Maturity Onset Diabetes of the Young

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Classification according to ICD-10
E11.- Diabetes mellitus, type 2
ICD-10 online (WHO version 2019)

Maturity Onset Diabetes of the Young ( MODY diabetes , MODY syndrome ) is a hereditary "adult diabetes that occurs in adolescence" and is characterized by genetic defects in beta cell function.

This term has been used for some forms of diabetes mellitus since the 1970s . Since 1998 the MODY types have been classified into the various forms of “Type 3 diabetes” (actually: “Other specific types”). The term is still widely used in clinical practice.

Genetic cause

MODY diabetes is based on mutations in genes involved in glucose metabolism . He is monogenic autosomal - dominant inherited. It manifests itself in childhood or adolescence and does not require any insulin therapy , at least initially . The lack of diabetes-specific antibodies is also characteristic. About two to five percent of all diabetics have MODY diabetes.

To date, eleven forms of MODY diabetes have been described. This is based on mutations in various genes involved in glucose metabolism. Seven of these genes code for the transcription factors:

  • hepatic nuclear factor (HNF) -1alpha
  • Transcription factor 2 (HNF-1beta)
  • HNF-4alpha (or HNF-4α)
  • insulin promoter factor-1
  • NeuroD / BETA2
  • KLF11
  • Pax4

These genes are in the insulin-producing beta cells of the pancreatic islets expressed and induce mutant state interference organ differentiation, or insulin secretion.

One gene (MODY type 2) codes for glucokinase, an intracellular glucose sensor in the endocrine pancreas and at the same time an important enzyme for glycogen synthesis in the liver.

Depending on the affected gene, further symptoms can be found, for example a lowered kidney threshold for glucose with increased glucosuria , an altered lipid metabolism, as well as kidney cysts and changes in the genital organs.

to form

MODY type 1

  • There are mutations in the transcription factor HNF4a (hepatic nuclear factor 4a), a defective HNF-4α gene on chromosome 20.
  • This protein controls the transcription of genes that are necessary for glucose transport and metabolism as well as for the function of the islet cells. Glycogen synthesis can also be disturbed. As a superordinate transcription factor, HNF4a is also involved in the regulation of the transcription factor HNF1a.
  • Clinically, the hyperglycaemia that occurs is clear and progressive, so that typical diabetes complications can occur over time.
  • Low triglyceride levels are often noticeable.

MODY type 2

  • There are mutations in the glucokinase gene on chromosome 7. Glucokinase is expressed in the islet cells of the pancreas and in the liver. Its job in the liver is to provide glucose-6-phosphate for the formation of glycogen . In the islet cells, glucokinase is part of the body's own glucose sensor system.
  • Mild course, only insulin required in homozygous forms.
  • No evidence of long-term effects on the heart , blood vessels or kidneys , lower disease effects on the retina as in type 2 diabetes mellitus.

MODY type 3

  • There are mutations in the transcription factor HNF1a (hepatic nuclear factor 1a).
  • The HNF1a gene controls the expression of various genes in the liver such. B. the glucose transporter gene and is essential for the transcription of the insulin gene in the pancreas. Mutations in the HNF1a gene lead to a defect in insulin secretion and the resulting progressively limited insulin release.
  • The hyperglycaemia that occurs is clinically significant, so that long-term damage is to be expected.
  • A lowered kidney threshold for glucose is often noticeable.

MODY type 4

  • There are mutations in the insulin promoter factor IPF-1 or in the pancreaticduodenumhomöobox-1 PDX-1. The mutation is found on chromosome 13q .
  • The insulin transcription is disturbed by the defect.
  • Mostly mild course
  • If the expression is homozygous, pancreatic aplasia occurs .

MODY type 5

  • There are mutations in the transcription factor 2 (hepatic nuclear factor 1 beta) (defective HNF-1β gene)
  • The transcription factor 2 regulates the gene transcription of several dozen proteins.
  • The hyperglycaemia that occurs is clinically significant, so that long-term damage is to be expected.
  • Association with kidney defects such as cysts and hypoplasia and with malformations of the genital organs such as vaginal aplasia and uterine hypoplasia.

