The clinical laboratory plays a central role in diabetes mellitus diagnosis, which is based on two parameters: glycated hemoglobin (HbA1c) and blood glucose.

In the presence of typical symptoms of the disease (polyuria, polydipsia, and weight loss), the diagnosis of diabetes mellitus relies on the finding, even on one occasion, of random blood glucose ≥200 mg/dL (regardless of food intake).

In the absence of typical symptoms of the disease, the diagnosis of diabetes mellitus relies on the finding, confirmed on at least two different occasions, of:

– Fasting blood glucose ≥126 mg/dL (fasting means at least 8 h without food)

– Blood glucose ≥200  mg/dL 2 h after oral glucose tolerance test (OGTT) (performed with 75 g)

– HbA1c ≥48 mmol/mol (6.5%)

For diagnostic and screening purposes, blood glucose should be measured in the plasma.

The use of a glucometer is not recommended because it generates non-standardized measurements.

The following measurements are not helpful for the diagnosis of diabetes:

– Postprandial blood glucose or glycemic profile

– Insulinemia measured at basal or during OGTT

– C-peptide 

– Autoantibodies

In addition to diabetes, other states of dysglycemia are known. The following values of the main glycemic parameters are considered worthy of attention because they identify individuals at risk for diabetes and cardiovascular diseases:

– Fasting blood glucose of 100–125 mg/dL (impaired fasting glucose, IFG)

– Blood glucose of 140–199 mg/dL 2 hours after OGTT (impaired glucose tolerance, IGT)

– HbA1c of 42–48 mmol/mol (6.00–6.49%)

In subjects with IFG and/or IGT or HbA1c of 42–48 mmol/ mol (6.00–6.49%), other diabetes risk factors (obesity, family history of diabetes, etc.) should be investigated to plan an intervention to reduce the risk of the disease. In these subjects, it is also appropriate to search for any other cardiovascular risk fac tors (dyslipidemia, hypertension, etc.) to define the overall cardiovascular risk and initiate appropriate therapeutic measures.

In subjects with IFG, especially with other diabetes risk factors, it is helpful to perform the OGTT. Moreover, metabolic syndrome is associated with high risk of diabetes.

OGTT is performed by administering to the patient 75 g of glucose dissolved in 300 mL of water; blood glucose sampling must be performed before glucose solution (basal glycemia) and 2 h after the solution administration (Table 1).

Table1. Interpretation of the oral glucose tolerance test

Glycated hemoglobin is a more practical and reliable parameter than blood glucose; indeed, it has less pre- analytical instability than blood glucose, does not require preparation (e.g., fasting), and is not affected by acute events. The pre-analytical instability of glycemia is due to the in vitro glycolysis in red blood cells after blood sampling, causing a false reduction in blood glucose values. This phenomenon, defined as pseudo-hypoglycemia, can be avoided by centrifuging the samples immediately after the drawing or can be strongly limited by collecting blood in tubes pretreated with an anti-glycolytic solution.

There is ` hemoglobin and fasting or 2 hours blood glucose levels. This may be partly due to laboratory variability but also, to some extent, could reflect different physiological processes. It is, therefore, plausible that a subject may have diagnostic blood glucose values for diabetes and nor mal glycated hemoglobin values, or vice versa. For this rea son, an altered test must be confirmed by repeating the same test. If the patient has two different tests (i.e., fasting blood glucose and glycated hemoglobin) that agree, then a diagnosis can be made without further tests; if, instead, the patient has two different and discordant tests, then it is advisable to repeat the altered test and make the diagnosis based on this result.

Glycated hemoglobin has some limits because some clinical conditions, both physiological and pathological, can alter its levels, leading to false results (Table 2).

