5. Differential diagnosis of diabetes type 1, 2 and 3
The clinical pictures of manifest diabetes type 1, 2 and 3 can be confusing. For example: a 15 year old, school going girl must often leave lessons to have a pee. She has difficulty concentrating, which tires her after only a short while. With a BMI of 27, her shape is massive, which she tried to change several times by following various stringent diets. But each time she failed after a while and fell back into excessive eating. And so her size of waist grew instead of slenderizing. Her only younger brother has no diabetic problems and she has no knowledge of any diabetes in the family medical history. How is she to be diagnosed?
Juvenile diabetes (type 1 diabetes) generally develops at an age between 2 and 20 years. Adult-onset diabetes (type 2 diabetes) generally does not manifest itself until middle age (> 40 years). Which explains the names. But in some cases juvenile diabetes does not cause problems until middle age and adult-onset diabetes can sometimes be diagnosed in adolescents (2). Monogenic diabetes (type 3 diabetes) generally becomes manifest at a mature age (20 – 40 years), but it can already develop in young children. And so making a diagnosis based on the age of the patient may lead to problems.
Table 1. Age (in years) at which diabetes
generally becomes manifest
|juvenile diabetes (T1D)|
2 - 20
|monogenic dabetes (MODY) || |
20 - 40
|adult-onset diabetes (T2D) |
Ms J., 57 years old, suffers from thirst and fatigue to an increasing extent. She is no longer able to carry out her work activities as an accountant. The numbers start to dance before her eyes after only a few hours; she cannot concentrate and as the afternoon progresses, she feels dead tired. These symptoms developed gradually over the course of a few weeks. She has difficulty sleeping because of her thirst and because she has to urinate often. During the past week, she has had to drink at least a litre every night. Upon inquiry, it was found that she has always been in good health. According to her, there is no history of diabetes in her family.
She does not appear to be ill, but she does seem severely tired. Her body weight is 63 kg at a height of 1.69 m. Her blood pressure is 125/70 mmHg. What strikes the eye are the vitiligo segments on the back of her hand and lower arm. The peripheral vessels pulsate adequately and there are no heart murmurs. Lab tests confirm the probability of the diagnosis: the fasting plasma glucose level of the blood is 22 mmol/l (normally < 6,1). In view of her age, she is diagnosed with type 2 diabetes and treated with 1 mg of glimepiride per day. After a week, a fasting plasma glucose level of 9 mmol/l is measured. Despite increasing the dosage of glimepiride, the symptoms worsen. When the patient became extremely nauseous and could no longer keep any food or fluids down, she was found to be in ketoacidosis upon being taken to the emergency ward.
In this case, the diagnosis of type 2 diabetes was made too readily based on age alone and was most likely incorrect. If the classic characteristics of type 2 diabetes (family medical history, overweight, high blood pressure and an altered lipids profile in the blood) are lacking, then the diagnosis of type 1 diabetes should be considered. This certainly applies if there are symptoms that point to autoimmunity, as was the case with this patient (vitiligo). The diagnosis can be made by determining the presence of antibodies that target GAD antigens (2).
In juvenile diabetics, the β-cells have been shut down due to an auto-immune reaction. That process of inflammation causes antibodies that target GAD (glutamic acid decarboxylase), an enzyme that helps in the production of insulin (4). So the presence of antibodies that target GAD demonstrates the auto-immune reaction and is therefore evidence of juvenile diabetes. In the case of adult-onset or monogenic diabetes (MODY), an auto-immune reaction against the β-cells does not occur and so the anti-GAD test is then negative.
The blood of juvenile diabetics no longer contains naturally produced insulin because the β-cells in these patients have been shut down (3). In the case of adult-onset and monogenic diabetes on the other hand, the presence of insulin in the blood can be demonstrated. And so, if no external insulin has been administered to a diabetic, then the presence of insulin in the blood is evidence of diabetes type 2 or type 3. Or in other words, the demonstrable presence of naturally produced insulin excludes the diagnosis of juvenile diabetes.
Naturally produced insulin, if any, in patients who are already being treated with synthetic insulin can still be established indirectly. In the natural production of insulin by the β-cells, pro-insulin is split up into equal amounts of insulin and C-peptide (connecting peptide) (3). No C-peptide is formed as part of the production of synthetic insulin. The presence of this substance in the blood therefore points to the production of natural insulin (1). And so a juvenile diabetic who is injected with synthetic insulin, has insulin in his blood but no C-peptide. Alternately, the presence of C-peptide can be demonstrated in those suffering from adult-onset or monogenic diabetes.
The hereditary predisposition for diabetes type 1, 2 and 3 consists of specific gene-mutants in one’s DNA. So a genome analysis will make the differences between these disorders evident. DNA-research is equally essential in the case of monogenic diabetes if one is to come to a precise diagnosis (MODY 1- 6).
The fasting plasma glucose concentration (FPG) and HbA1c fraction of the blood can be routinely determined in any laboratory. A FPG level > 7.0 mmol/l and/or a HbA1c fraction > 53 mmol/mol are an indication of manifest diabetes. Prediabetes is diagnosed on the basis of a FPG > 6.0 mmol/l and/or a HbA1c fraction > 42 mmol/mol. C-peptide and anti-GAD titres are only carried out on special medical grounds. DNA-research is not conducted in an average lab. And so general practitioners usually make the diagnosis of diabetes based on FPG and HbA1c levels in the blood of a patient while the distinction between juvenile, adult-onset and monogenic diabetes usually relies on the age of the patient; because it cannot be routinely based on C-peptide, anti-GAD and/or DNA analysis. However, the mentioned case, taken from the Internal Medicine manual (2), reveals that this procedure is not always justified. And as a consequence, one must critically reconsider the posed diagnosis based on age, if the initial regulation of a diabetic patient encounters problems.
Suppose that blood analysis of the school-girl in the opening paragraph reveals the following (in brackets are normal values):
Hb: 8.0 mmol/l (7.5-10.0)
HT: 0.40 l/l (0.36-0.47);
FPG: 7.0 ! mmol/l (4.0-6.0)
HbA1c: 65 ! mmol/mol (30-42);
C-peptide 0.40 nmol/l (0.26-0.62)
anti GAD65 <3 U/ml (< 35);
DNA research for MODY: no gene-mutants present.
Then the diagnosis should be: adult-onset diabetes (T2D), in spite of her juvenile age.
1. Manifest diabetes is diagnosed on the grounds of a HbA1c fraction > 53 mmol/mol and/or FPG > 7.0 mmol/l.
2. Juvenile diabetics do not produce natural insulin and therefore have no C-peptide in their blood; but they do have antibodies that target GAD.
3. Adult-onset diabetics produce natural insulin and as a consequence they have C-peptide in their blood, but no anti-GAD.
4. The diagnosis of monogenic diabetes (MODY 1- 6) requires DNA research into specific gene-mutants.
5. The age of a diabetic does not offer enough to go on in distinguishing between juvenile, adult-onset and monogenic diabetes.
6. When the initial regulation of a diabetic patient meets with problems, one should reconsider the posed diagnosis based on age.
1. MedicineNet.com (2016). Definition of C-peptide
2. 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 842-843
3. Wikipedia.en (2016) Insulin
4. Wikipedia.en (2016) Glutamate decarboxylase
© Leo Rogier Verberne
Juvenile, Adult-onset and Monogenic diabetes
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