MODY type 6

  • There are mutations in the NeuroD1 / Beta gene.
  • The NeuroD1 regulates insulin transcription.
  • rare, so far only a few cases have been described.

MODY type 7

  • The causative mutation affects the cripple-like factor 11 (KLF11).
  • This protein acts as a transcription factor.
  • only a few families affected

MODY type 8

  • A change in the gene is responsible for the bile salt dependent lipase (carboxyl-ester lipase; CEL).
  • Above all, this lipase is crucial for the exocrine function of the pancreas, but in the event of a loss of function it also leads to the failure of the endocrine activity of the pancreas.
  • So far only a few affected families have been identified.
  • Homozygous, the mutation leads to pancreatic aplasia.

MODY type 9

  • Mutations in the Pax4 gene lead to this MODY form.
  • Pax4 is an important transcription factor that plays a major role in organ development (including the pancreas).
  • This guy is a rarity.

MODY type 10

  • A certain change in the insulin gene can also cause a MODY (type 10).
  • Only a few individual cases are described.

MODY type 11

  • The responsible gene (BLK) codes for a tyrosine kinase, which is found as a signal protein primarily in B lymphocytes, but also in glandular cells such as those of the pancreas.
  • There are only a few families affected.

MODY type 12

  • The defective gene is ABCC8.

MODY type 13

  • The defective gene is KCNJ11.

Other special forms (neonatal diabetes mellitus)

Unlike the classic MODY, monogenic diabetes mellitus can affect not only adolescents but even newborns. Various other genetic defects are then the cause. These initially include very rare cases of homozygous MODY mutations (e.g. MODY 2 with immediate insulin requirement after birth, MODY 4 and MODY 8 with pancreatic aplasia).

In addition, the above-mentioned (MODY type 12 and 13) gene changes are included, which impair the function of certain potassium channels in the pancreas (KCNJ11 and ABCC8). The latter forms can be treated very well with sulfonylurea supplements.

diagnosis

The patients usually have a normal weight habit, the onset is often insidious. In this form of diabetes, high postprandial (after eating) blood sugar levels are clinically apparent. There is decreased insulin secretion, which is why an impaired oral glucose tolerance test (oGTT) is found in the 1 or 2 hour value. Insulin resistance is typically not found; H. the body's cells respond normally to insulin. Concomitant diseases in the sense of a metabolic syndrome are usually not present. Environmental factors such as lack of exercise and malnutrition do not contribute to the onset of the disease.

Differentiating it from type 1 diabetes mellitus, the most common form of diabetes in children and adolescents, which manifests itself in a slim habit and has to be treated with insulin, presents a particular challenge. MODY begins insidiously, shows mild hyperglycaemia, shows an increase in insulin in the plasma under glucose stress, is not prone to ketoacidosis, has no autoimmune components and responds well to oral antidiabetic agents or the smallest doses of insulin. Insulin autoantibodies are not part of the clinical picture.

Since there are no reliable clinical criteria for differentiation, both biochemical laboratory parameters and a detailed family history must be used for the differential diagnosis.

MODY occurs in families, the mutations can be detected by DNA sequencing ( polymerase chain reaction ).

therapy

literature

  • Helmut Schatz (Ed.): Diabetology compact. 4th edition. 2006, ISBN 3-13-137724-0 .
  • HC Fehmann, MZ Strowski, B. Göke: Maturity-onset diabetes of the young (MODY) - six mutated genes - six diseases with different therapies. In: Deutsches Ärzteblatt. 2004; 101, pp. A860-A867.
  • Richard Daikeler, Götz Use, Sylke Waibel: Diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , pp. 11-16.

Web links

Individual evidence

  1. ↑ Alphabetical directory for the ICD-10-WHO Version 2019, Volume 3. German Institute for Medical Documentation and Information (DIMDI), Cologne, 2019, p. 562
  2. ↑ Anna M. Steele, Beverley M. Shields, Kirsty J. Wensley, Kevin Colclough, Sian Ellard, Andrew T. Hattersley: Prevalence of Vascular Complications Among Patients With Glucokinase Mutations and Prolonged, Mild Hyperglycemia. In: JAMA. 311, 2014, p. 279, doi: 10.1001 / jama.2013.283980 .