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Table 26.5 Interpretation of the oral glucose tolerance test

Test Fasting glycemia 2-hours glycemia

Normal <100mg/dL

IFG (impaired fasting glucose) IGT (impaired glucose tolerance) Diabetesmellitus

(<5.6mmol/L) 100–125mg/dL (5.6–6.9mmol/L)

≥126mg/dL (≥7.0mmol/L)

<140mg/dL (<7.8mmol/L)

140–199mg/dL (7.8–11.0mmol/L)

≥200mg/dL (≥ 11.1mmol/L)

Glycated hemoglobin is a more practical and reliable parameter than blood glucose; indeed, it has less preanalytical 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, dened 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reect different physiological processes. It is, therefore, plausible that a subject may have diagnostic blood glucose values for diabetes and normal glycated hemoglobin values, or vice versa. For this reason, an altered test must be conrmed 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26.6).

In these cases, it is possible to measure glycated albumin, which reects 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 reects blood glucose over the previous 35–45days. Glycated albumin can also be used in poorly compensated diabetes, gestational diabetes, postprandial hyperglycemia, uctuating 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26.7).

Table 26.6

levels

Physiological conditions Pathological conditions

Pregnancy, age, gender

Table 26.7

mellitus

Symptoms Always present (polyuria,

Tendency to ketosis Weight Generally normal Generally increased Age at onset Commonly <30years;

Chronic complications Circulating insulin Autoimmunity Present Absent Therapy Insulin needed from onset Diet, oral

Conditions associated with altered glycated hemoglobin

Hemolytic anemia, iron deciency anemia, transfusions, splenectomy, renal failure, antiretroviral therapy, alcohol addiction, thalassemia

Differential clinical features of type 1 and type 2 diabetes

Type 1 diabetes Type 2 diabetes

Often modest or polydipsia, weight loss, muscle asthenia) Often striking and abrupt onset (ketoacidosis coma) Present Absent

frequent in pediatric age Not earlier than a few years after diagnosis Reduced or absent Normal or

absent

Commonly

>40years

Often present at the

time of diagnosis

increased

medications,

insulin

The clinical picture is often sufcient for differentiating between type 1 and type 2 diabetes mellitus; however, in some cases, it may be necessary to assess autoimmunitybiomarkers (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 classied 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/m

– History of autoimmune diseases, type 1 diabetesor auto-

immune diseasesfamily hystory

– 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.

26 Diabetes Mellitus: FromDenition toTherapy

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Practical diagnostic tests to conrm LADA clinical suspi-

cion 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 pan-

creatic 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 specic 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 specic 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 granules. It is a very early and specic marker. These autoantibodies have been observed in 26% of DM1 patientspreviously classied as antibody-negative.

Table 26.8 shows when the measurement of antibodies is

appropriate.

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 decit 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 classication. 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 rst 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 specic 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.26.9).

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

– Positive family history of diabetes in rst-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

Table 26.8 Conditions in which autoantibodies measurement is indicated

LADA Conrm diagnostic suspicion Patients with other organ-specic autoimmune diseases First-degree relatives of patients with DM1

Clinical utility

Early identication of individuals at DM1risk Early identication of individuals at DM1risk

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26.9).

Women with GDM should be screened for diabetes mellitus 2 by performing a classic OGTT with 75g glucose after

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First visit during pregnancy

Screening for overt

diabetes

Overt Diabetes

OGTT 75 g at 24–28

weeks

Positive

Gestational diabetes

mellitus

Screening for gestational

diabetes

Risk factor assessment

OGTT 75 g at 16–18

weeks

NegativePositive

Fig. 26.9 Diagnostic algorithm for gestational diabetes mellitus. (Copyright EDISES 2021. Reproduced with permission)

