Pathophysiology of Type 1 Diabetes

Question 1

1. Define the metabolic and immunologic events in each of the proposed stages for the progression of type 1 diabetes (TID).

Answer 1

Phase 1 genetic predispostion–> environmental trigger

phase 2 Bet cell injury—> T cell autoimmunity

phase 3- prediabetes loss of first phase insulin response/ glucose intolerance
One of the first identifiable metabolic abnormalities is a decrease in the FPIR. This decrease may occur years prior to the development of T1D.

phase 4- diabetes- clinical onset
Generally, patients present with the classic signs and symptoms of diabetes when 80-90% of the β cell mass has been destroyed*.

Hyperglycemia –> osmotic diuresis–>polyuria –>polydipsia –> nocturia, and new onset enuresis (bed wetting).
Weight loss or lack of expected weight gain may also occur.
If this continues untreated, insulin deficiency may result in the development of diabetic ketoacidosis (DKA), which can be life threatening.

Question 2

2. Define the four autoantigens that are characteristic of TID

Answer 2

The autoimmune response can be identified and followed by the presence of diabetes related autoantibodies (DAA). These are antibodies against proteins in the islet and can be found years prior to the development of diabetes.

Islet cell autoantibody (ICA)
Insulin, IA-2, GAD65, ZnT8

T-cell response
Markers of the Metabolic Changes
IV glucose tolerance test
Oral glucose tolerance test

Antibodies against insulin, GAD65 and IA2 identify people who have an increased risk for the development of diabetes. Progression to expressing multiple autoantibodies is necessary in the development of Type 1 Diabetes.

Question 3

3. Predict the likelihood of progression to TID given the presence of 1, 2, or 3 autoantibodies in a child over the ensuing 10 years.

Answer 3

It is now known that with > 2 islet autoantibodies, individuals will progress to T1D with overt hyperglycemia.

Question 4

4. Explain how specific HLA genotypes can confer either risk or protection from the development of T1D.

Answer 4

There is only a 5-10% correlation between genetics and Type 1 Diabetes (contrast to >50% correlation in Type 2). However, the risk of development of T1D in siblings and offspring of people affected with Type 1 Diabetes is clearly increased. Twin studies demonstrate this increased risk: approximately 50% of monozygotic twins developing TID while discordant dizygotic twins have a diabetes risk similar to that of non-twin siblings. Risk of developing multiple autoantibodies increases with more than 1 immediate relative diagnosed with TID.

Genetic Predictors for Developing Type 1 Diabetes:
HLA = Human Leukocyte Antigen, a human MHC cell-surface protein important for self vs. nonself distinction
Class II HLA (DR, DQ) is the one we care about in Type 1 Diabetes
HLA-DR3/4 = Greatest Risk! Rate of 1:15
VNTR Insulin Gene (INS) and the IDDM2 locus

Question 5

5. Apply the criteria for diagnosing diabetes and differentiate type 1 from type 2 diabetes based on clinical presentation and laboratory findings.

Answer 5

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