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 deficit with a consequent chronic increase in glycemia (Fig. 1).

Fig1. Pathogenesis of type 1 diabetes. (Copyright EDISES 2021. Reproduced with permission)

In the initial phase, the autoimmune response, although not clinically detectable, is demonstrated by the presence of autoantibodies directed against specific β-cellular antigens leading to insulitis, an inflammation of the islets of Langerhans in which the β-cells reside, characterized by infiltration 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 dis ease have been identified. 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 inflammatory 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 sufficient to determine the dis ease 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 infiltrates 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 identified. 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 macro phages or dendritic cells. APCs hydrolyze proteins into peptides to be presented by HLA class II molecules to proinflammatory T-helper 1 (Th1) lymphocytes. The latter triggers immune responses cascade, including the activation of:

– B lymphocytes, which produce autoantibodies against insular antigens

– Specific cytotoxic T lymphocytes against β-cell antigens

In addition, APCs may present antigenic peptides to regulatory T lymphocytes (T regs) that, under normal conditions, suppress the proinflammatory 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 phosphatase- related islet antigen 2 (IA-2), and zinc transporter 8 autoantibody (ZnT8).

It has been hypothesized that the cell-mediated autoimmune response is initially directed toward a primary antigen, causing an initial tissue damage with the release of degradation products that induce secondary immune responses con tributing 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:

– 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 environ mental factors.

DM2 is characterized by variable degrees of insulin resistance, altered insulin secretion, and increased glucose pro duction, leading to hyperglycemia (Fig. 2).

Fig2. Pathogenesis of type 2 diabetes. (Copyright EDISES 2021. Reproduced with permission)

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 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 insufficient, characterized by a progressive decline in cell mass and function, leading to hyperglycemia and overt DM2. In rare cases of primary β-cellular insufficiency, 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 significantly 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 identified. In recent years, genome-wide association studies (GWASs) identified 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

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.

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 sufficient 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. 3). Furthermore, hyperinsulinism can deter mine the onset of respiratory distress syndrome in newborns due to the insulin inhibition on the phosphatidylcholine syn thesis, which is the main constituent of lung surfactant.

Fig3. Pathogenesis of gestational diabetes mellitus. (Copyright EDISES 2021. Reproduced with permission)

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 defined 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 1).

Table1. Genetic–biochemical–clinical characteristics of MODY

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.

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