Juvenile, Adult-onset and Monogenic diabetes

diabetes type 1, 2 and 3


Leo Rogier Verberne


8. Heredity and external factors



Genes
Long strands of DNA are present in every nucleus-containing cell. They consist for approx. 1% of genes (1). In humans, each cell nucleus contains approx. 20,000 genes containing the codes for the production of more than 100,000 different proteins (1). Not every deviating gene-mutant causes an illness or disorder: some are the result of a combination of gene-mutants. For example, monogenic diabetes (MODY) is caused by the presence of only one single deviating gene in the DNA that causes diabetes. Juvenile diabetes and adult-onset diabetes on the other hand are based on 19 and 40 different deviating genes respectively, that in part or all combined enable the development of diabetes type 1 or diabetes type 2. All genes, including the deviating mutants, are passed on from one generation to the next.

Juvenile diabetes
With respect to the hereditary predisposition for juvenile diabetes, 19 different deviating gene-mutants can contribute to the actual development of the disease (1). But each of these mutants does not contribute equally. One of them is the HLA-gene (human leucocyte anti-gen) which determines the predisposition for type 1 diabetes for 70% (1). The other 18 each contribute in part to the remaining 30% of the hereditary predisposition. It is not necessary that all 19 gene-mutants are present in the DNA in order to develop juvenile diabetes: the fewer mutants present in the DNA, the later juvenile diabetes will become manifest: the age at which the symptoms develop generally varies between age 2 and 20.

External factors
The development of juvenile diabetes may vary from one individual to another, even if the same genes are present in the DNA. Identical twins, for example, have identical DNA. But if one of them were to develop juvenile diabetes, then this does not mean that the other one will automatically develop diabetes as well: that chance is found to be only 36% (1). And so it takes more than the presence of a number of deviating genes in the DNA alone in order to actually develop type 1 diabetes. Other non-hereditary factors also play a role in the manifestation of the hereditary predisposition. Which is why it is called a ‘multi-factor hereditary disease’. In the case of juvenile diabetes, the gene-mutants contain the code for the production of certain T-lymphocytes that are ‘hostile’ towards the β-cells in the pancreas. Thereafter, external factors initiate the auto-immune reaction (the attack of those T-lymphocytes on the β-cells) as a result of which the β-cells are eliminated. It is still not clear however, which external factors play a role. What is certain, is that type 1 diabetes does not develop if none of the 19 deviating genes for juvenile diabetes are present in the DNA.

Offspring
As the development of juvenile diabetes can depend upon a varying number of 19 deviating genes, the risk that someone will pass the disorder on to his/her children varies between 1 to 10% (1). The risk is 10% if the parent concerned developed diabetes at an early age, i.e. prior to the 11th birthday. Then many of the gene-mutants are present in the DNA. If both of the parents have juvenile diabetes, then the risk for their children is 10 to 25%, depending upon the number of mutants in the DNA of each of the parents (1). Genome analysis detects deviating gene-mutants in DNA (6). But at the moment, in the Netherlands that technology is solely aimed at scientific research in the genetic laboratories and it is not accessible to diabetes research.

Adult-onset diabetes
The tendency to develop adult-onset diabetes is also genetically determined: the family connection is even more evident than it is for juvenile diabetes. Not all of the deviating gene-mutants that are responsible for the development of diabetes type 2 are known as yet, but 40 have been identified (4). How fast or rather how slow the symptoms of the disease will develop and at which age the disorder becomes manifest will mainly depend upon the number and the type of gene-mutants present in the DNA. Thus the TCF7L2-gene (transcription factor 7 like 2-gene) is of great influence (5). The relative significance of the other 39 mutants is yet to be cleared up (4). The risk of developing the disorder for the children of parents with adult-onset diabetes is not yet known (1).

