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Diabetes in Humans
type 1, 2 and 3

Leo Rogier Verberne

9. Epidemic

On 1 January 2011, there were 801,000 cases of diabetes known to general practitioners in the Netherlands (7). But a considerable number of diabetics remained undiagnosed. The estimated real number was about one million. In addition, there was an estimated number of 750,000 people with prediabetes. These people are not aware of their condition because the characteristic symptoms of manifest diabetes (excessive thirst and frequent urination) are still lacking. So in 2011, there were altogether nearly 1.8 million people with (pre)diabetes in the Netherlands, being 10% of the population. And their number is increasing every year. With that, diabetes is the no.1 disease and it can be considered an epidemic. Of all manifest diabetics, ± 90% suffers from adult-onset diabetes; an estimated number of 100,000 people deals with juvenile diabetes and about 20,000 humans has some type of MODY.

Rapid expansion
Juvenile diabetes remained limited in patient numbers for centuries because the disease develops between the age of 2-20 and is fatal if not treated with insulin. Thus in the past, patients generally died before having any children and so the deviating genes were scarcely passed along to any offspring. That changed in 1922 after Banting and Best isolated insulin and injected it into children with diabetes. They recovered, grew up and had children. The process of natural selection came to an end and the deviating genes were passed on from one generation to the next. Which is why, since 1922, juvenile diabetes is expanding with each new generation. Moreover, the rise of the percentage of humans with T1D in a population means an increasing chance for a juvenile diabetic to meet another as sexual partner. That enlarges the risk of type 1 diabetes in their children about fourfold: from an average of about 5% with one diabetic parent to ± 20% (3). This explains how inbreeding increases the incidence of T1D in closed populations, as in remote regions or on islands.

Adult-onset diabetes does not usually manifest itself until middle age (over 40 years of age). Thus carriers of these gene-variants in their DNA were always able to pass these genes along to their children. There was no natural selection and the deviating genes spread through the population for centuries. This explains why there are so many people with type 2 diabetes. But it does not explain why the past decades have seen the number of patients increasing more and more quickly. There are 2 reasons for that:
1. As an increasingly larger part of the population becomes a carrier of these gene-variants, there is a growing risk that both parents in a family have this hereditary predisposition. Which considerably increases the risk that the children will develop adult-onset diabetes at a later age as well.
2. Any hereditary predisposition for type 2 diabetes becomes manifest sooner and more often nowadays as a result of over-eating, lack of physical exercise and stress.

MODY(1-10) generally becomes manifest at the age of 10-25 years. The hereditary predisposition is based on one single deviating gene (3) and therefore it is passed on to future generations according to the laws of Mendel (4). Because that gene is dominant, half of the children of a parent with MODY will develop the same disorder. Imagine that in 1920 there were, for example, 2,500 people in the Netherlands with MODY and that they had an average of 4 children (not a lot in 1920). The number of carriers of a deviating gene will then have doubled in the next generation. If counting 30 years for a change of generation, then the number of carriers will have increased to 5,000 in 1950; to 10,000 in 1980 and 20,000 in 2010. Thus type 3 diabetes is also increasing in the population.

In 2011, the costs of diabetes care in the Netherlands came to 1.7 billion Euros (6); and that amount is substantially increasing every year. The costs concern the day to day regulation of 1 million manifest diabetics, their medical control by general practitioners, internists and ophthalmologist; acute complications like severe hypo- or hyper-glycemia that lead to hospitalization, and all kinds of long-term complications. Which occur among more than half of all diabetics and require intensive treatment often causing permanent disability and need of care. And let’s not forget the costs of scientific research. How can these huge costs be restrained and reduced?

1. Sensor-driven insulin pump
Only 20% of the adults with type 1 diabetes in the Netherlands succeed in achieving the present regulation target of HbA1c < 53 mmol/mol (8). This result is even poorer if measured while including diabetic children and it will worsen even more when the target is lowered to HbA1c < 48 mmol/ mol. Yet that is the limit to prevent long-term diabetes complications and the inclusive costs. Careful regulation of this kind is easy with a self-dosing insulin pump, i.e. an automatic pump driven by a glucose-sensor. Which keeps the blood glucose level, during the day and night, below 8.0 mmol/l and the HbA1c fraction below 48 mmol/mol. The research for such a ‘closed-loop’ insulin pump has been underway for many years, but is still not ready for marketing.

2. Screening for prediabetes
Long-term diabetes complications start in the phase of prediabetes. Blood glucose concentrations that damage the inner surface of blood vessels exceed 48 mmol/mol in HbA1c values. So starting in the prediabetic range. Which explains why nearly half of the people that are diagnosed for manifest diabetes (HbA1c >53), already have retinopathy to some degree (2). Atherosclerosis (hardening of the arteries), heart attack and strokes are also correlated to prediabetes. So screening for prediabetes and treatment in that foregoing phase of the manifest disease will help to prevent long-term diabetes complications. People could be selected for that screening on the basis of massive overweight (5).

3. Family planning
Because diabetes type 1, 2 and 3 are genetically based, the prevention lies in large scale DNA-research and family planning. The regular testing of blood from the heel prick in infants could be extended with DNA-research for gene-variants and lead to an extensive data base. The significance of each gene-variant could be evident from that base. Future parents must know the gene-variants they carry in their own DNA and have knowledge of the risk each gene-variant poses for the development of diabetes in their offspring. Thus they can choose for family planning. Because no one wishes a life with diabetes for her or his child.

1. The number of people in the Netherlands with manifest diabetes is over 1 million; moreover, the number of prediabetics is estimated at 750,000 being 10% of the Dutch population combined.
2. The natural selection process for juvenile diabetes has ceased since insulin became available in 1922; since then the hereditary predisposition is expanding within the population with each generation.
3. The hereditary predisposition for adult-onset diabetes is spreading more quickly than ever because deviating genes are more often present in the DNA of both parents; moreover, the predisposition manifests itself sooner as a result of the modern lifestyle.
4. The hereditary predisposition for MODY in one of the parents is passed on to half of the children.
5. A self-dosing insulin pump, driven by a glucose sensor, will prevent both acute complications and the development of complications at a later age.
6. Screening for prediabetes on the basis of overweight followed by early treatment will reduce long-term diabetes complications.
7. Analysis of the blood obtained from the heel prick in babies could be extended with DNA-testing; an extensive database would reveal the significance of each gen-variant.
8. Knowing the gen-variants present in the own DNA offers future parents the opportunity of family planning to reduce birth of diabetic children.

1. DiabetesFonds (2015) Wat is prediabetes?
2. DiabetesFonds (2015) Complicaties van diabetes
3. 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
4. Mendel Gregor (1866) Versuche über Pflanzen-Hybriden
5. Nationaal Kompas Volksgezondheid (2014) Hoeveel mensen hebben overgewicht?
6. Nationaal Kompas Volksgezondheid (2014)
Hoeveel zorg gebruiken patiënten met diabetes mellitus en wat zijn de kosten?
7. RIVM (2013) Meer dan 800.000 mensen met diabetes in Nederland; toename fors
8.Torren CR vd. en Roep BO (2012). Ned Tijdschr Geneeskd. 2012;156:A4268
Immunotherapie voor diabetes mellitus type 1

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© Leo Rogier Verberne