin Invest. 2011;41:323–33.

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