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Diabetes in Humans
type 1, 2 and 3


Leo Rogier Verberne


4. How to diagnose Prediabetes and Manifest diabetes

Numerous people in the western world are overweight. In many cases, adult-onset diabetes or prediabetes plays a causative role. An insulin level that is too low causes a diminished intake of glucose into the brain, resulting in increased appetite. Which is, in fact, pathologic. But most prediabetics feel fit: they rather look like Burgundians. How can, among all men and women with overweight, the prediabetics be diagnosed?

FPG
Before breakfast, the normal blood glucose concentration in humans is between 4.0 and 6.0 mmol/l. That is called the FPG (Fasting Plasma Glucose level). Patients suffering from manifest diabetes have a FPG > 7.0 mmol/l (6) and their blood glucose level during the day surpasses 11.0 mmol/l (the kidney threshold). Then the kidneys secrete glucose in the urine. Thus the classic symptoms of manifest diabetes are: frequent pees of great quantities of urine and excessive thirst. Repeated FPG values > 6.0 up to and including 7.0 mmol/l are distinctive for prediabetes (table 1). That is the foregoing, ‘silent’ phase of manifest adult-onset diabetes (4). The kidney threshold is not exceeded so that prediabetics have no extra production of urine nor increased thirst. Unfortunately, the results of FPG tests have a considerable variability between 12 – 15% (7).

Table 1. Diagnostic criteria for Prediabetes and Manifest diabetes

Measurement unit

Prediabetes

Manifest diabetes

FPG mmol/l

> 6.0

> 7.0

2HPG mmol/l

> 7.8

> 11.0

HbA1c mmol/mol

> 42

> 53


FPG: fasting plasma glucose level
2HPG: 2-hours plasma glucose level
HbA1c: glycated hemoglobin fraction

2HPG
Prediabetes can also be diagnosed by an oral glucose-tolerance test. After fasting, FPG is measured. Then a 75 gram glucose solution has to be swallowed. After that, the course of the blood glucose level is tested at regular intervals (9). In non-diabetic subjects, the highest plasma glucose level is reached about one hour after drinking the solution (figure 1 red curve). The blood glucose concentration returns to its starting level in approx. two hours. That is the 2HPG (2 Hours Plasma Glucose level). Next, the level drops a bit more and after a while it returns to its initial level. The 2HPG is considered the cut-off point for manifest diabetes.

glucose-tolerance test

Figure 1. Oral glucose-tolerance test in a healthy subject (red curve)
and in a prediabetic (green curve); the 2HPG is conclusive (5)

In case of manifest diabetes, the 2HPG will surpass 11.0 mmol/l. 2HPG values from 7.8 up to and including 11.0 mmol/l are indicative of prediabetes (table 1). The green curve (figure 1) has a preliminary FPG level of 6.8 mmol/l. After drinking the glucose solution, the 2HPG is 10.5 mmol/l. So the diagnosis in this case is ‘prediabetes’. However, the results of the oral glucose-tolerance test proved to be inconsistent (6). A 2-hours postprandial level (2 hours after lunch) can be used instead (8).

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. Glucose in the plasma penetrates the red blood cells and attaches itself to hemoglobin. The degree of glycation is in proportion to average plasma glucose levels. The higher the blood glucose level, the greater the fraction of Hb converted into HbA1c. And once glycated, it remains HbA1c. The variability of the test is < 2% (7). The life time of human red blood cells is 4 months and so the HbA1c fraction reflects the average plasma glucose level over a 2 month period of time.

Table 2. 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 values

Hemoglobin
The glycated hemoglobin fraction (HbA1c) depends not only on the average plasma glucose level but also on changes in the hemoglobin concentration. When the Hb concentration increases, for example during pregnancy or after EPO injections, HbA1c values decrease, while the plasma glucose level remains unchanged. When the Hb concentration decreases, for example by blood loss or (iron deficiency) anemia, HbA1c values increase. In such cases, FPG or 2HPG values should be preferred over HbA1c fractions. But in normal cases, the international expert committee report on the role of the HbA1c assay in the diagnosis of diabetes (7) prefers the HbA1c assay as the most reliable test. However, the Dutch NHG-Standaard (guideline for general practitioners) prefers FPG and 2HPG tests over the HbA1c assay for the diagnosis of diabetes (8).

Diabetic eye problems
Depending on the portion of carbohydrates in the daily diet, normal HbA1c values in human blood (group A in table 2) vary from 20 to 42 mmol/mol. In manifest diabetes (group C), HbA1c values are over 53 mmol/mol and can even rise up to 120 mmol/mol in severe cases (10). Values from 43 up to and including 53 mmol/mol (6.1-7.0%) are an indication of prediabetes (table 1 and 2). HbA1c fractions correlate well with microvascular complications like diabetic retinopathy. Its occurrence increases almost linearly with HbA1c fractions (figure 2). In 28,000 subjects aged 20-79 years from 9 countries there was no prevalence of moderate diabetic retinopathy if HbA1c was below 6.0% (42 mmol/mol) (7).

Figure 2. HbA1c and moderate diabetic retinopathy (7) HbA1c and retinopathy

HbA1c is expressed as % (old unit); the new unit is mmol/mol

The inflection point in the diagram is 6.5% (48 mmol/mol). That point is considered by the ADA (American Diabetes Association) as the threshold for the diagnosis of diabetes (1): HbA1c up to 6.5% (48 mmol/mol) is considered as normal, higher values mean diabetes mellitus and should be treated to avoid microvascular complications.

Conclusions
1. With fasting plasma glucose concentrations (FPG), prediabetes is diagnosed by FPG > 6.0 mmol/l; cut-off 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 months;
HbA1c > 42 mmol/mol points to prediabetes and > 53 mmol/mol means manifest diabetes.
4. The prevalence of moderate diabetic retinopathy increases almost linearly with rising HbA1c values, starting from 48 mmol/mol(6.5%);
that value is the threshold for the diagnosis of diabetes in America.

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.co.uk (2017). Convert HbA1c to Average Blood Sugar Level
3. Diabetes Fonds (2015) Complicaties van diabetes
4. Diabetes Fonds (2015). Wat is prediabetes?
5. Guyton AC and Hall JE. Insulin, glucagon and diabetes mellitus
In: Textbook of Medical Physiology 12th ed.(2011); p 939-954;ISBN 978-1-4160-4574-8
6. Haalboom JRE. Diabetes mellitus In: Leidraad farmacotherapie (2011)
ISBN 90-313-4211-4; p 101-112
7. 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
8. NHG-Standaard. Diabetes mellitus type 2 (derde herziening 2013)
9. Scal Medische Diagnostiek (2015). GTT (glucose tolerantie test)
10 Tack CJ en Stehouwer CDA. Meting van het geglyceerd hemoglobine
In: Interne geneeskunde. eds. Stehouwer, Koopmans en van der Meer. 14e druk (2010);
ISBN 978-90-313-7360-4; p 846

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© Leo Rogier Verberne
ISBN/EAN:978-90-825495-4-6
www.diabetesbook.org


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