Table 26.9 Oral glucose tolerance test in pregnancy

Times Diagnostic glycemia (mg/dL) 0min 1hour 2hours

≥92 ≥180 ≥153

– Laboratory tests: fasting lipid prole, including total

cholesterol, high-density lipoprotein (HDL) choles-

terol, triglycerides, and low-density lipoprotein (LDL)

cholesterol; liver function tests and any further investi-

gations, if steatosis or hepatitis is suspected; urinary

albumin in all patients with type 2 diabetes and type 1

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 dening thegeneral clinical conditions, focusing on any possible chronic complications, through laboratory and instrumental tests. In

diabetes with disease duration >5years; creatininemia (in children only in the presence of proteinuria) and estimated glomerular ltration; 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 classication of the type of diabetes; and urine test to evaluate ketonuria, proteinuria, and

sediment particular, the initial assessment of a patient with diabetes mellitus is based on:

Complications

– Family history – Physiological history (physical activity practiced, life-

style, etc.) – Pathological history – Physical examination

Complications of diabetes mellitus can be classied into acute and chronic.

Diabetic ketoacidosisis the typical acute complication of

DM1. It may represent the clinical onsetmanifestation, espe-

26 Diabetes Mellitus: FromDenition toTherapy

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cially in children. Hyperosmolar hyperglycemic coma is theacute DM2 complication.

Diabetic ketoacidosis is due to insulin deciency and

excess counterregulatory hormones (catecholamines, glucagon, growth hormone, cortisol).

In particular, ketosis results from an increased hepatic

synthesis of ketone bodies, which, in turn, resultsfrom the increased hepatic inux of fatty acids from the adipose tissue, in which the lack of inhibition by insulin of hormonesensitive lipase determines the hydrolysis of triglycerides into glycerol and fatty acids, which are released into the circulation and reach the liver, where the fatty acids undergo β-oxidation leading to acetyl-CoA synthesis. The ketone bodiessynthesis is favored when the acetyl-CoAconcentration the Krebs cycle’s oxidative capacity. At physiological pH, ketone bodies are present as ketoacids and are neutralized by bicarbonates; however, metabolic acidosis appears when the bicarbonate reserves are exhausted. The main symptoms are nausea, vomiting, abdominal pain, polyuria, polydipsia, asthenia, anorexia, mental statusalterations, and dyspnea. The most frequent signs are tachycardia, dry skin, and mucous membranes, Kussmaul breathing, tachypnea, respiratory distress, dehydration, hypotension, fever, lethargy, sensory obnubilation, cerebral edemaup to coma.

Hyperosmolar coma is a metabolic complication of type 2

diabetes mellitus that mainly occurs in elderly; the precipitating event is an inadequate water intake that, in subjects already at risk of dehydration due to polyuria, leads to hypovolemia, with a reduction in glomerular ltration that aggravates hyperglycemia. The main signs and symptoms are nausea, vomiting, dehydration, dry skin and mucous membranes, hypotonia of the eyeballs, hypotension, drowsiness, lethargy, and convulsions up to coma. It can be precipitated by infections, stroke, acute myocardial infarction, pancreatitis, uremia, parenteral nutrition, diuretics, peritoneal dialysis, or drugs (e.g., phenytoin, steroids). The diagnosis is based on:

– Severe hyperglycemia(>600mg/dL) – Hyperosmolarity (>320mOsm/L) – Marked dehydration – Absent or traceketones – Absence of acidosis (pH >7.3; HCO3>15mEq/L)

Chronic complications can be divided into nonvascular

and vascular. The latter, in turn, is classied into microangiopathies, affecting the small vessels, mainly in the retina and renal glomerulus, and macroangiopathies, affecting the peripheral and coronary circulation, with early atherosclerotic lesionsformation (Table26.10). Nonvascular complications include gastroparesis, infections, and skin lesions; in addition, long-term diabetes may be associated with hearing loss.

Table 26.10 Chronic complications of diabetes mellitus

Microvascular Macrovascular Nonvascular Retinopathy,

neuropathy, nephropathy

Coronopathy, arterial peripheral disease, cerebral vasculopathy

Gastrointestinal, genitourinary, dermatological infections, cataract, glaucoma, periodontal disease

The risk of complications increases according to the hyperglycemiaduration; since type 2 diabetes is often preceded by a long period of asymptomatic hyperglycemia, many patients already have almost acomplication at the time of diagnosis. Chronic hyperglycemia determines chronic complications through various mechanisms, including nonenzymatic glycation with the formation of advanced glycation end products (AGEs), activation of protein kinase C (PKC), and defects in the polyol pathway leading to increased oxidative stress.

