Pathophysiology of Type 1 Diabetes

Question 1

Progression from normal ==> overt T1D

Answer 1

• T1DM is a slowly progressive largely T-Cell mediated autoimmune illness. Antibodies play a minor role.
• Genetic susceptibility
• Some precipitating event is that starts autoimmune process and β cell destruction, silent
• Labile blood sugars eventually
• This time course can take years, variable from person to person

Question 2

Positive antibody (possible) in T1D

Answer 2

• Diabetes Associated Autoantibodies (DAA)
  
  • against proteins in the the islet can be found years prior to diabetes diagnosis.
• Islet Cell Antibodies (ICA or IA-2, GAD65)
• Insulin Autoantibody (IAA)
• Zinc Transporter Ab (ZnT8)
• Multiple antibodies has a much higher risk of getting T1D than single antibody

Question 3

Environmental factors associated w/T1D

Answer 3

• Occurs in lean kids
• Incident Event-unsure of what environmental factors these may be but cause “Silent” β-cell loss.
• Infections: e.g. Virus
• Diet
• Hygiene hypothesis
• Accelerator hypothesis

Question 4

Possible role of diet in development of T1D

Answer 4

• Increased incidence with shorter duration of breastfeeding AND
• earlier introduction of cow’s milk and cereals

Question 5

“Hygiene hypothesis” & T1D

Answer 5

• we are too clean!
• Immune system is bored and attacks normal β cells instead

Question 6

Accelorator hypothesis & T1D

Answer 6

• Accelerator hypothesis → link between childhood obesity and increase in the incidence in T1D.
• Obesity leads to β-cell stress exposing β-cell antigen to the immune system and initiating an immune response.

Question 7

Genetic factors that predispose to T1D

Answer 7

• HLA is the strongest genetic predictor.
  
  • Class 2 HLA is most important: DQ, DR;
  • DR 3/4 - DQ8 and DR 4/4-DQ8 are the highest risk
• The insulin gene IDDM2 is the 2nd highest genetic risk factor
  
  • VNTR Class I (few copies of promoter = less insulin expression in thymus) is higher risk
• Risk of HLA DR3/4 + VNTR Class I is additive

Question 8

Familial/ethnic genetic factors that predispose to T1D

Answer 8

• Most common in younger, white children
• Risk for developing multiple Ab is much higher if both parents or a parent + sibling have diabetes

Question 9

Protective genetic factors against T1D

Answer 9

• IDDM2 (insulin gene) locus:
  
  • VNTR Class III is protective

Question 10

Immune system components involved in T1D

Answer 10

• T cell mediated damage against β cells as a result of Diabetes Associated Antibodies (DAA).
• Both CD4 and CD8 T-cells play a role.
• The autoimmune attack against the β-cells can be identified by the presence of autoantibodies against islet proteins in the sera of at risk individuals and are predictive of development of the disorder