Juvenile, Adult-onset and Monogenic diabetes

diabetes type 1, 2 and 3

Leo Rogier Verberne

9. Epidemic

According to the RIVM (National Institute for Public Health and the Environment), there were 801,000 cases of diabetes known to general practitioners in the Netherlands on 1 January 2011. But a considerable number of diabetics was undiagnosed (8). The estimated real number was about one million. In addition, there was an estimated number of 750,000 people with prediabetes (8). These people are not aware of their condition (1) because the characteristic symptoms of manifest diabetes (excessive thirst and frequent urination) are still lacking. And so there were altogether nearly 1.8 million people with (pre)diabetes in the Netherlands, being over 10% of the population. With that, diabetes is the no.1 disease and, in view of the increasing number of cases every year, can be considered an epidemic. Of the 1 million people with manifest diabetes, approx. 5.5% has juvenile diabetes (type 1) (4); an estimate of 89% suffers from manifest adult-onset diabetes (type 2) and about 5% has a monogenic diabetes (MODY 1- 6) or diabetes type 3 (3). The 57 other types make up a mere ± 0.5% of all manifest diabetics.

Rapid expansion
Juvenile diabetes remained limited in patient numbers for centuries because the disease develops between the age of 2-20 and because it 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 succeeded in isolating insulin from the pancreas of slaughter animals. By injecting this into the children with diabetes, they remained alive and their lives became almost normal. They 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 more and more with each new generation.

Adult-onset diabetes does not usually manifest itself until middle age (over 40 years of age). Thus carriers of these gene-mutants in their DNA were always able to pass these genes along to their children. And so 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 gene-mutants, 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 as well.
2. In the past decades, any hereditary predisposition for type 2 diabetes became manifest sooner and more often as a result of over-eating, lack of physical exercise and stress.

Monogenic diabetes (MODY 1- 6) generally becomes manifest at a mature age (20-40 years). MODY stands for maturity onset diabetes of the young. 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 (5). Because that gene is dominant, half of the children of a parent with type 3 diabetes will develop the same disorder. Imagine that in 1920 there were 5,000 people with the various types of monogenic diabetes in the Netherlands 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 10,000 in 1950; to 20,000 in 1980 and 40,000 in 2010. And so type 3 diabetes is spreading through the population more and more quickly.

In 2011, the costs of diabetes care in the Netherlands came to 1.7 billion Euros (7); and it is substantially increasing every year. The costs concern the day to day regulation of 1 million manifest diabetics, their medical 3-monthly checkups and annual consultations with the ophthalmologist; acute complications like severe hypo- or hyperglycemia that lead to hospitalization and long-term complications which require intensive treatment in more than half of all diabetics and often cause permanent disability and need of care. And let's not forget the costs of scientific research. How can those huge costs be restrained and reduced?

1. Screening for prediabetes
Long-term diabetes complications start in the phase of prediabetes. The toxic threshold value for average plasma glucose that damages the inner surface of blood vessels is in the prediabetic range. Which explains why nearly half of the people that are diagnosed for manifest diabetes, already have retinopathy in some degree (2). Atherosclerosis (hardening of the arteries), heart attack and strokes are also connected to prediabetes. So screening for prediabetes and treatment in that foregoing phase of the manifest disease can partly prevent long-term diabetes complications. People could be selected for that screening on the basis of overweight, for instance on BMI > 25 (6).

2. Sensor-driven insulin pump
Only 20% of the adults with type 1 diabetes succeed in achieving the present regulation target of HbA1c < 53 mmol/mol (9). This result is considerably poorer still if measured while including diabetic children. And that percentage of successful regulation will worsen even more when the target will be lowered to HbA1c < 48. And yet, meticulous regulation of the blood glucose level below that target is the way to prevent both, acute and long-term diabetes complications. 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 concentration, during the day and night, around an average of 7.0 mmol/l and, as a consequence, the HbA1c fraction below 48 mmol/mol. However, such an insulin pump is not yet available although research has been underway for many years.

Family planning
Because diabetes type 1, 2 and 3 are genetically based, the ultimate relief of costs lies in large scale DNA-research and family planning. To that end, parents should know which gene-mutants they carry in their own DNA. Next they must know which risk each gene-mutant poses for the development of diabetes in their offspring.

The blood from the heel prick of infants could be tested for gene-mutants in the DNA. That enables building a large-scale database from which the significance of each mutant will become evident. Imagine that in the coming generation, thanks to the heel prick and DNA research, a husband and wife both know that they each carry a number of gene-mutants for adult-onset diabetes in their DNA. Therefore they dread the development of overt diabetes in the years to come. Then they can opt:
1. to change their lifestyle to keep the blood glucose at a constantly safe level thus delaying the onset of manifest diabetes and preventing long-term complications at a later age and
2. to choose for family planning, for instance by embryo selection, to exclude or reduce the risk of diabetes for their children.
The procedures for embryo selection are burdening. Nevertheless for the future its application on a large scale may be expected,

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 over 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 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 monogenic diabetes in one of the parents is passed on to half of the children; therefore it expands with each new generation.
5. Blood from the heel prick of infants could be tested for gene-mutants in the DNA, offering the opportunity of family planning.
6. Screening for prediabetes on the basis of overweight and early treatment will reduce long-term diabetes complications.
7. A self-dosing insulin pump, driven by a glucose sensor, will prevent both acute and long-term diabetes complications.

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. LUMC afdeling endocrinologie (2011) Diabetes mellitus type 1
5. Mendel Gregor (1866) Versuche über Pflanzen-Hybriden
6. Nationaal Kompas Volksgezondheid (2014) Hoeveel mensen hebben overgewicht?
7. Nationaal Kompas Volksgezondheid (2014) Hoeveel zorg gebruiken patiënten met diabetes mellitus en wat zijn de kosten?
8. RIVM (2013) Meer dan 800.000 mensen met diabetes in Nederland; toename fors
9.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
ISBN/EAN: 978-90-825495-0-8

diabetes book Leo Rogier Verberne

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