Monitoring

The clinical laboratory also plays a fundamental role in monitoring patients with diabetes mellitus to evaluate the correct glycemic compensation and/or the possible onset of alterations allowing to promptly modify treatment.

The following laboratory tests must be performed at least once a year:

– Urinalysis to assess glycosuria (glycemia >180 mg/dL);

ketonuria (frequent in decompensated DM1); and albu-

minuria (>30 mg/24 h or > 30 mg/g creatinine), which

represents an important biomarker of diabetic nephropa-

thy and is associated with a signicant risk of cardiovas-

cular disease

– Estimated GFR (eGFR) to assess renal function – Ketonemia – Complete lipid prole – HbA1c to assess long-term glycometabolic control – Glycated albumin to assess midterm glycometabolic

control

– C-peptide to assess the residual secretory capacity of pan-

creatic β-cells

– Insulin, especially in patients with DM2, to assess the

degree of insulin resistance. Insulin should be mea-

sured after stimulation (OGTT). In patients with

DM2, the insulinemic response will be delayed and

persistent.

Measurement of glycated hemoglobin is the gold standard for glycometabolic controlevaluation in diabetic patients (Table26.11).

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Table 26.11

HbA1c Interpretation 20–41mmol/mol

(4–5.9%) 42–48mmol/mol (6–6.49%) ≥48mmol/mol (≥6.5%) <53mmol/mol (<7%) Therapeutic goal in patients with diabetes

<48mmol/mol (<6.5%) >64mmol/mol (>8%) Modifythe diabetes mellitustherapy

Interpretation of glycated hemoglobin (HbA1c) values

Normal values

High risk of diabetes mellitus

Diabetes mellitus diagnosis

mellitus Low risk of complications in patients with diabetes mellitus

The guidelines recommend to measure HbA1C:

– Two times per year in patients with stable metabolic con-

trol and who have reached the therapeutic target

– More than two times per year in patients with unstable

metabolic control

It is inappropriate to measure HbA1C less than 2months

apart.

Therapy

dene the optimal insulin regimen. In addition, weight gain often associated with intensive antidiabetic treatment should be minimized.

A DM1 patient can also undergo pancreas or islets of Langerhans transplantation, which aims to reduce the need for exogenous insulin while eliminating dangerous manifestations such as hypoglycemia.

Pregnantwith gestational diabetes during should has the following glycemic goals:

– Fasting blood glucose <92mg/dL – Blood glucose 1h after meals <140mg/dL – Blood glucose 2h after meals <120mg/dL – HbA1C<42mmol/mol (<6%)

The treatment of gestational diabetes is primarily nutritional, to provide adequate maternal and fetal nutrition, adequate caloric, vitamin, and mineral intake, and optimal glycemic control without ketonuria/ketonemia. If glycemic goals are not achieved after 2weeks of a properdiet, then insulin therapy should be instituted. Oral hypoglycemic drugs are not currently recommended in pregnancy. Immediately after the diagnosis of gestational diabetes, pregnant should self-monitor glycemia by daily measurements.

Glycemic goals in patients with type 1 and type 2 diabetes are:

– Glycated hemoglobin <53mmol/mol (<7%) – Fasting and preprandial blood glucose of70–130mg/dL – Postprandial blood glucose <160mg/dL

Glycated hemoglobin represents the primary treatment target due tothe close relationship between this index of glycemic control and micro- and macroangiopathic complications.

Thediabetes treatment relies on a correct diet, physical activity, and, if necessary,glucose loweringdrugs (insulin, oral hypoglycemic drugs).

DM1 requires therapy with exogenous insulin, due tothe insulinopenia resulting fromthe pancreatic β-cellsdestruc- tion; in DM2, on the other hand, treatment is based on lifestyle interventions (diet and exercise), oral hypoglycemic drugs, and, in some cases, insulin. In patients with DM2,metformin is the drug of the rst choice. If monotherapy cannot achieve the glycemic goal, then combination therapy with metformin associated with other molecules can be evaluated. Insulin therapy is essential when glycemic control isunsatisfactory, even in polytherapy.

