Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes

Nat Clin Pract Endocrinol Metab. 2008 Apr;4(4):200-13. doi: 10.1038/ncpendmet0778. Epub 2008 Feb 26.


Monogenic diabetes resulting from mutations that primarily reduce beta-cell function accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications. Firstly, diabetes diagnosed before 6 months of age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1 subunits of an ATP-sensitive potassium channel, and improved glycemic control can be achieved by treatment with high-dose sulfonylureas rather than insulin. Secondly, patients with stable, mild fasting hyperglycemia detected particularly when they are young could have a glucokinase mutation and might not require specific treatment. Thirdly, individuals with familial, young-onset diabetes that does not fit with either type 1 or type 2 diabetes might have mutations in the transcription factors HNF-1alpha (hepatocyte nuclear factor 1-alpha) or HNF-4alpha, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease (caused by mutations in HNF-1beta) or deafness (caused by a mitochondrial m.3243A>G mutation), usually require early treatment with insulin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Diabetes Mellitus / classification*
  • Diabetes Mellitus / diagnosis
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology
  • Diagnosis, Differential
  • Female
  • Glucokinase / genetics
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 4 / genetics
  • Humans
  • Infant, Newborn
  • Insulin-Secreting Cells / pathology*
  • Male
  • Mutation
  • Potassium Channels / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Receptors, Drug / genetics
  • Sulfonylurea Receptors


  • ATP-Binding Cassette Transporters
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Kir6.2 channel
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors
  • Glucokinase