Classification of Diabetes and pathogenesis of Type 1 Diabetes

DIABETES MELLITUS CLASSIFICATION AND PATHOGENESIS OF TYPE 1 DIABETES
  • Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia
  • Hyperglycemia can result due to
    •  Defects in insulin secretion
    • Defects in insulin action
    •  Both
Diabetes is classified into
  •  
    • Type 1 Diabetes ( β- cell destruction leading to absolute insulin deficiency)
      • Immune mediated
      • Idiopathic
    • Type 2 Diabetes (Combination of insulin resistance and β- cell dysfunction)
    • Genetic defects in β cell function
      • Maturity onset diabetes of the young (MODY) caused by mutations in
        • Hepatocyte nuclear factor 4α (HNF 4α) – MODY 1
        • Glucokinase – MODY 2
        • Hepatocyte nuclear factor 1α (HNF 1α) – MODY 3
        • Pancreatic and duodenal homeobox 1 (PDX1) – MODY 4
        • Hepatocyte nuclear factor 1β (HNF 1β) – MODY 5
        • Neurogenic differentiation factor 1 (NEUROD 1) – MODY 6
      • Neonatal diabetes (activating mutations in KCNJ11 adn ABCC8, encoding Kir6.2 and SUR1, respectively
      • Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243→G)
      • Defects in proinsulin conversion
      • Insulin gene mutation
    • Genetic defects in insulin action 
      • Type A insulin resistance
      • Lipoatrophic diabetes
    • Exocrine pancreatic defects
      • Chronic pancreatitis
      • Pancreatectomy/trauma
      • Neoplasia
      • Cystic fibrosis
      • Hemochromatosis
      • Fibrocalculous pancreatopathy
    • Endocrinopathies
      • Acromegaly
      • Cushing syndrome
      • Hyperthyroidism
      • Pheochromocytoma
      • Glucagonoma
    • Infections
      • Cytomegalovirus
      • Coxsackie B virus
      • Congenital rubella
    • Drugs
      • Glucocorticoids
      • Thyroid hormone
      • Interferon – α
      • Protease inhibitors
      • β- Adrenergic agonists
      • Thiazides
      • Nicotinic acid
      • Phenytoin
      • Vacor
    • Genetic syndromes associated with diabetes
      • Downs syndrome
      • Klinefelter syndrome
      • Turner syndrome
      • Prader-Willi syndrome
    • Gestational diabetes mellitus
Etiopathogenesis of type 1 Diabetes
    • The fundamental immune abnormality is failure of self tolerance in T cells
    • This is due to combination of defective clonal deletion of self reactive T cells in the thymus as well as defective regulatory T cells or resistance of effector T cells to suppression by regulatory cells
    • Develops in childhood, manifests in puberty and progresses with age
    • Inaccurate to call as “juvenile diabetes” as it can occur at any age
    • GENETIC SUSCEPTIBILITY
      • Genetic susceptibility loci for type 1 diabetes is HLA gene cluster on chromosome 6p21
      • Individuals who have either DR3 or DR4 concurrently with DQ8 haplotype – highest risk
      • Insulin gene – variable number of tandem repeats in the promoter region are associated with disease susceptibility. The polymorphism affects the level of expression of insulin in the thymus, thus affecting the negative selection of insulin reactive T cells
      • Other genes involved are
          –  CTLA4 and PTPN 22 (autoimmune thyroiditis)
          –  AIRE (Autoimmune polyendocrinopathies)
    • ENVIRONMENTAL FACTORS
      • Viral infection – Virus might share epitopes with islet antigens and immune response to virus results in cross reactivity and destruction of islet tissue (molecular mimicry)
    • The initial activation of immune cells occur in peripancreatic lymphnodes probably in response to antigens that are released from damaged islets
    • Islet autoantigens that are targets of immune attack may include
        –  Insulin
        –  β cell enzyme glutamic acid decarboxylase
        –  Islet cell autoantigen 512 (ICA512)
      ´But the roles of antibodies in type 1 Diabetes is suspicious
 
Reference-
  • Anirban Maitra. The Endocrine system.In: Robbins and Cotran Pathologic basis of disease.9th edition.volume II.chapter 24. pp 1073-1141.