In a DM1 patient, the goal is to balance and combine caloric intake with the appropriate amount of insulin; therefore, diet and blood glucose monitoring must be integrated to

Recommended Readings

Ahmed A (2002, April) History of diabetes mellitus. Saudi Med J

23(4):373–378

Ashcroft FM (2005) ATP-sensitive potassium channelopathies: focus

on insulin secretion. J Clin Invest 115:2047–2058

Associazione Medici Diabetologi (AMD) – Società Italiana di

Diabetologia (SID) Standard italiani per la cura del diabete mellito (2016)

Basta G, Del Turco S, De Caterina R (2004) Prodotti di glicosilazi-

one avanzata: possibili implicazioni per l’aterosclerosi nel diabete. Febbraio 95(2)

Bellia C, Zaninotto M, Cosma C, Agnello L, Bivona G, Marinova

M, Lo Sasso B, Plebani M, Ciaccio M (2018) Clinical usefulness of glycated albumin in the diagnosis of diabetes: results from an Italian study. Clin Biochem 54:68–72. https://doi.org/10.1016/j.

clinbiochem.2018.02.017

Bellia C, Zaninotto M, Cosma C, Agnello L, Lo Sasso B, Bivona G,

Plebani M, Ciaccio M (2017) Denition of the upper reference limit of glycated albumin in blood donors from Italy. Clin Chem Lab Med

56(1):120–125. Bernoville F, Beck-Peccoz P (1999) Diabetes Mellitus. Jain Publishers Bonora E etal (2004) Population-based incidence rates and risk fac-

tors for type 2 diabetes in white individuals. The Bruneck Study.

Diabetes 53:1782–1789 Brocco S etal (2007) Monitoring the occurrence of diabetes mellitus

and its major complications: the combined use of different adminis-

trative databases. Cardiovasc Diabetol 6:5 Charbonnel B, Schernthaner G, Brunetti P et al (2005) Long-term

efcacy and tolerability of add-on pioglitazone therapy to failing

monotherapy compared with addition of gliclazide or metformin in

patients with type 2 diabetes. Diabetologia 48:1093–1104

https://doi.org/10.1515/cclm- 2017- 0179

26 Diabetes Mellitus: FromDenition toTherapy

https://t.me/medicina_free

397

Chilelli NC, Piarulli F, Sartore G, Lapolla A (2016) Ruolo dei prodotti

di glicazione avanzata nelle complicanze microvascolari del diabete di tipo 2: “attori protagonisti” nella memoria metabolica? G It Diabetol Metab 36:22–27

de Vegt F, Dekker JM, Stehouwer CD, Nijpels G, Bouter LM, Heine RJ

(1998) The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance: poor agreement in the Hoorn Study. Diabetes Care 21(10):1686–1690

DeFronzo RA, Barzilai N, Simonson DC (1991) Mechanism of met-

formin action in obese and lean non insulin-dependent diabetic subjects. J Clin Endocrinol Metab 73:1294–1301

Drucker DJ (2006) The biology of incretin hormones. Cell Metab

3:153–165

Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like pep-

tide- 1 receptor agonists and dipeptidylpeptidase4 inhibitors in type 2 diabetes. Lancet 368:1696–1705

Ferrera A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM (2004)

An increase in the incidence of gestational diabetes mellitus: northern California, 1991–2000. Obstet Gynecol 103(3):526–533

Fourlanos S, Perry M, Stein MS etal (2006) A clinical screening tool

identies autoimmune diabetes in adults. Diabetes Care 29:970–975

Groop L, Tuomi T, Rowley M etal (2006) Latent autoimmune diabetes

in the adults (LADA) more than a name. Diabetologia 49:1996–1998

Group NDD (1979) Classication and Diagnosis of Diabetes Mellitus

and Other Categories of Glucose Intolerance. Diabetes 28(12):1039–

1057. https://doi.org/10.2337/diab.28.12.1039

Hasslacher C (2003) Multinational Repaglinide Renal Study

Group. Safety and efficacy of repaglinide in type 2 diabetic

patients with and without impaired renal function. Diabetes

Care 26:886–891 Holst JJ (2006) Glucagon-like peptide-1: from extract to agent. The

Claude Bernard lecture, 2005. Diabetologia 2:253–260 International Expert Committee (2009) International expert commit-

tee report on the role of HbA1c assay in the diagnosis of diabetes.

