Juvenile, Adult-onset and Monogenic diabetes

diabetes type 1, 2 and 3


Leo Rogier Verberne


4. Diabetes and prediabetes



The diagnoses of manifest diabetes and prediabetes, require measuring the blood glucose level. To that purpose serve the measurement of FPG, 2HPG and HbA1c.

FPG (fasting plasma glucose concentration)
After a period of fasting, defined as no caloric intake for at least 8 hours, patients suffering from manifest diabetes have a FPG (fasting plasma glucose concentration) > 7.0 mmol/l (6). In those patients the glucose concentration surpasses 11.0 mmol/l (the kidney threshold) during the day and thus they develop the classic symptoms of manifest diabetes like frequent urination and excessive thirst.
FPG values from 6.1 up to and including 7.0 mmol/l are distinctive for prediabetes (table 2). That is the foregoing phase of manifest diabetes type 2 (3). Herein the kidney threshold is not exceeded and thus prediabetics have no extra production of urine and no increased thirst. Unfortunately, the results of FPG testing have a considerable variability between 12–15% (6).

Prediabetes foregoes adult-onset diabetes (3). However, when diagnosed in a younger person, it might as well point to the coming of juvenile diabetes. But the transitional phase between normal blood glucose values and levels characteristic of manifest juvenile diabetes is only a few weeks; while that period lasts for 6 or more years in adult-onset diabetes. And so if a FPG level is found between 6.0 and 7.0 mmol/l, it nearly always indicates an adult-onset prediabetic.

2HPG (2 hours plasma glucose concentration)
Manifest diabetes and prediabetes can also be diagnosed by an oral glucose-tolerance test. After fasting, FPG is measured. Then the concerning patient has to drink a 75 gram glucose solution. After that the course of the blood glucose level is tested at regular intervals (7). In a healthy subject, the highest plasma glucose level is reached about one hour after drinking the solution and the blood glucose concentration returns to its starting level after approx. two hours. Next the level drops a bit more and after a while it returns to its initial level (figure 1, red curve). The green curve belongs to a prediabetic. His preliminary FPG level is in this case 6.8 mmol/l. Two hours after drinking the glucose solution, the maximum blood level of 10.5 mmol/l is reached, remaining under the kidney threshold. Five hours from the start, the blood glucose concentration has not yet returned to its starting level (figure 1).

glucose-tolerance test

Figure 1. Oral glucose-tolerance test in a healthy subject (red) and in someone with prediabetes (green) (5)

In a 75 gram oral glucose-tolerance test, the 2 hours plasma glucose concentration (2HPG) of 11.1 mmol/l is the diagnostic cut-off point for manifest diabetes. This has been considered the gold standard for the diagnose of diabetes for a long time. Results of the testing from 7.8 up to and including 11.0 mmol/l indicate impaired glucose tolerance or prediabetes. But the performance and interpretation of the test proved to be inconsistent, making the results less reliable (6).

HbA1c
To determine the average blood glucose concentration over a longer period of time (weeks, months), the glycated fraction of the hemoglobin (HbA1c) is measured. Blood glucose penetrates the red blood cells and attaches to hemoglobin. The degree of glycation is in proportion to the average plasma glucose level: the higher the level, the greater the fraction of Hb converted into HbA1c. And once glycated, it will remain HbA1c (6). The life time of red blood cells is ± 4 months. So the HbA1c fraction reflects the average plasma glucose level (APG) over a 2 to 3 month period of time.

Table 1. HbA1c fractions (old and new units) and
average plasma glucose concentrations (8)

HbA1c

% (old)

HbA1c

mmol/mol (new)

average plasma glucose

mmol/l
A 5.0 30 5.4
5.5 35 6.2
6.0 40 6.9
6.2 42 7.2

B 6.3 43 7.3
6.8 48 8.0
7.0 50 8.2
7.3 53 8.6

C 7.4 54 8.7
8.0 60 9.6
8.5 65 10.2
9.0 70 10.9

A: normal range; B: prediabetes C: manifest diabetes
(bold: toxic glucose threshold value);

Red blood cell turnover
The HbA1c fraction depends not only on the average plasma glucose level; it partly depends on red blood cell turnover and hemoglobin concentration. The Hb values change for instance during pregnancy and after the use of EPO; after blood transfusion, blood loss and during anemia (for example due to an iron shortage or old age). In those special cases, the FPG or/and 2HPG tests should be preferred over the HbA1c assay. Nevertheless the variability of HbA1c is < 2% while there is 12-15% variation in FPG test results (6).

