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Diabetes Mellitus: FromDefinition

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toTherapy

MarcelloCiaccio, AnnaMariaCiaccio, andLuisaAgnello

Introduction

This chapter provides an in-depth description of the various types of diabetes mellitus, from the denition to the classication, epidemiology, pathogenesis, diagnosis, monitoring, and therapy. In addition, a description of glucose metabolism will be provided to facilitate theunderstanding of the diabetic disease.

Denition

Diabetes mellitus is a chronic heterogeneous disease characterized by altered metabolism of glucoseand other energy substrates. From a biochemical point of view, it is characterized by hyperglycemia due to a relative or absolute insulindecit.

M. Ciaccio (*) Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, University Hospital “P.Giaccone”, Palermo, Italy

Department of Laboratory Medicine, University Hospital “P.Giaccone”, Palermo, Italy e-mail: marcello.ciaccio@unipa.it

A. M. Ciaccio Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE) “G.D’Alessandro”, University Hospital “P.Giaccone”, Palermo, Italy

L. Agnello Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, University Hospital “P.Giaccone”, Palermo, Italy

Historical Background

The rst hints of this disease were found in Egyptian papyrus. However, the Greeks described it in detail. The term “diabetes” derives, indeed, from the Greek verb διαβήτης, which means “to pass through,” alluding to the ow of water, since the most striking symptom is polyuria. The sufx mellitus derives, instead, from the Latin mel (honey, sweet) and alludes to the sweetish taste of the blood and urine of patients with diabetes, a characteristic already known by the ancient Egyptians, Greeks, and Indians.

Blood Glucose Regulation

Glucose is a monosaccharide (aldohexose) and represents the primaryenergy source for our organism’s cells and the only energy source for central nervous system (CNS) cellsand erythrocytes. The circulating glucose comes mainly from the diet, where it is present as monosaccharides and complex carbohydrates (polysaccharides, e.g., starch); a small amount comes from endogenous synthesis (gluconeogenesis). Glucose circulates in free form, and its levels are maintained within a relatively narrow range (70–100mg/dL) by hormones, such as insulin and glucagon, which ensure that the balance between glucose production and utilization (Fig.26.1).

In particular, in the postprandial period, most glucose derivesfrom the diet and is metabolized by the body’s cells. Glucose enters cells by facilitated diffusion mediated by glucose transporters (GLUTs), of which there are several isoforms with different characteristics (Table26.1). The most important areGLUT-2, acting as a “blood glucose sensor” in pancreatic β-cells that synthesize and secrete insulin, and GLUT-4, which acts on insulin-dependent tissues (the adipose and muscle tissues), and its expression is induced by insulin. Following its entry into a cell, glucoseis immediately phosphorylated at glucose-6-P (G-6-P), preventing its escape from the cell (Fig.26.2).

383

384

Production Use

(12 hours)

Glucose

(12 hours)

(>15 days)

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100%

Liver

Short

fasting

75%

Intestine

55%

Brain

25% Liver

Postprandial Postprandial

55%

Liver

45% Kidney

Prolonged

fasting

15% Kidney

15% Muscle

15% Other

Short

fasting

30%

Brain

25%

Liver

25%

Muscle

20%

Other

Fig. 26.1 Glucose production and utilization. (Copyright EDISES 2021. Reproduced with permission)

Table 26.1 Characteristics of glucose transporters (GLUTs)

Location Glucose afnity Functions

GLUT-1 Erythrocytes, brain, allbody

tissues GLUT-2 (glycemic sensor)

Liver, pancreatic β-cells, serous

surfaces of the intestines and

High (Km=1mmol/L) Glucose uptake to maintain basal intracellular glucose

levels

Low (Km=15–20mmol/L)

Glucose sensor for pancreatic β-cells

the kidneys GLUT-3 Brain, kidneys High (Km <1mmol/L) GLUT-4 (insulin- ependent) GLUT-5 Intestine, liver, spermatozoa,