Diabetes Care 32:1327–1334 ISTAT (2015) Annuario statistico italiano. http://www.istat.it/it/

archivio/171864

Lapolla A, Dalfrà MG (2006) Screening e diagnosi del diabete gestazi-

onale. Biochimica Clinica 30:5–6 Linee guida gravidanza siologica. Ministero della Salute (n.d.). http://

www.salute.gov.it/imgs/C_17_pubblicazioni_1436_allegato.pdf

Rendell M (2004) The role of sulphonylureas in the management of

type 2 diabetes mellitus. Drugs 64:1339–1358 Roberto T, Rita BA (2013) Le proteine glicosilate nel diabete. Riv Ital

Med Lab 9:218–224 Thanabalasingham G, Pal A, Selwood MP etal (2012) Systematic

assessment of etiology in adults with a clinical diagnosis of

young- onset type 2 diabetes is a successful strategy for iden-

tifying maturity- onset diabetes of the young. Diabetes Care

35:1206–1212 Van de Laar FA, Lucassen PL, Akkermans RP et al (2005) Alpha-

glucosidase inhibitors for type 2 diabetes mellitus. Cochrane

Database Syst Rev:CD003639

Diabetes Mellitus: TheRole

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oftheLaboratory

AndreaMosca andMartinaMontagnana

Introduction

The laboratory plays a central role in diagnosing and monitoring diabetes mellitus. The list of the main tests that can be used in this setting is shown in Table27.1. The information was taken from the American Diabetes Association (ADA) guidelines, the consensus document of the Italian standards of care for diabetes mellitus, and various documents prepared by the intersociety study group of the Italian Society of Clinical Biochemistry and Molecular Biology and the Italian Society of Clinical Pathology and Laboratory Medicine (SIBioC-SIPMeL) on diabetes mellitus.

Role oftheLaboratory inScreening andDiagnosis

Concerning preclinical diagnosis (screening), it is useful to treat type 1 diabetes separately from type 2 and gestational diabetes.

For type 1 diabetes, various evidence from studies on animal models suggests that an immune therapeutic intervention before the onset of symptoms can delay or prevent their onset. However, the numerous clinical trials conducted on humans have produced disappointing results. Nevertheless, the ADA recommends that rst-degree relatives of patients with type 1 diabetes be screened for autoantibodies, specic markers of immune aggression to β-cells, with the recom-

Table 27.1

diabetes mellitus

Diagnosis Preclinical (screening)

Clinic Glycemia

Surveillance Acute conditions

Chronic conditions

HbA1c glycated hemoglobin

Role of the laboratory in the management of patients with

Type of exams

Immunological biomarkers (insula cytoplasmic antibodies, anti-insulin antibodies, glutamic acid carboxylase autoantibodies, anti-tyrosine phosphatase antibodies, zinc transporter 8 antibodies) Genetic biomarkers (e.g., human leukocyte antigens) Test for insulin secretion (fasting, in response to glucose load) Glycemia HbA1c

Oral glucose tolerance test HbA1c Ketone bodies (in urine and blood)

Glycemia Chetonic bodies Acid-base state (pH, bicarbonate) Lactate Other examinations related to pathophysiology or therapy (e.g. potassium, sodium, phosphate, osmolality) Glycemia Glycated proteins (HbA1c, glycated albumin) Urinary proteins (urinary albumin excretion, albuminuria) Tests to evaluate complications (e.g., creatinine, cholesterol, triglycerides) Tests to evaluate pancreas transplantation (C-peptide, insulin) Eligibility for implantation of the insulin pump (C-peptide)

A. Mosca Department of Physiopathology and Transplantation and Center for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy

M. Montagnana ( Section of Clinical Biochemistry, University Hospital of Verona, Verona, Italy e-mail: martina.montagnana@univr.it

mendation that those who screen positive should then be referred to specialist centers.

Human leukocyte antigen genotype research, perhaps interesting from a research point of view, is not currently recommended for diabetes screening. Similarly, measurement of insulin secretion, the first functional abnormality found at the onset of both type 1 and type 2

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diabetes, is not currently recommended in routine laboratory testing.