Table2. Conditions associated with altered glycated hemoglobin levels

In these cases, it is possible to measure glycated albumin, which reflects the albumin glycation and is indicative of blood glucose in the 15–20 days before sample collection. Therefore, glycated albumin is a midterm indicator of blood glucose, earlier than glycated hemoglobin, which reflects blood glucose over the previous 35–45 days. Glycated albumin can also be used in poorly compensated diabetes, gestational diabetes, postprandial hyperglycemia, fluctuating diabetes, gastrectomy because provides information on the medium- to short-term glycometabolic compensation status.

The appropriate differential diagnosis of diabetes mellitus has important prognostic and therapeutic implications (Table 3).

Table3. Differential clinical features of type 1 and type 2 diabetes mellitus

The clinical picture is often sufficient for differentiating between type 1 and type 2 diabetes mellitus; however, in some cases, it may be necessary to assess autoimmunity bio markers (insulin autoantibodies (IAAs), GAD autoantibody (GADA), tyrosine phosphatase-related islet antigen 2 (IA-2), ZnT8) and β-cell secretion. A modest percentage of patients initially diagnosed as type 2 diabetes mellitus is affected by LADA. According to the clinical criterion, such patients are classified as type 2 diabetes mellitus and begin treatment based on diet and oral hypoglycemic agents. However, they progressively manifest β-cell function deterioration up to insulin therapy is required. Clinically, LADA should be suspected if one or more of the following features are present:

– Age <50 years

– Body mass index (BMI) <25  kg/m2

– History of autoimmune diseases, type 1 diabetes or auto immune diseases family history

– The need for insulin therapy within 6–12 months of diagnosis

However, age of onset >50 years and obesity should not lead to a priori exclusion of the LADA diagnosis when the other criteria are met.

Practical diagnostic tests to confirm LADA clinical suspicion are:

– Biomarkers of autoimmunity (autoantibodies)

– β-cell function assessment by C-peptide

The antibodies evaluated in clinical practice are: 

– Islet cell antibodies (ICAs): antibodies directed against pancreatic islet cells that bind various islet cell proteins. They have been the gold standard for more than 15 years, but due to the complexity of the analysis, their use is now limited.

– Glutamic acid decarboxylase autoantibodies (GADAs): autoantibodies directed against glutamic acid decarboxylases but not specific to β-cells because these enzymes are present in other organs, such as the brain. GADA is a very early marker.

– Tyrosine phosphatase-related islet antigen 2 (IA-2) anti bodies: IA-2 is a transmembrane protein in the secretory granules of endocrine cells, where it is involved in insulin secretion.

– Insulin autoantibodies (IAAs): insulin is the only antigen highly specific for β-cells. These antibodies are detected in approximately 50% of pediatric patients with type 1 diabetes.

– Zinc transporter 8 autoantibodies (ZnT8): ZnT8 is a membrane protein of insulin-containing secretory gran ules. It is a very early and specific marker. These autoantibodies have been observed in 26% of DM1 patients previously classified as antibody-negative.

Table 4 shows when the measurement of antibodies is appropriate.

Table4. Conditions in which autoantibodies measurement is indicated

C-peptide should be measured after glucagon stimulation or a mixed meal. Testing after glucagon stimulation should be performed on fasting. It consists of blood collection at basal and after 6 min following endovenous injection of 1 mg glucagon. C-peptide values <0.2 nmol/L at baseline or < 0.6 nmol/L after stimulation indicates severe insulin secretion deficit and the need for insulin treatment. Blood glucose values >180 mg/dL contraindicate the execution of the test, as the resulting hyperstimulation of the cell would induce an insulin secretion overestimation. The test is helpful for the diagnostic and prognostic framing of cases of uncertain classification. However, it is not the only criterion to guide the therapeutic choice. Concerning MODY, the clinical criteria are:

– Age of onset <25 years

– Metabolic control maintained without insulin for more than 2 years

– Autosomal dominant inheritance (at least three generations of subjects affected by diabetes in the family pedigree)

– Absence of autoimmunity

A strong clinical suspicion of MODY requires the detection of the underlying genetic defect. The appropriate diagnosis of MODY is essential for the prognostic evaluation and family screening.

