2. Various causes of diabetes mellitus
Diabetes mellitus is a group of metabolic diseases characterized by an increased blood glucose level (hyperglycemia) resulting from defects in insulin secretion, insulin action, or both (1). Insufficient insulin secretion is brought about when the β-cells in the pancreas function poorly or no longer function at all. If there is a shortage of insulin, then the organs absorb less or no glucose from the blood, which increases the blood glucose level. Chronic hyperglycemia of diabetes is associated with long-term damage and dysfunction of different organs, especially the eyes, kidneys, nerves, heart and blood vessels. The World Health Organization (WHO) distinguishes between 60 different disorders that can cause hyperglycemia (5).
On 1 January 2011 there were 801,000 cases of diabetes known to general practitioners in the Netherlands, according to a report by the RIVM (National Institute for Public Health and the Environment) (8). Moreover it was estimated that 25% of all diabetics were yet to be diagnosed. So the actual number of patients at that time amounted to more than one million. In a country with 16,6 million inhabitants this means 6% of the population. And an additional 87,000 new cases came about in the course of 2011 (8), which means that the total number of manifest diabetics was still growing.
Of all the people with manifest diabetes, ± 5.5% have juvenile diabetes or diabetes type 1 (6). Derailed T-lymphocytes attack the body’s own β-cells in the pancreas instead of foreign intruders. Which is called an auto-immune reaction. When the β-cells have been shut down, the blood glucose level is no longer monitored and the production of insulin ceases. If left untreated, glucose can no longer be absorbed by the organs due to a lack of insulin and the blood glucose level increases tremendously as a consequence. The disorder is fatal within a few months unless external insulin is injected daily. Juvenile diabetes develops at an average age of 11 or 12 years (2-20) (9). Which explains the name. But in some cases it does not manifest
itself until the adult age. Therefore it is also named type 1 diabetes.
An estimated 89% of all manifest diabetics has adult-onset diabetes (diabetes type 2). In this case, the functioning of the β-cells decreases slowly due to a degeneration process. Deposits of amyloid are formed in the islets of Langerhans (2). The relevance of this for the development of the disease is not clear. The degeneration process progresses insidiously (7) and, as a result, the insulin level in the blood decreases very slowly, causing a dragging rise of the blood glucose level over years. It is not until the kidney threshold for glucose is exceeded that the classic symptoms of diabetes (excessive thirst and frequent urination) manifest themselves. And so it takes generally 6 years or more until adult-onset diabetes becomes manifest (8). Thus insulin is present in type 2 diabetics, but not enough to keep the blood glucose level sufficiently low. Physical exercise can help to open up the glucose gates in the organ membranes, which reduces the blood glucose level. Adult-onset diabetes usually does not become manifest until middle age (> 40 years). Which explains the name. But sometimes adolescents develop it as well, and that is why it is preferably referred to as type 2 diabetes.
Approx. 5% of all diabetics in the Netherlands have monogenic diabetes. This third type of diabetes often does not develop until one reaches a mature age (20-40 years) and is therefore referred to as MODY (Maturity Onset Diabetes of the Young). It is distinguished from juvenile and adult-onset diabetes through its alternate pattern of inheritance: the genetic profile contains only one single deviating gene. But that gene is not always the same: at least 6 different gene-mutations can single-handedly cause this type of diabetes (3). If the hereditary deviation is in the glucokinase-gene, then this leads to a mild form of diabetes that is called MODY 2. A deviating mutation in the gene HNF-1α causes MODY 3, which has a more serious course of the illness (3). Sometimes monogenic diabetes affects even young children (4). Which is why the name MODY is confusing and it might be better referred to as diabetes type 3 .
DNA-research is required for the differential diagnosis of MODY types 1- 6. And with that, the distinction between monogenic diabetes and juvenile or adult-onset diabetes will become evident as well. Since 2015 it is possible to draw up a complete genetic profile (gene-passport) in the Netherlands (10). But for the time being, that service is only available for scientific research into hereditary forms of cancer. Yet diabetes types 1, 2 and 3 are also determined by heredity and they occur more frequently. And so, the determination of the gene-passport should become available for research into diabetes.
Other forms of diabetes
The 57 other forms of diabetes collectively make up a mere ± 0.5% of the Dutch diabetics. In these cases, the increased blood sugar level is often secondary to, for example, pancreatic cancer or an inflammation (pancreatitis), or it is resulting from alcoholism. The pancreas is damaged by the primary disease and β-cells subsequently shut down. Large doses of corticosteroids (stress hormones) or progesterone (pregnancy hormone) may also be the cause of diabetes as these hormones increase the blood glucose level. Gestational diabetes is the most frequently occurring in this group. Thus the ‘other forms of diabetes’ comprise a heterogeneous group of disorders that lead to an increased blood glucose concentration.
1. Juvenile diabetes (type 1 diabetes) causes ± 5.5% of the manifest diabetes in the Netherlands.
2. Adult-onset diabetes (type 2 diabetes) is the cause of manifest diabetes in approx. 89% of the Dutch patients.
3. Monogenic diabetes (type 3 diabetes) is responsible for approx. 5% of the cases.
4. The 57 remaining diabetic disorders collectively comprise only a fraction (± 0.5%) of the diabetes patients in the Netherlands.
5. Juvenile diabetes develops as a result of an auto-immune reaction in the pancreas that shuts down the β-cells.
6. In adult-onset diabetes, the functioning of the β-cells decreases due to a degeneration process.
7. Monogenic diabetes has a varied clinical picture and requires DNA-research for a precise diagnosis (MODY 1-6).
1. American Diabetes Association (2010). Diabetes Care Jan. 2010; vol. 33 supplement 1; S62-S69.
Diagnosis and classification of diabetes mellitus
2. Hayden MR and Tyagi SC (2001). "A" is for Amylin and Amyloid in type 2 diabetes mellitus
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. Koning E de (2011). MODY: veel diabetes binnen één familie. Bloedsuiker 26e jaargang nummer 2; p 10-11
5. International Expert Committee (2009). Diabetes Care July 2009; vol. 32 no. 7; p 1327-1334;
Report on the role of the A1C assay in the diagnosis of diabetes
6. LUMC afdeling endocrinologie (2011). Diabetes mellitus type 1
7. LUMC afdeling endocrinologie (2011). Diabetes mellitus type 2
8. RIVM (2013). Meer dan 800.000 mensen met diabetes in Nederland; toename fors
9. 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
10. Zeemeijer Ilse (2015). Het FD Ondernemen 20 mei 2015. Delftse start-up BlueBee ziet grote toekomst in dna-analyse
© Leo Rogier Verberne
Juvenile, Adult-onset and Monogenic diabetes
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