Screening for type 2 diabetes in asymptomatic subjects has been a matter of much controversy. However, the rationale is that since it is estimated that, on average, about 30% of individuals with type 2 diabetes have the disease without having yet received a diagnosis, to prevent complications, the diagnosis should be made as early as possible. Currently, the ADA recommends screening for all asymptomatic individuals over 45years of age. Screening can be done on younger subjects in the presence of risk factors (e.g., in the case of familial or ethnic group membership). In particular, based on the increasing prevalence of type 2 diabetes among adolescents, screening is recommended if there are conditions associated with increased insulin resistance or if there is a history of diabetes in the mother before pregnancy or gestational diabetes. Screening should be repeated every 3years, starting at age 10.

In some countries, there may be signicant differences. For example, in Israel, the prevalence of undiagnosed diabetes is negligible; the entire population is subjected continuously throughout their lives (at school age, during and after military service, etc.) to rigorous medical testing.

Finally, as regards the diagnosis, in the absence of symptoms, the measurement of fasting blood glucose, glycated hemoglobin (HbA1c), or the oral glucose tolerance test (OGTT) can be performed and should be repeated on a second occasion. See below for threshold values and interpretation.

lance of complications are also achieved by measuring creatinine, urinary albumin secretion, and lipid balance. Finally, the success of new therapies, such as islet cell or pancreatic transplantation, can be followed by measuring C-peptide or insulin concentrations.

Antibodies

Autoantibodies are helpful markers in diagnosing type 1 diabetes mellitus, especially in the preclinical period (prediabetes). Indeed, it has been demonstrated that at least one autoantibody is present in the serum of 95–98% of these patients. The most important autoantibodies are antipancreatic insulin (ICA), anti-glutamic acid carboxylase (GAD), anti-insulin (IAA), anti-tyrosine phosphatase (IA2A), and anti-transporter of zinc 8 (ZnT8).

In 1977, the presence of ICA was also identied in some patients diagnosed with type 2 diabetes. This type of autoimmune diabetes evolving towards insulin dependence was named latent autoimmune diabetes in adults. It is a form of diabetes that does not require insulin therapy for at least 6months after clinical diagnosis and is characterized by the presence of autoantibodies against GAD, IA-2, and, more rarely, ZnT8 and insulin.

The following are the main autoantibodiesused so far. From an analytical point of view, autoantibodies must be measured only in an accredited laboratory with a quality control program and an external quality assurance program.

Role oftheLaboratory inSurveillance

The laboratory also plays an essential role in the surveillance of acute and chronic complications. For the former, especially in diabetic ketoacidosis, nonketotic hyperosmolar coma, and hypoglycemia, several molecules can be frequently measured to help clinicians implement appropriate therapy to return glycemic control to physiologic conditions and to correct other metabolic disorders. The National Academy of Clinical Biochemistry guidelines provide helpful information on the tests that can be performed in these acute conditions.

Regarding the surveillance of diabetes and the development of chronic complications, the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have excellently documented the extent to which good glycemic control signicantly reduces the development of micro- and macrovascular complications of diabetes. Therefore, the measurement of glucose and glycated proteins provides short- and long-term indices of the degree of such control. Detection and surveil-

Pancreatic Insula Cytoplasmic Antibodies (ICA)

They are a group of autoantibodies directed against pancreatic islet cells that bind to multiple islet cell proteins. They appear early and are present in 70–80% of new diagnoses of type 1 diabetes. They have long represented the gold standard for evaluating anti-islet antibodies. Currently, they are no longer evaluated, partly due to the difculty of standardizing the immunouorescence methodology used for their measurement but above all due to the difcult availability of the human pancreas necessary for their execution.

GAD Antibodies (GADA)

These are tests for autoantibodies directed against β-cell proteins (antigens) but not specic for β-cells. They represent the most frequent marker of autoimmunity found in new diagnoses of diabetes (about 70–80%), present in signicant percentages in every age group.