Diagnosis
Based on an extensive review and epidemiological evidence, the ADA (American Diabetes Association) accepted the relationship between average plasma glucose (APG) levels and the presence of moderate retinopathy as the basis for the diagnosis of diabetes (1,6). APG and, as a consequence, HbA1c fractions correlate well with microvascular complications like retinopathy and, to a lesser extent, with macrovascular complications. The occurrence of retinopathy increases almost linearly with HbA1c fractions (figure 2). The inflection point in the diagram is 6.8% (48 mmol/mol) which is taken by ADA as the threshold for the diagnosis of diabetes (1).

Figure 2. HbA1c and diabetic retinopathy (6) HbA1c and retinopathy

HbA1c values are expressed here as % (old unit); the new unit for HbA1c is mmol/mol (8)

Regulation
In patients with a HbA1c fraction of 53 mmol/mol (7.3%), being the threshold for manifest diabetes, the prevalence of moderate retinopathy is about 5% (figure 2). However, nearly half of the patients with that HbA1c level has such eye problems in a lighter degree (2). Therefore the current target value for the regulation of diabetes, being HbA1c < 53, would be safer if adjusted to < 48 mmol/mol.

Normal HbA1c
The HbA1c value 48 mmol/mol is not the dividing line between normal glycemia and diabetes: people with HbA1c values 42 - 48 mmol/mol (6.2 – 6.8%) can also develop diabetic retinopathy, be it in a low percentage (figure 2). With HbA1c < 42 mmol/mol (< 6.2%) the incidence of retinopathy is nearly zero (figure 2). Which is arbitrarily chosen as the upper limit for normal HbA1c values (table 1).

Table 2. Diagnostic criteria for prediabetes and manifest diabetes

Measurement unit

Prediabetes

Manifest diabetes

HbA1c mmol/mol

> 42

> 53

FPG mmol/l

> 6.0

> 7.0

2HPG mmol/l

> 7.8

> 11.0


HbA1c : glycated hemoglobin; FPG: fasting plasma glucose level
2HPG: 2-hours plasma glucose (in an oral glucose-tolerance test)

Conclusions
1. With fasting plasma glucose (FPG) concentrations prediabetes is diagnosed by FPG > 6.0 mmol/l; cut point for manifest diabetes is > 7.0 mmol/l.
2. In an oral glucose-tolerance test a 2 hours plasma glucose concentration or 2HPG > 7.8 mmol/l means prediabetes and > 11.0 means manifest diabetes.
3. The glycated hemoglobin fraction (HbA1c) represents the average plasma glucose concentration over the foregoing 2 to 3 months; HbA1c > 42 mmol/mol points to prediabetes and > 53 mmol/mol means manifest diabetes.
4. HbA1c, FPG and 2HPG are related to long-term complications; the incidence of diabetic retinopathy increases almost linearly with rising HbA1c values starting from 48 mmol/mol.
5. In nearly half of the diabetes type 2 patients, some retinopathy is already present when manifest diabetes is diagnosed; so it is apparently caused by prediabetic blood glucose concentrations.

References
1. American Diabetes Association (2010). Diabetes Care Jan. 2010; vol. 33 supplement 1; S62-S69
Diagnosis and classification of diabetes mellitus
2. Diabetes Fonds (2015) Complicaties van diabetes
3. Diabetes Fonds (2015). Wat is prediabetes?
4. Guyton AC and Hall JE. Insulin, glucagon and diabetes mellitus. In: Textbook of Medical Physiology 12th ed.(2011); ISBN 978-1-4160-4574-8; p 939-954
5. Haalboom JRE. Diabetes mellitus. In: Leidraad farmacotherapie. (2011); ISBN 90-313-4211-4; p 101-112
6. 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
7. Scal Medische Diagnostiek (2015). GTT (glucose tolerantie test)

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© Leo Rogier Verberne
ISBN/EAN: 978-90-825495-0-8
www.diabetesbook.org
www.juvenile-diabetes-cure.org


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Juvenile, Adult-onset and Monogenic diabetes
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