Insulin-sensitive tissues:

adipose tissueand muscle

Average (Km=2.5–5mmol/L)

Only fructosetransport

kidneys, muscle, adipose tissue GLUT-7 Endoplasmic reticulum of

hepatocytes

Regulates the free glucose ow from theendoplasmic reticulumlumen following the action of glucose-6phosphatase, an enzyme that dephosphorylates glucose-6-phosphate

55%

Brain

Liver Muscle Other

Prolonged

fasting

C — OH

Fig. 26.2 Glucose phosphorylation reaction. (Copyright EDISES

2021. Reproduced with permission)

This phosphorylation reaction is mediated by hexokinases, of which four isoforms are known, with different characteristics (Table26.2).

Hexokinase

ADPAT P

OH—P

H2C — O

Table 26.2

Characteristics of hexokinases

Location Substrate Afnity Regulation Hexokinase I Brain Glucose, Hexokinase II Muscle Hexokinase III Ubiquitous

galactose, Fructose,

High Inhibition

by G-6-P

glucosamine

Hexokinase IV

Liver Glucose Low or glucokinase

In particular, hexokinase IV, also known as glucokinase, is expressed exclusively in the liver and, compared to other hexokinases, it is not inhibited by product (from G-6-P), and, therefore, even in the presence of high glucoseconcentrations, it mediates phosphorylation. This feature is impor-

sequence

Pre-pro-insulin

Pro-insulin Insulin C-peptide

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

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385

tant because the liver represents the main glucosestorage organ.

The postabsorptive period (6–12h after food ingestion, when the contents of the small intestine have been digested and absorbed) is characterized by a progressive accentuation of hepatic glycogenolysis. Duringshort fasting (e.g., overnight fasting), circulating glucose derives primarily from the liver, by glycogenolysis (glycogen breakdown) and gluconeogenesis (synthesis of glucose from non-saccharide precursors).

During prolonged fasting (>15days), circulatingglucose derives from the liver and partly from the kidneys, where gluconeogenesis is activated (Fig. 26.1). After glycogen reservesdepletion, free fatty acids from the adipose tissue are mobilized as the liver’s and muscle’s primary source of energy. The brain and anaerobic tissues receive glucose that derives primarily from gluconeogenesis. In addition, hepatic ketone bodies are synthesized from acetyl coenzyme A (acetyl- CoA), released into the circulation and used as an alternative energy sourceby tissues, including the CNS.

Several hormones are involved in blood glucoseregulation (Table26.3).

Specically, insulin is a peptide hormone synthesized by pancreatic β-cells, consisting of an α-chain and a β-chain linked by a disulde bridge. It is synthesized as a preprohormone (signal peptide + proinsulin, formed from insulin + C-peptide) and converted to proinsulin by the signal peptideremoval in the endoplasmic reticulum; after S–S bridge formation, proinsulin translocates to the Golgi apparatus, where peptide is removed by proteolytic cutting(Fig. 26.3).

The mature insulin and C-peptide are stored in secretory granules within β-cells to be released into the circulatory stream by exocytosis in response to an appropriate stimulus. C-peptide is essential for the proper proinsulin folding. Hyperglicemia isthe primary stimulus for insulin secretion. Insulin secretion is biphasic, with the rst early peak due to secretion of preformed insulin and the second late peak due to ex novo synthesis. Insulin has a short plasma half-life of about 6min, which determines its rapid circulating concen-

trationvariations; 40–60% of the hormone is catabolized in the liver and the remaining amount in the kidneys. The numerous cellular processes regulated by insulin depend on its binding to its receptor located on the membrane of the cells of the target organs, mainly the liver, muscles, and adipose tissue. The receptor is a heterodimer in which the subunits (α and β) are bound by S–S bridges (Fig.26.4). Both subunits are extensively glycosylated. The α-subunit is extracellular and, therefore, itinteracts with insulin; the β-subunit consists of a transmembrane and a cytoplasmic portion

