Maturity-Onset Diabetes of the Young: Molecular Genetics, Clinical Manifestations, and Therapy

  • Markus StoffelEmail author
Reference work entry


Monogenic diabetes, accounting for 1–3% of diabetes cases, results from mutations that impair pancreatic β-cell function. Monogenic forms of diabetes are often misdiagnosed as either type 1 or type 2 diabetes. A molecular diagnosis based on an emerging genetic classification enables personalized treatment, better prediction of disease progression, as well as screening, early diagnosis, and genetic counseling of family members. Historically, monogenic forms of diabetes were termed maturity-onset diabetes of the young (MODY). The different MODY subtypes differ in age of onset, manifestation of hyperglycemia, patterns of glucose-stimulated insulin secretion, and response to treatments. Furthermore, several monogenic forms of childhood and adolescent diabetes are associated with extrapancreatic manifestations and can feature a range of genetic syndromes. In this chapter, monogenic β-cell diabetes subtypes will be described according to their molecular etiologies and categorized based on their clinical implications.


Diabetes mellitus Pancreatic beta cells Genetics Classification Diagnosis Treatment Mutation 


  1. 1.
    Patel KA, Oram RA, Flanagan SE, et al. Type 1 diabetes genetic risk score: a novel tool to discriminate monogenic and type 1 diabetes. Diabetes. 2016. pii: db151690.Google Scholar
  2. 2.
    Deeb A, Habeb A, Kaplan W, et al. Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates. Am J Med Genet. 2016;170:602–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Docherty LE, Kabwama S, Lehmann A, et al. Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients. Diabetologia. 2013;56:758–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Babenko AP, et al. Activating mutations in the ABC C8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–66.CrossRefPubMedGoogle Scholar
  5. 5.
    Babiker T, Vedovato N, Patel K, et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia. 2016;59:1162–6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Greeley ASW, Naylor RN, Philipson LH. Bell, GI Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr Diab Rep. 2011;11:519–32.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Støy J, Steiner DF, Park SY, Ye H, et al. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord. 2010;11:205–15.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Liu M, Sun J, Cui J, et al. INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol Aspects Med. 2015;42:3–18.CrossRefPubMedGoogle Scholar
  9. 9.
    Cuesta-Muñoz AL, Tuomi T, Cobo-Vuilleumier N, et al. Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY). Diabetes Care. 2010;33:290–2.CrossRefPubMedGoogle Scholar
  10. 10.
    Osbak KK, Colclough K, Saint-Martin C, Beer NL, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30:1512–26.CrossRefPubMedGoogle Scholar
  11. 11.
    Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990;39:647–52.CrossRefPubMedGoogle Scholar
  12. 12.
    Byrne MM, Sturis J, Clement K, et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest. 1994;93:1120–30.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Njolstad PR, Sovik O, Cuesta-Munoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998;338:226–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Grupe A, Hultgren B, Ryan A, Ma YH, Bauer M, Stewart TA. Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Cell. 1995;83:69–78.CrossRefPubMedGoogle Scholar
  16. 16.
    Velho G, Petersen KF, Perseghin G, et al. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest. 1996;98:1755–61.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998;19:268–70. [see comments].CrossRefPubMedGoogle Scholar
  18. 18.
    Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328:697–702. [see comments].CrossRefPubMedGoogle Scholar
  19. 19.
    Pearson ER, Velho G, Clark P, et al. Beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes. 2001;50 Suppl 1:S101–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Frayling TM, Evans JC, Bulman MP, et al. Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes. 2001;50 Suppl 1:S94–100.CrossRefPubMedGoogle Scholar
  21. 21.
    Yamagata K, Oda N, Kaisaki PJ, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996;384:455–8. [see comments].CrossRefPubMedGoogle Scholar
  22. 22.
    Yamagata K, Yang Q, Yamamoto K, et al. Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative. Diabetes. 1998;47:1231–5.PubMedGoogle Scholar
  23. 23.
    Kaisaki PJ, Menzel S, Lindner T, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4. Diabetes. 1997;46:528–35. [erratum appears in Diabetes 1997 Jul;46(7):1239].CrossRefPubMedGoogle Scholar
  24. 24.
    Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab. 1999;84:1077–82.PubMedGoogle Scholar
  25. 25.
    Owen KR. RD Lawrence lecture 2012: assessing aetiology in diabetes: how C-peptide, CRP and fucosylation came to the party! Diabet Med. 2013;30:260–6.CrossRefPubMedGoogle Scholar
  26. 26.
    McDonald TJ, Ellard S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem. 2013;50:403–15.CrossRefPubMedGoogle Scholar
