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Part VII. DISEASES OF THE ENDOCRINE SYSTEM AND METABOLIC DISORDERS

Chapter 51. Diabetes Mellitus

Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia due to the impaired insulin secretion, insulin action, or both. Chronic hyperglycemia in DM is associated with damage, dysfunction and insufficiency of various organs, especially of the eyes, kidneys, nerves, heart, and blood vessels.

Epidemiology

Worldwide, it is currently known of 425 million patients with DM. International Diabetes Federation predicts that the number of DM patients till 2040 will be up to 630 million. According to the Russian Federation State Register as of December 31, 2017, 4,498,955 DM patients (3.06% of the Russian Federation population) were subject to regular medical check-up due to this condition, including 5.7% (256.1 thousand) with type 1 DM, 92.1% (4.15 million) with type 2 DM, and 1.9% (83.8 thousand) with other types of DM. Taking into account the evident clinical picture and acute onset, the actual and recorded prevalence of type 1 DM is the same. In contrast to the type 1, the type 2 DM statistics do not reflect the actual situation, since only detected and registered cases of the disease are taken into account. According to the large NATION epidemiological study, 5.4% of patients in the Russian Federation suffer from type 2 DM, whereas half were not aware about their disease before participating in the study. Thus, a significant proportion of type 2 DM patients remain undiagnosed, do not receive treatment, and are considered to be at high risk of complications.

Classification

In accordance with the WHO classification (1999), the following clinical DM categories are distinguished.

  • Type 1 DM (autoimmune, idiopathic) develops at a young age as a result of pancreatic β-cell destruction leading to absolute insulin deficiency.
  • Type 2 DM (with predominant IR and relative insulin deficiency, or predominant insulin secretion violation, with or without IR) develops in middle and old age and is characterized by relative insulin deficiency associated with tissue hormonal resistance, being often combined with obesity. As a result of progressive pancreatic β-cell function deterioration in type 2 DM patients, relative insulin deficiency is replaced by absolute. In this regard, some patients require insulin treatment.
  • Gestational DM (occurs during pregnancy).
  • Other types of DM include:
    • genetic disorders of β-cell functions: MODY 1 (chromosome 20, HNF-4α), MODY 2 (chromosome 12, HNF-1α), MODY 3 (chromosome 7, glucogenase), rare forms of MODY, transient and permanent neonatal DM, mutation of mitochondrial DNA;
    • genetic disorders of insulin action: type A IR, leprechaunism, Rabson–Mendenhall syndrome, lipoatrophic diabetes;
    • exocrine pancreatic disorders (pancreatitis, pancreonecrosis, trauma/pancreatectomy, tumors, cystic fibrosis, hemochromatosis, fibrocalcular pancreatopathy, etc.);
    • endocrine system diseases (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteroma, etc.);
    • drug- or chemically induced DM: nicotinic acid, GCs, thyroid hormones, α-adrenomimetics, β-adrenomimetics, β-blockers, thiazide diuretics, diazoxide dilantin, pentamidine, interferon alpha, other agents (HIV therapy, post-transplant DM);
    • DM associated with infectious diseases (cytotoxic damage to β-cells by rubella, Сoxsackie virus, mumps, influenza, parainfluenza, cytomegalovirus);
    • unusual forms of immunologically mediated DM: insulin ABs, insulin receptor ABs, muscle stiffness syndrome (stiff-man syndrome), type I and II autoimmune polyglandular syndromes;
    • other genetic syndromes, occasionally associated with DM: Down syndrome, Friedreich ataxia, Huntington’s chorea, Klinefelter syndrome, Laurence-Moon syndrome, myotonic dystrophy, porphyria, Prader–Willi syndrome, Turner syndrome, Wolfram syndrome.

Etiology and Pathogenesis

Several pathogenetic mechanisms are involved in the development of DM. Insulin effect insufficiency due to inadequate secretion and/or reduced tissue response to insulin are responsible for disorders in metabolism of carbohydrates, fats and proteins.

Type 1 DM results from the interaction of genetic, environmental, and autoimmune factors. According to modern concepts, type 1 DM is a T-cell-mediated autoimmune disorder, that is mainly based on a violation of immunological tolerance. The appearance of autoaggressive T-cells and immunocompetent cellular infiltration of Langerhans islets cause insulitis, β-cell destruction with further absolute insulin insufficiency development. Autoimmune β-cell destruction has both multiple genetic predisposition and is associated with environmental factors. Genetic predisposition to type 1 DM is mainly associated with the major histocompatibility complex HLA antigens (IDDM1 locus). In addition, an important role in coordinating the immune response belongs to the genes of insulin (INS), cytotoxic T-lymphocyte receptor (CTLA-4), and tyrosine phosphatase (PNPN-22). The role of genetic factors is confirmed by the occurrence of the disease in 30–40% of identical twins. In addition, patients with type 1 DM may have other autoimmune diseases: Graves’ disease, chronic autoimmune thyroiditis, Addison’s disease, autoimmune hepatitis, and pernicious anemia. Among the environmental factors potentiating genetic predisposition to type 1 DM, of the greatest importance are viruses affecting β-cells (mumps, rubella, Coxsackie B viruses), and toxic substances (nitrosamines, nitrates, heavy metals). Despite the acute onset, type 1 DM is characterized by a long latent period during that immune disorders already develop while maintaining normal insulin secretion. During this period, immunological markers of type 1 DM — autoantibodies to β-cell antigens, insulin, glutamic acid decarboxylase (GAD65), tyrosine phosphatases IA-2 and IA-2β — can be identified. Type 1 DM manifests clinically after the death of 80–90% of β-cells.

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