Table 26.3 Characteristics of the hormones involved in blood glucose regulation

Synthesis Hormone Action Pancreas Insulin

Glucagon

Somatostatin

Adrenal gland

Pituitary gland

Thyroid Thyroxine

Adrenaline

Cortisol

Adrenocorticotropic hormone (ACTH)

Growth hormone (GH) Insulin antagonist

↑ Glucose input (muscle and adipose tissues) ↑ Glycolysis, hepatic glycogen synthesis, and fat synthesis ↓Lipolysis and gluconeogenesis

↑ Hepatic glycogenolysis and gluconeogenesis

↑ Lipolysis ↓Release of insulin,

glucagon, and pituitary hormones

↑ Glycogenolysis and lipolysis

↑ Gluconeogenesis and lipolysis Insulin antagonist

↑ Release of cortisol and lipolysis

↑ Glycogenolysis and hepatic gluconeogenesis ↑ Intestinal absorption of carbohydrates

Effect on glycemia

↓

↑

↑ ↑

Fig. 26.3 Insulin biosynthesis. (Copyright EDISES 2021. Reproduced with permission)

Signal

C-peptide

–

COO

C-peptide

386

Magnesium

Structure of the Insulin Receptor and Mechanism of Action of Insulin

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Glucose

Insulin

Insulin receptor

Autophosphorylation

Amino Acids

M. Ciaccio et al.

Potassium Phosphate

P P

Pl-3

phosphate

Pl-3 Kinase

GLUT4 Transporters

Glycogen

Lipids

Fig. 26.4 Structure of the insulin receptor and insulinmechanism of action. The insulin receptor is a heterodimer, consisting of two extracel-

Pyruvic acid

Nucleus

Phosphorylation/Dephosphorylation

Activation/deactivation

Induction/suppression

lular α-chains and two transmembrane β-chains. The α-chains interact with insulin, whereas β-chains mediate intracellular signal transduction.

TirTir

Insulin

receptor

substrates

Target enzymes

mRNA

Insulin-sensitive genes

DNA

In particular, insulin activates different cellular pathways leadingto the GLUT-4 transporter expressionon the plasma membrane, the regulation of the activity of different enzymes, and the transcription of insulin-sensitive genes. (Copyright EDISES 2021. Reproduced with permission)

Tyrosine kinase

Membrane signals

Mitogenic signals

Transcription

factors

Protein synthesis

Fig. 26.5 Anabolic and anticatabolic effects of insulin. aa,

Liver

amino acids. (Copyright EDISES

2021. Reproduced with permission)

Anabolic effects

Anticatabolic

effects

responsible for signal transduction. The receptor has a halflife of 7–12h without and 2–3h with insulin. Insulin is the primary hormone with anabolic and anticatabolic action, promoting the glucose and amino acids uptakeby the cells of numerous tissues, stimulating the synthesis of glycogen, fatty acids, and proteins, and inhibiting catabolic processes, such as hormone-sensitive lipase in the adipose tissue and the process of β-oxidation of fatty acids (Fig.26.5).

Adipose tissue

Muscle

Glucagon is a protein hormone synthesized by the pancreaticα-cells in response to various stimuli, such as hypoglycemia. It is synthesized as a prehormone, accumulated in secretory vesicles, and is released by exocytosis in response to stimuli. It represents the hormone of energy emergency as it intervenes duringsubstrate deciency. Glucagon exerts its hyperglycemic action mainly by inducing glycogenolysis (demolition of glycogen) and gluconeogenesis in the liver.

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Classication ofDiabetes Mellitus

Since the term “diabetes mellitus” encompasses a group of metabolic disorders that share hyperglycemia, over the decades, these clinical conditions have been classied according to different criteria.