  27. 27.
    Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med. 2000;17:543–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen WS, Manova K, Weinstein DC, et al. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev. 1994;8:2466–77.CrossRefPubMedGoogle Scholar
  29. 29.
    Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A. 1997;94:13209–14.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Malecki MT, Yang Y, Antonellis A, Curtis S, Warram JH, Krolewski AS. Identification of new mutations in the hepatocyte nuclear factor 4alpha gene among families with early onset Type 2 diabetes mellitus. Diabet Med. 1999;16:193–200.CrossRefPubMedGoogle Scholar
  31. 31.
    Pearson ER, Pruhova S, Tack CJ, et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte.nuclear factor 4alpha mutations in a large European collection. Diabetologia. 2005;48:878–85.CrossRefPubMedGoogle Scholar
  32. 32.
    Byrne MM, Sturis J, Fajans SS, et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes. 1995;44:699–704.CrossRefPubMedGoogle Scholar
  33. 33.
    Herman WH, Fajans SS, Smith MJ, Polonsky KS, Bell GI, Halter JB. Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene. Diabetes. 1997;46:1749–54.CrossRefPubMedGoogle Scholar
  34. 34.
    Shih DQ, Dansky HM, Fleisher M, Assmann G, Fajans SS, Stoffel M. Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes. 2000;49:832–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384:458–60.CrossRefPubMedGoogle Scholar
  36. 36.
    Navas MA, Munoz-Elias EJ, Kim J, Shih D, Stoffel M. Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). Diabetes. 1999;48:1459–65.CrossRefPubMedGoogle Scholar
  37. 37.
    Moller AM, Urhammer SA, Dalgaard LT, et al. Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM. Diabetologia. 1997;40:980–3.CrossRefPubMedGoogle Scholar
  38. 38.
    Hani EH, Suaud L, Boutin P, et al. A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest. 1998;101:521–6.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dutta S, Gannon M, Peers B, Wright C, Bonner-Weir S, Montminy M. PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. Proc Natl Acad Sci U S A. 2001;98:1065–70.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993;12:4251–9.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 1994;371:606–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 1998;12:1763–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–10.CrossRefPubMedGoogle Scholar
  44. 44.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17:138–9.CrossRefPubMedGoogle Scholar
  45. 45.
    Stoffers DA, Stanojevic V, Habener JF. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J Clin Invest. 1998;102:232–41.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hani EH, Stoffers DA, Chevre JC, et al. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest. 1999;104:R41–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Macfarlane WM, Frayling TM, Ellard S, et al. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J Clin Invest. 1999;104:R33–9.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Naya FJ, Huang HP, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 1997;11:2323–34.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet. 1999;23:323–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Coffinier C, Thepot D, Babinet C, Yaniv M, Barra J. Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Development. 1999;126:4785–94.PubMedGoogle Scholar
  51. 51.
    Barbacci E, Reber M, Ott MO, Breillat C, Huetz F, Cereghini S. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development. 1999;126:4795–805.PubMedGoogle Scholar
  52. 52.
    Horikawa Y, Iwasaki N, Hara M, et al. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet. 1997;17:384–5.CrossRefPubMedGoogle Scholar
  53. 53.
    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.CrossRefPubMedGoogle Scholar
  54. 54.
    Bingham C, Bulman MP, Ellard S, et al. Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet. 2001;68:219–24.CrossRefPubMedGoogle Scholar
  55. 55.
    Bingham C, Ellard S, Allen L, et al. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta. Kidney Int. 2000;57:898–907. [see comments].CrossRefPubMedGoogle Scholar
  56. 56.
    Gudmundsson J, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007;39:977–83.CrossRefPubMedGoogle Scholar
  57. 57.
    Pearson ER, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor 1a and -1b mutations. Diabetes Care. 2004;27:1102–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A > G mitochondrial point mutation. Diabet Med. 2008;25:383–99.CrossRefPubMedGoogle Scholar
  59. 59.
    Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet. 2007;71:379–91.CrossRefPubMedGoogle Scholar
  60. 60.
    Raeder H, Johansson S, Holm PI, et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet. 2006;38:54–62.CrossRefPubMedGoogle Scholar
  61. 61.
    Raeder H, et al. Pancreatic lipomatosis is a structural marker in nondiabetic children with mutations in carboxyl-ester lipase. Diabetes. 2007;56:444–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Institute of Molecular Health Sciences, Swiss Federal Institute of TechnologyZurichSwitzerland

Personalised recommendations