27 Diabetes Mellitus: TheRole oftheLaboratory

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Tyrosine-Phosphatase 2 Antibodies (IA-2A)

These are tests for autoantibodies directed against β-cell antigens, but they are not specic. They are positive in approximately 60% of patients with type 1 diabetes. Tyrosine phosphatase 2 (IA-2) is a transmembrane glycoprotein in the secretory granules of endocrine cells involved in insulin secretion. It has been demonstrated by radioimmunoassays that IA-2 autoantibodies are highly specic for type 1 diabetes and directed towards different epitopes depending on the age of onset.

Anti-insulin Antibodies (IAA)

These are autoantibodies directed against insulin; insulin is the only antigen considered highly specic for β-cells. These antibodies are found in approximately 50% of pediatric patients with type 1 diabetes, while they are not commonly measured in adults. A limitation of this test is that it does not distinguish between autoantibodies that recognize endogenous insulin and antibodies produced against exogenous insulin.

Zinc Transporter 8 Antibodies (ZnT8)

This autoantibody is directed toward a membrane protein, zinc transporter, ZnT8, which is found in the insulin secretory granules.

Glucose

Fasting Blood Glucose

The measurement of fasting blood glucose is a crucial test for the diagnosis of diabetes mellitus and for the screening of subjects at high risk of developing this disease. This measurement must be carried out in a laboratory, and great care must be taken in the appropriate collection and storage of the sample (preanalytical phase), in the choice of the method (analytical phase), and in the reporting and communication of results (post-analytical phase).

Preanalytical Aspects

Several preanalytical variables can affect blood glucose measurement.

As reported in the most recent recommendations on screening and diagnosis of diabetes mellitus, glycemia must be measured in venous plasma, respecting a fasting time of not less than 8 and not more than 12 h. The choice of the biological matrix to be used (whole blood,

plasma, or serum) is essential because the results obtained on different matrices present a significant variation: glycemia measured in whole blood is lower than that measured in plasma since red blood cells contain less water than plasma and glucose dissolves in free water. The molality of glucose (i.e., the amount of glucose per unit mass of water) is identical in whole blood and plasma. Although red blood cells are freely permeable to glucose, the water content is about 93% in plasma and 73% in erythrocytes. Consequently, if the hematocrit is normal, plasma glucose is about 10–12% higher than whole blood glucose. Serum blood glucose is also about 5% higher than plasma.

Another critical aspect is the choice of glycolysis inhibitor, which must be contained in the tube if the plasma cannot be separated from the corpuscular elements within 30min of collection.

To minimize glycolysis, guidelines recommend placing the tube in water with melting ice immediately after collection and separating the plasma from the cells by centrifugation.

The addition of sodium fluoride, an enolase inhibitor, produces an antiglycolytic action. However, a study has shown that this inhibition is lost within 4h of collection. In this regard, SIBioC issued a formal recommendation in 2018 that the ternary mixture with citrate, sodium fluoride, and ethylenediaminetetraacetic acid (EDTA) should be used for blood glucose measurement for diagnostic purposes. Lithium heparin with sodium fluoride may still be used to monitor the ward’s glycemic control.

The glucose consumption rate invitro, at room temperature, averages 5–7% per hour, which can be quantified as approximately 0.6mmol/L (10mg/dL). However, some variables, such as glucose concentration, storage temperature, the number of white blood cells, and hematocrit, can increase or decrease the rate of glycolysis in whole blood. Proper storage of the sample allows blood glucose to remain stable for a more extended period. Glucose concentration stability in separated, unhemolyzed, sterile serum without glycolysis inhibitors has been demonstrated for 8h at 25°C and 72h if the sample is stored at 4°C.

Intraindividual (CVi) and interindividual (CVg) biological variabilities were 4.5% and 5.8% on plasma and 5.6% and 7.5% on serum, respectively.

There is, moreover, a circadian variability of glycemia, determined by the secretion of hormones that inuence glucosidic metabolism (growth hormone, cortisol, and corticotropin); the average values of fasting glycemia are therefore higher in the morning than in the afternoon. For this reason, it is recommended to have blood glucose measurements between 7 and 10a.m.

