Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

MODY Diabetes (Maturity-Onset Diabetes Of The Young) [E11.9]

OMIM numbers: 600496 (MODY3), 142410 (HNF1A), 125851 (MODY2), 138079 (GCK), 125850 (MODY1), 600281 (HNF4A), 137920 (RCAD), 189907 (HNF1B), 606392 (MODY4), 600733 (PDX1)

Dipl.-Biol. Birgit Busse, Dipl.-Biol. Wolfgang Rupprecht

Scientific Background

Maturity-onset diabetes of the young (MODY) is an autosomal dominant inherited group of clinically heterogenous types of diabetes which are not always insulin dependent. They are characterized by various disorders in the functions of beta cells in the pancreas. MODY is the most frequent form of monogenic diabetes and causes up to 5% of all diabetic diseases in Europe. It is usually diagnosed before the 25th year of life; however, frequently, it is initially interpreted as diabetes type 1 or 2. If gestational diabetes is present, the possibility of MODY diabetes (in approx. 5%) should be considered as well.

Diagnostic criteria for MODY are:

  • age of manifestation early adolescence
  • first-degree relative affected
  • antibodies test GAD, IA-2 and/or islet cell negative
  • moderate (on an empty stomach) hyperglycemia (30-250 mg/dl, or 7-14 mM) before 30th year of life
  • constantly low insulin demand (e.g. < 0.5/u/kg/d)
  • gestational diabetes
  • cystic kidney disease in the patient or close relative
  • positive glucose tolerance test
  • renal glycosuria
  • type 2 diabetes or metabolic syndrome has been ruled out

The various forms of MODY diabetes have been classified according to their signs and symptoms as well as the respective genes affected by mutations. Today, there are 13 different types, while with a frequency of 83%, MODY type 2 and 3 are the most frequently occurring forms.

MODY Type 2 exhibits a persistent, mild hyperglycemia, which usually does not require medical treatment and can be easily treated by adapting the diet. It is caused by mutations in the glucokinase gene (GCK).

MODY Type 3 is marked by severe hyperglycemia. The affected patients respond very well to treatment with sulfonylureas or to smallest doses of insulin and show above average frequent episodes of hypoglycemia under treatment. It is caused by mutations in the HNF1A gene, which encodes for the transcription factor hepatocyte nuclear factor 1-α.

The other forms of MODY type 1, 4 and 5 are caused by mutations in the genes of various transcription factors (HNF4A, PDX1 and HNF1B). The signs and symptoms of MODY type 1 are similar to the ones of type 3. The occurring hyperglycemia requires medical intervention. MODY type 4 has been associated with a mild course of the disease due to its mild hyperglycemia. MODY 5 is a rare condition. Besides severe hyperglycemia, the clinical signs and symptoms furthermore include polycystic kidney disease or malformations in the urogenital tract, which allows a clear distinction from other forms.

A clear description of the clinical signs and symptoms of the MODY types 6-13 (NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8 and KCNJ11) has so far not been possible due to their rarity. It has been assumed that there are additional, so far unkown genes associated with MODY, since not in all patients with MODY diabetes mutations in the respective genes are found.

Schematic representation of insulin production in a beta cell. Glucose is transported into the cell through the glucose transporter GLUT2. The enzyme glucokinase, which functiones as glucose sensor in the cell, converts the glucose into glucose-6-phosphate. ATP is formed through glycolysis and the Krebs cycle, which binds to the ATP sensitive potassium channel thereby preventing potassium efflux. This leads to the depolarization of the cell membrane causing the voltage-dependent calcium channel to open. The influx of Ca2+ ions and their release through the endoplasmic reticulum leads to fusion of the insulin vesicle with the cell membrane and therefore to the release of insulin. In this process, different transcription factors (HNF-1α, HNF-4α, HNF-1β, IPF-1 and NeuroD1) regulate the expression of important enzymes in the glucose metabolism.
Insulin production in a beta cell and MODY diabetes