Ethnic differences
The risk of developing adult-onset diabetes is found to be considerably higher for Hindustani, but also for Moroccan and Turkish people, compared to autochthonous Dutch inhabitants (4). Whether more or other gene-mutants play a role in these ethnic differences is not known. In comparing the genetic predisposition of people from various population groups, the role of differences in nutrition, physical exercise, smoking and stress must also be considered because these factors vary considerably between groups and exactly these external factors may trigger the hereditary predisposition for adult-onset diabetes to become manifest. So type 2 diabetes is also a multi-factor hereditary disease. The same applies here: type 2 diabetes does not develop if none of the deviating genes are present in the DNA, irrespective of external factors or the ethnic group involved (2).

Association
Overweight, a lack of physical exercise, smoking and high blood pressure are more often found in adult-onset diabetics compared to people who do not have type 2 diabetes (2,4). This association (statistical correlation) is usually seen as a causal connection, that is to say: it is generally assumed that overweight and an unhealthy lifestyle cause adult-onset diabetes because of the association. That conclusion is incorrect: the association demonstrates that adult-onset diabetes, more than coincidentally, goes hand in hand with overweight and an unhealthy lifestyle. But it does not prove that these external factors are the cause of type 2 diabetes. These factors do facilitate the manifestation of the hereditary predisposition if present. And that explains the association. But people who do not have any of these gene-mutants in their DNA do not develop adult-onset diabetes, not even if they are overweight and have high blood pressure, and not even if they do not get enough exercise and are heavy smokers. Conversely, people who do have all of the bad mutants in their DNA can postpone the development of diabetes by leading a healthy life and avoiding overweight. Nevertheless it is nearly inevitable that they eventually develop adult-onset diabetes.

Monogenic diabetes
Monogenic diabetes (MODY) is the third type of diabetes that is genetically determined. It is caused by the presence of a single deviating gene-mutant in the DNA and it therefore has a different pattern of inheritance compared to juvenile and adult-onset diabetes. There are at least 6 different gene-mutants that qualify as that one deviating gene. And that one is dominant. Thus half of the children will inherit this disorder in a family in which one of the parents has monogenic diabetes (MODY 1- 6) (1). These gene-mutants can be demonstrated by DNA-diagnostics (1,3).

Conclusions
1. Juvenile diabetes is a hereditary disorder that is induced by external factors; but no juvenile diabetes will develop without the presence of a deviating gene-mutant in the DNA.
2. The risk of developing the disorder for children of a parent with juvenile diabetes varies between 1 to 10 %; the risk is 10 to 25% if both parents have juvenile diabetes.
3. Adult-onset diabetes is a hereditary disorder that is induced by external factors; but no adult-onset diabetes will develop without the presence of a deviating gene-mutant in the DNA.
4. The risk of developing the disorder for children of parents with adult-onset diabetes is as yet unknown.
5. Monogenic diabetes (MODY 1- 6) is an hereditary form of diabetes that is caused by one single dominant gene-mutant.
6. The chance of developing the same disorder for children of a parent with monogenic diabetes is 50%.

References
1. Hes FL en Breuning MH. Klinische genetica. In: Interne geneeskunde. eds. Stehouwer, Koopmans en van der Meer. 14e druk (2010); ISBN 978-90-313-7360-4; p 75-97
2. LUMC afdeling endocrinologie (2011). Diabetes mellitus type 2
3. Overzicht van DNA-diagnostiek in Nederland (2015). www.dnadiagnostiek.nl
4. Tack CJ en Stehouwer CDA. Diabetes mellitus. In: Interne geneeskunde. eds. Stehouwer, Koopmans en van der Meer. 14e druk (2010); ISBN 978-90-313-7360-4; p 835-865
5. van Vliet-Ostaptchouk JV (2010). Thesis RU Groningen; ISBN 978-94-6070-015-6;
Revealing the genetic roots of obesity and type 2 diabetes
6. Zeemeijer Ilse. Het FD Ondernemen 20 mei 2015;
Delftse start-up BlueBee ziet grote toekomst in dna-analyse

read more

© Leo Rogier Verberne
ISBN/EAN: 978-90-825495-0-8
www.diabetesbook.org
www.juvenile-diabetes-cure.org


diabetes book Leo Rogier Verberne

Juvenile, Adult-onset and Monogenic diabetes
paperback, 72 pages
price € 14.95
order here