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Analytical Aspects

Blood glucose measurement is performed in most laboratories using well-standardized enzymatic methods. Although enzymatic methods based on glucose oxidase and glucose dehydrogenase are also commercially available, guidelines recommend using methods based on hexokinase. The latter, using ATP, catalyzes the phosphorylation of glucose into glucose-6-phosphate. Glucose-6-phosphate dehydrogenase, in the presence of nicotinamide adenine dinucleotide phosphate (NADP), causes the oxidation of glucose-6-phosphate to gluconate-6-phosphate. The rate of NADPH formation during the reaction is directly proportional to glucose concentration and is measured photometrically.

The methods based instead on glucose oxidase are more subject to interference from various types of substances (e.g., uric acid, bilirubin), which reduce hydrogen peroxide (H2O2) with the risk of underestimating glycemia. The inuence of hemolysis and lipemia is negligible.

Based on biological variability, the glucose determination should have an analytical imprecision of <2.9%, bias, <2.2%, and total error of <6.9%.

Postanalytical Aspects

Blood glucose values should be expressed in mmol/L, the unit of measure adopted by the international system and, as such, the international reference standard. However, blood glucose is still expressed in mg/dL in many laboratories.

Fasting plasma glucose concentration increases with increasing age between the third and sixth decades and then remains constant.

Extreme blood glucose values, that is, below 2.2mmol/L (40mg/dL) or above 27.7mmol/L (500mg/dL), should be reported as quickly as possible so that the clinician can implement measures to resolve the acute critical event (severe hypo or hyperglycemia).

Postprandial Blood Glucose

Postprandial hyperglycemia is a fairly common event in patients with type 1 and type 2 diabetes mellitus and can occur even in the presence of good metabolic control, as evidenced by acceptable HbA1c values.

Postprandial hyperglycemia is an independent risk factor for macrovascular disease, correlates with increased risk of retinopathy and carotid intima-media thickness, and causes oxidative stress, inammation, and endothelial dysfunction.

Plasma glucose, which should be measured strictly 2h after the meal, should not exceed a concentration of

7.8mmol/L (140mg/dL). Self-monitoring of blood glucose using point of care testing (POCT) is currently the most practical method of monitoring postprandial blood glucose.

Please refer to the section “Fasting blood glucose” for

preanalytical, analytical, and postanalytical aspects.

Oral Glucose Tolerance Test

OGTT is one of the tests that can be used to diagnose diabetes mellitus or impaired glucose tolerance (IGT), and it is useful for a better diagnostic and prognostic assessment, especially in subjects with impaired fasting glucose (IFG), because a signicant proportion of these subjects have a glucose response compatible with the diagnosis of diabetes.

The OGTT, an examination with low reproducibility, must be performed correctly and standardized. Two samples are collected, the rst on an empty stomach and the second 2h after oral intake of a glucose solution (300mL) containing anhydrous glucose (75g in adults and 1.75 g per kg of body weight in children, up to a maximum of 75g).

Preanalytical Aspects

The test should not be performed in subjects with a documented history of diabetes mellitus or with investigations indicating the presence of diabetes mellitus; it should not be performed during acute pathologies and in the presence of factors that may inuence the test itself, such as in the presence of recent infections, during convalescence from surgery, or during treatment with life-saving drugs; and nally, it should not be performed in gastro-resected subjects because of the risk of evoking the symptoms of the syndrome of impaired gastric emptying.

In the 3 days preceding the test, the subject should consume a standardized amount of carbohydrates (100–150 g per day) without changing the diet. The intake of nonlifesaving drugs (e.g., thiazides, contraceptives, and corticosteroids) should be postponed until after the OGTT has been performed.

The examination should be carried out on an empty stomach (at least 8h and not more than 14h).

The speed of intake of the glucose drink, administered at a temperature of 15–25°C, should not exceed 5min.

During the test, the subject must remain seated and is not allowed to drink, eat, or smoke. The test must be performed in the morning to avoid alterations in glycemia due to the previously mentioned circadian variability.

Throughout the procedure, the subject must remain in an area under the control of medical personnel, who can intervene in cases of illness and possibly decide to suspend the examination. The examination is not valid if vomiting occurs.

Analytical Aspects

Plasma blood glucose is measured using the methods described in section “Fasting blood glucose.”

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