In 1979, a treatment-based classication of the various forms of diabetes was proposed. It distinguished between insulin-dependent type 1 diabetes mellitus (IDDM) and noninsulin- dependent type 2 diabetes mellitus (NIDDM). In 1997, following advances in the understanding of the etiology and pathogenesis of diabetes, the American Diabetes Association (ADA) revised this classication and decided to eliminate the terms insulin-dependent and non-insulindependent and the related acronyms (IDDM and NIDDM). On the other hand, the terms type 1 and type 2 diabetes mellitus are maintained, thus achieving a classication based on etiology. Currently, international guidelines classify diabetes mellitus into:

– Type 1 diabetes: It is an autoimmune diseasecaused by

β-cell destruction. It is characterized by an absolute

insulin deciency (the latent autoimmune diabetes in

adults (LADA) variant), has a slow course, and appears in

adults.

– Type 2 diabetes: It is caused by insulin resistance and

β-cell dysfunction.

– Gestational diabetes: It is diagnosed during preg-

nancy, and must be distinguished from overt diabetes.

Gestational diabetes is caused by functional defects simi-

lar to type 2 diabetes; it is rst diagnosed during pregnancy

(commonly between the second and third trimesters) and

usually regresses after delivery and then recurs, often at a

distance, with the characteristics of type 2 diabetes.

Other types of diabetes may be due to genetic defects of the β-cells of the pancreas, such as maturity-onset diabetes of the young (MODY), a form of type 2 diabetes with juvenile onset; intake of drugs or toxic substances; genetic defects of insulin action; infections; diseases of the exocrine pancreas; alterations of the immune system (rare forms); endocrinopathies; and rare genetic syndromes.

spread to all age groups, and the severity of complications associated with the disease make diabetes one of the major health problems on a global scale. It has been estimated that every year there are 5–7 new cases of type 2 diabetes per 1000 people, without signicant gender differences. Type 1 diabetes is a rarer condition, with a peak incidence between 5 and 15years.

The prevalence of LADA, a slower-progressing form of autoimmune diabetes, is 4.5%; about 20% of patients initially dened as type 2 diabetes are affected by LADA.

Concerning gestational diabetes, it is estimated that about 7% of pregnancies are complicated by diabetes. The prevalence of gestational diabetes varies widely among different populations, being higher in women of Asian and Hispanic origin (9.7% and 8.3%, respectively) and lower in nonHispanic white women (5.7%). Within each ethnic group, the prevalence of gestational diabetes mellitus has increased over time, in parallel with the increase in obesity inreproductive agewomen.

Etiopathogenesis

Type 1 Diabetes

Type 1 diabetes mellitus (DM1) is a multifactorial disease in which exposure to various environmental factors triggers, in a subject with genetic predisposition, an autoimmune response that destroys pancreatic β-cells, leading to an insulin decit with a consequent chronic increase in glycemia (Fig.26.6).

Genetic predisposition

(HLA-DR3 and -DR4)

Environmental factors

(viruses)

Time

Epidemiology

Diabetes mellitus represents one of the three health emergencies identied by the United Nations (UN) and World Health Organization (WHO), along with malaria and tuberculosis. The percentage of people with diabetes mellitus is estimated to be around 5% of the world’s population, of which about 10% have type 1 diabetes mellitus and the remaining 90% have type 2 diabetes mellitus. The size of the problem, the

Type 1 diabetes

Fig. 26.6 Pathogenesis of type 1 diabetes. (Copyright EDISES 2021. Reproduced with permission)

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In the initial phase, the autoimmune response, although not clinically detectable, is demonstrated by the presence of autoantibodies directed against specic β-cellular antigens leading to insulitis, an inammation of the islets of Langerhans in which the β-cells reside, characterized by inltration of lymphocytes. At the beginning of this phase, the β-cells still maintain their functionality. As the autoimmune response progresses, the number of β-cells decreases, and their capacity to produce insulin decreases leading to hyperglycemia. Atstage,diabetes is diagnosed. The rate of β-cell destruction varies widely among individuals, as some cases progress rapidly to clinical diabetes, whereas others evolve more slowly. The rapidly progressing form is commonly seen in children, whereas the slow-onset form occurs in adults (LADA). Clinical manifestations do not become apparent until most β-cells (approximately 80%) are destroyed.

