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Diabetes mellitus is a condition in which the body does not make enough insulin, called Type 1 diabetes mellitus (T1D), or can not use it properly because the body’s cells are insulin resistant (T2D).

What is diabetes mellitus?

T1D is caused when the immune system, the body’s defense system against foreign intruders like bacteria, and viruses, and against sick cells like cancer cells, by mistake attacks the beta-cells of the pancreatic islets. These are the only cells in the body that produce insulin.

In Type 2 diabetes mellitus (T2D), the cells in the body cannot respond properly to the insulin that is present in the blood stream. This is called insulin resistance and can be caused by high levels of fat and cholesterol in the blood and by hormonal changes that are caused by obesity. Stress can also contribute to insulin resistance. The body reacts with producing more insulin, which is very stressful to the beta-cells. Eventually the beta-cells cannot keep up with the increased demand and blood sugar levels soar.

In pregnancy, the demand of insulin is also increased compared to other times. In women whose beta-cells are already compromised due to a genetic predisposition, this can lead to their failure to be able to satisfy the increased demand and the blood sugar will be high during pregnancy. This condition is called gestational diabetes. After delivery, the blood sugar usually returns to normal levels, but women with gestational diabetes during their pregnancy have an increased risk to develop T2D within the next ten years.

What are the genetic risk factors for Type 1 diabetes mellitus?

Studies with twins and other family members of T1D patients have shown that this disease has a strong genetic component. An identical twin of a T1D patient for example has an up to 30 times higher risk developing the disease than the general population. However, unlike some other conditions where the presence of the disease gene leads to the disease in 100% of the cases, there must be other factors, called environmental triggers, present to cause the disease. Otherwise identical twins of a T1D patient would always get the disease.

What makes the genetics of T1D (and T2D) all the more complicated is the fact that more than one gene contributes to the risk, as is seen from the fact that the risk of identical twins, who share all their genes, to both get the disease is higher than the risk of other sibling pairs.

The most important genetic risk factor is located in an area that contains the genes for the tissue type. People that have the HLA-DR3 gene on one chromosome and the HLA-DR4 gene on the other have the highest risk. The products of these genes are important for the initiation of an immune response and scientists believe that they are responsible for making the immune system susceptible to the erroneous attack on the beta-cells. Other genes that contribute to the T1D risk are the insulin gene itself, and genes for certain messenger molecules in the immune system.

A large study, called the TEDDY-study, which goal is to determine what environmental factors contribute to the triggering of the disease is currently under way in many different laboratories around the world.

What are the genetic risk factors for Type 2 diabetes mellitus?

The genetic basis of T2D is even stronger than the one of T1D, which means that having close family members (like parents and siblings) with T2D is the strongest risk factor for developing the disease.

The exact genes that are responsible for somebody being susceptible to developing T2D are not that well known. However, researchers believe they are responsible for the health of the beta-cells in the pancreas and for the way the cells of the body respond to insulin.

Interestingly, it seems that environmental factors also play a stronger role for the development of T2D than for T1D, as people with a family history of T2D do not develop the disease, if they lead a healthy life style.

Are there other, not genetically controlled risk factors for diabetes mellitus?

Many different environmental triggers for T1D have been suspected since the early 1980s. Baby formula based on cow’s milk was a suspect for a while, but despite the clear evidence that shows various benefits of breast feeding, among which are immune system related ones, like a decreased risk of developing allergies, conclusive evidence for cow’s milk contributing to T1D risk has remained elusive.

Certain virus infections like e.g. the Coxsackie B virus that can cause intestinal infections with nausea, vomiting and diarrhea, are believed to be able to trigger an immune response in susceptible people that does not only eradicate the virus infection, but cross-reacts with the beta-cells of the pancreas, setting a process in motion that can lead to T1D. Since this process consists of many steps, each of which with its own controls and counterbalances, other genetic and environmental factors, many of which not known in detail, need to come together, before the development of overt T1D.

The TEDDY-study (The Environmental Determinant of Diabetes in the Young), that is currently ongoing in many laboratories and countries all over the world follows thousands of children that have certain genetic risk factors from birth, tracking eating habits, infections and other criteria in an effort to decipher environmental triggers of T1D.

In the recent years, T2D has become a major epidemic around the world. The reason for this is not that the genetic risk factors somehow become more frequent in our population, but that our lifestyle makes it more likely to develop the disease. Obesity increases the insulin requirement in all people, as it induces insulin resistance through hormonal changes and through the action of high levels of fats and cholesterol in the blood. The body reacts by producing more insulin to keep up with the increased demand. Obese people with a genetic risk to developing T2D might become insulin resistant at a lower weight than other people making their beta-cells work harder. Additionally, their beta-cells are more sensitive to being over-worked, and eventually they will not be able to provide the insulin needed to keep the blood sugar at healthy levels. Keeping a healthy weight with regular exercise is a very efficient way to prevent the development of T2D, even with a family history of it.

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