Concerning gestational diabetes, it is essential to distinguish between gestational diabetes and overt diabetes diagnosed in pregnancy. Pregnant women’s normal fasting blood glucose reference value is <92 mg/dL. A fasting glycemia ≥126 mg/dL during the first trimester indicates overt diabetes; instead, a fasting glycemia between 92 and 125 mg/dL indicates gestational diabetes. If fasting glycemia is <92 mg/ dL, based on the evaluation of the specific risk factors, the pregnant should undergo an OGTT between the 24th and 28th weeks of gestation, in the case of moderate risk, or between the 16th and 18th weeks in the case of high risk, and if OGTT is negative, it should be repeated between the 24th and 28th weeks (Fig. 1).

Fig1. Diagnostic algorithm for gestational diabetes mellitus. (Copyright EDISES 2021. Reproduced with permission)

Moderate risk factors for GDM (OGTT at 24–28 weeks) are:

– Positive family history of diabetes in first-degree relatives

– Previous gestational diabetes (even if normal screening at 16–18 weeks)

– Fetal macrosomia in previous pregnancies

– Overweight or obesity (BMI ≥25  kg/m2)

– Age ≥35 years

– High-risk ethnic groups (South Asia, Middle East, and Caribbean)

High risk factors for GDM (OGTT at 16–18 weeks) are:

– Obesity (BMI ≥ 30 kg/m2

– Previous gestational diabetes mellitus

– Fasting blood glucose of 100–125 mg/dL at the beginning of pregnancy or in the past

In pregnancy, an OGTT should be performed as in the general population; therefore, 75 g of glucose dissolved in 300 mL of water, but blood glucose sampling should be measured at basal (on an empty stomach), i.e., before glucose solution administration, after 1 hour, and 2 hours (Table 5).

Table5. Oral glucose tolerance test in pregnancy

Women with GDM should be screened for diabetes mellitus 2 by performing a classic OGTT with 75 g glucose after 6 weeks and within 6 months of childbirth. If the test is negative, then the OGTT should be repeated every 3 years; if impaired glucose tolerance (IFG or IGT) is found, then the test should be repeated every year.

Once the diagnosis of diabetes mellitus (any form) has been made, the initial assessment of the patient must include a complete medical examination aimed at defining the general clinical conditions, focusing on any possible chronic complications, through laboratory and instrumental tests. In particular, the initial assessment of a patient with diabetes mellitus is based on:

– Family history

– Physiological history (physical activity practiced, life style, etc.)

– Pathological history

– Physical examination

– Laboratory tests: fasting lipid profile, including total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol; liver function tests and any further investigations, if steatosis or hepatitis is suspected; urinary albumin in all patients with type 2 diabetes and type 1 diabetes with disease duration >5 years; creatininemia (in children only in the presence of proteinuria) and estimated glomerular filtration; in patients with type 1 diabetes at diagnosis: screening for autoimmune thyroiditis and celiac disease; anti-insulin and/or anti-GAD and/or anti-IA-2 and/or anti-ZnT8 autoantibodies for the correct classification of the type of diabetes; and urine test to evaluate ketonuria, proteinuria, and sediment

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المزيد

مواضيع ذات صلة

ultrasound of the thyroid (US Thyroid, Thyroid echogram, Thyroid sonogram)

zinc protoporphyrin (ZPP)

urinalysis (UA)

Laboratory Investigations of Ovarian Hormones

Zika virus (ZIKV)

d-xylose absorption test (Xylose tolerance test)

wound culture and sensitivity (C&S)

white blood cell scan (WBC scan, Inflammatory scan)

white blood cell count and differential count (WBC and differential, Leukocyte count)

vitamin D (25-hydroxy vitamin D2 and D3 ; 1,25-dihydroxyvitamin D [1,25(OH)2 D])

Basal Hormone Measurements of Testis

vitamin B12 (Cyanocobalamin and methylmalonic acid [MMA])