TheDM1 etiopathogenesis, therefore, is the result of the interaction between genetic, environmental, and immunological factors.

Genetic Factors

Several genes or chromosomal loci associated with the disease have been identied. However, the human leukocyte antigen (HLA) systemis the most important. The HLA system is a set of genes located on the short arm of chromosome 6 and forms a region known as the major histocompatibility complex (MHC). The HLA region includes more than 200 genes coding for 3 classes of proteins. Class I and II proteins are membrane glycoproteins that mediate the recognition of foreign peptides, whereas class III proteins play a crucial role in the inammatory process.

Some alleles of the DR and DQ genes in the HLA class II locus are strongly associated with DM1 and contribute up to 50% of the risk. In the Caucasian population, the association with the HLA-DR3 and HLA-DR4 alleles and some alleles of the HLA-DQB1 locus (DQB1* 0302 and DQB1*0201) is more pronounced. In general, the association of the various haplotypes with the disease varies from highly predisposing haplotypes to strongly protective haplotypes, neutral haplotypes, and moderately protective haplotypes.

Other genes that individually confer a modestly increased risk of developing DM1 are the PTPN22 gene, which regulates the innate immune response, and the insulin gene (IDDM2).

Environmental Factors

Numerous epidemiological data suggest that the genetic component, although fundamental in the development of type 1 diabetes, is not alone sufcient to determine the diseaseonset. It is, therefore, increasingly likely that the environment may play an essential role in the DM1 etiology.

Environmental factors associated with the risk of developing DM1 are:

– Viruses, especiallyEnteroviruses, such asCoxsackie B4

virus – Mycobacteria – Feeding: Cow’s milk,and diabetogenic substances in soy

and wheat

Immunological Factors

In DM1, chronic hyperglycemia results from selective destruction of the islets of Langerhansβ-cells mainly mediated by T-lymphocytes, both CD4 (T helper) and CD8 (T cytotoxic). In the lymphocyte inltrates of the Langerhans islets(insulitis) of DM1 subjects, in addition to TCD8 (the most abundant) and TCD4, B lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages have been identied. All these immune system cell typesmay contribute to the DM1pathogenesis.

Proteins released from damaged or destroyed β-cells (e.g.,

during viral infection or exposure to toxins) are phagocytosed by antigen-presenting cells (APCs), such as macrophages or dendritic cells. APCs hydrolyze proteins into peptides to be presented by HLA class II molecules to proinammatory T-helper 1 (Th1) lymphocytes. The latter triggers immune responsescascade, includingthe activation of:

– B lymphocytes, which produce autoantibodies against

insular antigens – Specic cytotoxic T lymphocytes against β-cell antigens

In addition, APCs may present antigenic peptides to regu-

latory T lymphocytes (T regs) that, under normal conditions, suppress the proinammatory cascade and prevent β-cell destruction. Pancreatic tissue destruction is mainly due to cell-mediated immunity reactions, whereas autoantibody production is considered an epiphenomenon (i.e., they are not pathogenic), secondary to pancreatic β-cell destruction.

Both autoreactive T lymphocytes and autoantibodies can

recognize different insular antigens, such as insulin, glutamic acid decarboxylase (GAD), tyrosine phosphataserelated islet antigen 2 (IA-2), and zinc transporter 8 autoantibody (ZnT8).

It has been hypothesized that the cell-mediated autoim-

mune response is initially directed toward a primary antigen, causing an initial tissue damage with the release of degradation products that induce secondary immune responses contributing to the extension and chronicization of the process.

