Diabetes mellitus type 1 pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Priyamvada Singh, M.B.B.S. [2]; Cafer Zorkun, M.D., Ph.D. [3]Vishal Devarkonda, M.B.B.S[4] Anahita Deylamsalehi, M.D.[5]

Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels. Type 1 diabetes is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. Currently, 58 genomic regions are known to be associated with type 1 DM. There are environmental factors that can play a protective role in Type 1 diabetes like higher maternal vitamin D, probiotic and omega-3 fatty acids intake during prenatal period. Conversely, environmental factors such as caesarean section, congenital rubella, maternal enteroviral infection and abnormal microbiome are among environmental factors that are able to trigger Type 1 DM. Furthermore, some immunological components are responsible for type 1 DM pathogenesis.

• Type 1 diabetes is a disorder characterized by abnormally high blood sugar levels.
• In this form of diabetes, specialized cells in the pancreas called beta cells stop producing insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Lack of insulin results in the inability to use glucose for energy or to control the amount of sugar in the blood.
• Possible thymus and bone marrow deficiency includes defective thymic selection, faulty self antigen presentation, thymic VNTR and Aire expression, mobilopathy and defective lymphocyte precursors are some possible proceeding triggers that underlie type 1 DM.^[1]

• Type 1 DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency.
• Concordance of type 1 DM in identical twins ranges between 40 and 60%, indicating the presence of additional modifying factors.
  
  

• Genes associated with Diabetes mellitus include the following: ^{[2][3][4][5][6][7]}
  • Currently, 58 genomic regions are known to be associated with Type 1 DM.
  • Major susceptibility gene for type 1 diabetes is located on HLA region of chromosome 6. It accounts for 40-50% of the genetic risk for type 1 diabetes. This region encodes for class II major histocompatibility complex (MHC) molecules. major histocompatibility complex (MHC) molecules play an important role in presenting antigen to T helper cell and initiating immune response.
  • Other major susceptibility genes which were associated with Type 1 DM include polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, Insulin-VNTR, AIRE, FoxP3, STAT3, HIP14 and PTPN22 etc.^[8][9]
  • Presence of certain genes confer protection against the development of the disease. Haplotype DQA1*0102, DQB1*0602 is extremely rare in individuals with type 1 DM (<1%) and appears to provide protection from type 1 diabetes.
  • There is a relationship between some human leukocyte antigens (HLA) and type 1 diabetes, such as DQB1, DQA1, and DRB1. There are some supporting data on DR4-linked haplotypes transmission from type 2 diabetes parents to offspring with type 1 diabetes. Patients with latent autoimmune diabetes of adults also have been related to HLA alleles DQB1*0302 and 02. ^[9]

• Environmental factors were found to influence Diabetes mellitus type 1 through various pathways. Some were found to confer protection against Diabetes mellitus type 1, while others were associated with the progression and promotion of Diabetes mellitus type 1, including:^[10][11]

• Several studies have found that abnormalities in the humoral and cellular arm of the immune system, were identified to be associated with Diabetes mellitus type 1, these include:^{[12][13][14][15][16][1]}
  • Deficiency in immune regulation, such as effector T cells (Teff) resistance to Regulatory T cells (Treg) or Regulatory T cells (Treg) abnormalities
  • Islet cell autoantibodies
  • Defective cellular trafficking and adhesion
  • Activated lymphocytes in the islets, peripancreatic lymph nodes, and systemic circulation
  • Chronic activation of Antigen-presenting cells
  • T lymphocytes that proliferate when stimulated with islet proteins
  • Release of cytokines within the insulitis
  • An enzyme named glutamic acid decarboxylase (GAD65) found in β cells has similar amino acid sequence with the Coxsackie B4 P2-C protein, which augments the response of humoral immunity.
  • Autoantibodies against IA-2 and zinc transporter (ZnT8) have been positive in 60% and 60-80% of Diabetes mellitus type 1 at the time of diagnose, respectively.

• Conditions associated with diabetes mellitus type 1 include:^[7][17]
  • Autoimmune thyroid disease (ATD)
  • Celiac disease (CD)
  • Autoimmune gastritis (AIG)
  • Pernicious anemia (PA)
  • Vitiligo
  • Addison's disease
• The following table is a summary of some associated autoimmune conditions and their prevalence among type 1 diabetic patients and normal population.^[18]

• On gross pathology, pancreas may demonstrated the following changes:^[1]
  • Decreased overall weight and size
  • Dorsal region atrophy
  • Possible hypertrophy (related to hydrophic changes)

• On microscopic histopathological analysis, the following changes can be detected in islet cells:^[1]
  • Insulitis
  • Beta cell loss due to necrosis or apoptosis
  • Major histocompatibility complex class one hyperexpression
  • Reduction in insulin in remnant beta cells
  • Interferon alpha expression in beta cells
  • CD3-positive cells in Islet cell

Template:WH Template:WS Template:WH Template:WS

Template:WH Template:WS

Template:WH Template:WS