The immune response triggertoward self-antigens is due

to the loss of the physiological tolerancemechanism toward self-molecules. Several hypotheses have been proposed to explain this mechanism, among which the most accredited arethe following:

failure (rare)

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

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389

– Defect in lymphocyte selection in the thymus – Molecular mimicry – Alteration of suppressor mechanisms

Defect inLymphocyte Selection inThymus

The physiological tolerance of the immune system toward self-antigens is mainly controlled by the thymus, where the selection of the lymphocyte repertoire takes place, preventing the maturation or activation of potentially self-reactive lymphocytes (negative selection); an alteration of this process could occur in patients with DM1. HLA molecules play an important role in negative selection because they present self-antigens to immature T lymphocytes thatwill undergo negative selection. HLA susceptibility alleles to DM1 bind peptides of insular antigens with low affinity, resulting in an inefficient presentation of self-antigens to self-reactive T lymphocytes that could escape negative selection and reach the periphery.

Molecular Mimicry

It consists of the immune response toward an exogenous antigen, such as a viral protein, which has an amino acid sequence commonto a β-cell protein. Therefore, T lymphocytes also recognize the β-cell autoantigen, toward which they develop a reaction leading to its destruction. In this case, tolerance mechanisms are circumvented by the induction of an immune response against an exogenous antigen. For example, the Coxsackie B4 virus possesses sequence homology with GAD.

Alteration ofSuppressor Mechanisms

Under physiological conditions, most of the self-reactive lymphocytes are eliminated bythe thymus through the previously described mechanism of “clonal selection,” or areactively suppressed by T-reg lymphocytes. Alterations in the latter can contribute tothe developmentofthe immune reaction against the self.

Type 2 Diabetes

Type 2 diabetes mellitus (DM2) is a multifactorial disease resulting from the interaction between genetic and environmental factors.

DM2 is characterized by variable degrees of insulin resis-

tance, altered insulin secretion, and increased glucose production, leading tohyperglycemia (Fig.26.7).

Insulin resistance is the reduced sensitivity of target tis-

sues (muscles, liver, and adipose tissue) to insulin action, leading to:

– Reduced insulin-mediated glucoseuptake in the adipose

and muscle tissues – Reduced insulin-mediated inhibition of hepatic

gluconeogenesis – Reduced inhibition ofadipose tissue lipolysis due to the

lacking insulin inhibition ofhormone-sensitive lipase

In the early stages of the disease, insulin resistance leads

to compensatory hyperplasia of pancreatic β-cells with

Fig. 26.7 Pathogenesis of type 2 diabetes. (Copyright EDISES 2021. Reproduced with permission)

Genetic predisposition

Environmental factors

(obesity)

Insulin resistance

Euglycemia

Impaired glucose

tolerance

Diabetes

Primary β-cell

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hypersecretion of insulin, maintainingeuglycemia (normal glucose levels). Thus, initially, hyperinsulinism compensates for peripheral insulin resistance. This condition can last up to several years. However, over time, β-cells will become insufcient, characterized by a progressive decline in cell mass and function, leading to hyperglycemia and overtDM2. In rare cases of primary β-cellular insufciency, the onset of DM2 is not preceded by insulin resistance.The lattermay be due to receptor alterations (reduced synthesis, increased degradation, reduced phosphorylation-dependent activation) or to alterations in post-receptor events. Among the various factors causing insulin resistance, obesity has a crucial role, with a dose–response relationship between visceral fat and insulin resistancedegree.

DM2 results from the interaction between genetic and

environmental factors.

Genetic Factors

The strong genetic component of DM2 is supported by some literature evidence:

– Studies on twins revealed that DM2 concordance is 70%

in monozygotic twins and 20–30% in dizygotic twins.

– The risk of developing DM2 during lifetime is about 10%

in the general population, 40% in subjects having an affected parent, and 70% in subjects having both parents affected.

– The risk of developing DM2in a subject with a diabetic

sibling is signicantly increased compared to the risk ofthe general population.

However, unlike DM1, no genetic variants strongly predictive of the risk of developing DM2 have been identied. In recent years, genome-wide association studies (GWASs) identied severalloci associated with DM2, each with a very modest effect on individual disease risk (10–40%).

Environmental Factors

One of the most important environmental risk factors is obesity, particularly visceral obesity, which is present in about 90% of DM2patients. Age isanother important risk factor. Indeed, increasing age is associated with physiological reduction in peripheral tissues sensitivityto insulin.

Gestational Diabetes

GDM represents the most common metabolic alteration in pregnancy that, if not correctly recognized and adequately treated, is associated with high maternal–fetal morbidity, mainly related to excessive fetal growth (macrosomia).

During pregnancy, the organism undergoes a physiological adaptation, characterized by endocrine–metabolic changes necessary to ensure the supply of nutrients to the fetus and adequate preparation of the maternal organism for childbirth and lactation. Insulin resistance, which becomes more evident in the muscle and adipose tissues as pregnancy progresses, is a physiological condition aimed at fetal growth. The pathogenetic mechanisms of GDM are superimposable to those of DM2. An intolerance to carbohydrates develops when β-cellular secretion is no longer sufcient to compensate for peripheral insulin resistance, which is physiologically present during pregnancy. InGDM patients, the reduced action of insulin determines an excess ofcirculating nutrients, such as glucose, lipids, and amino acids. They can cross the placenta stimulating the fetal insulin secretion (hyperinsulinism), which in turn determines an increase in the adipose tissue with consequent organomegaly and macrosomia (Fig.26.8). Furthermore, hyperinsulinism can determine the onset of respiratory distress syndrome in newborns due to the insulin inhibitionon the phosphatidylcholinesynthesis, which is the main constituent of lung surfactant.

Other Types ofDiabetesMellitus

aturity-onset diabetes of the young (MODY) deserves particular attention. MODY is a monogenic form of diabetes with autosomal dominant transmission, so dened because it phenotypically presents the characteristics of type 2 diabetes but has a juvenile onset (before the age of 25years). MODY is a non-autoimmune form of diabetes caused by a point mutation or a deletion in genes encoding moleculesinvolved indevelopment or function of pancreatic β-cells, leading to altered insulin secretion. Currently, 14 different forms are known, but the most common are MODY 2, due to mutations in the gene encoding for glucokinase, and MODY 3, due to mutations in the gene encoding for hepatocyte nuclear factor-1α (HNF-1α) (Table 26.4).

Other less frequent monogenic forms are maternally transmitted diabetes with bilateral deafness, caused by mitochondrial DNA mutations or insulin gene mutations, which generally manifest as neonatal diabetes.

Gestational diabetes mellitus (GDM) is a condition of impaired glucose tolerance (IGT), of variable degree and severity, which occurs during pregnancy (usually in the second or third trimester) and generally regresses after delivery. However, it can recur at a distance, preferentially with the characteristics of type 2 diabetes.

Diagnosis

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

Placenta

and macrosomia

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

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Fig. 26.8 Pathogenesis of gestational diabetes mellitus. (Copyright EDISES 2021. Reproduced with permission)

391

FetusMother

Glucose

Insulin

Glucagon

Amino acids

Lipids

Ketones

Table 26.4

Genetic locus 20q 7p 12q 13q 17q Not known Gene Distribution (% of MODY households in Italy) Age onset >12years Pediatric Post-pubertal 30years >12years 25years Primitive defect Pancreas Pancreas

Severity of diabetes Severe Mild Severe ? Severe Mild Complications Frequent Rare Frequent Frequent Frequent Not known

Genetic–biochemical–clinical characteristics of MODY

MODY 1 MODY 2 MODY 3 MODY 4 MODY 5 MODY X

HNF-4α 0% 35–40% 15–20% 0% 1–5% 10%

GCK

Liver

HNF-1α

Pancreas Kidneys

Glucose

Hyperinsulinism Organomegaly

Amino acids

Lipids

Ketones

IPF-1

Pancreas Pancreas Insulin resistance

HMF-1β

Heterogeneous?

In the presence of typical symptoms of the disease (polyuria, polydipsia, and weight loss), the diagnosis of diabetes mellitus relies on the nding, 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 nding, conrmed 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 toler-

ance 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 prole – 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 fast-

ing 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 factors (dyslipidemia, hypertension, etc.) to dene 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26.5).

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