Autoimmune Insulin Dependent Diabetes

Question 1

Is the trigger for coeliac disease endogenous or exogenous?

Answer 1

Exogenous

Question 2

How is type 2 diabetes often picked up?

Answer 2

Not by clinical symptoms but by screening

Question 3

What is C peptide?

Answer 3

Part of proinsulin

Cleaved off in beta cell and secreted with insulin

Question 4

Why is C peptide measured?

Answer 4

Measure of endogenous insulin production

Question 5

How much more common is type 2 diabetes than type 1?

Answer 5

10x

Question 6

How is the incidence of type 1 diabetes changing?

Answer 6

Increasing

Question 7

Is type 1 diabetes present at birth?

Answer 7

No

Question 8

Why is there a significant burden of disease in type 1 diabetes?

Answer 8

Obligate use of exogenous insulin

Question 9

How is type 1 diabetes treated?

Answer 9

Short- or long-acting insulin

Question 10

What is the pattern of destruction of beta cells in the pancreas in type 1 diabetes?

Answer 10

From normal beta cell function to none at all

Not uniform destruction

Question 11

What causes the disease process in type 1 diabetes?

Answer 11

Inflammatory infiltrate

• T cells
• B cells
• Macrophages
• DCs

Question 12

Why are islets in type 1 diabetes called pseudo-atrophic?

Answer 12

Still have alpha cells and produce glucagon

Question 13

What do CD8 T cells release to destroy beta cells in type 1 diabetes?

Answer 13

Perforin

Granzymes

Question 14

What are the clinical features of type 1 diabetes?

Answer 14

Symptoms
- Polyuria
- Polydipsia
- Polyphagia
Weight loss
Ketoacidosis
Insulin requirement

Question 15

Do people with type 1 diabetes have autoantibodies?

Answer 15

Yes

Question 16

What proportion of people with type 2 diabetes develop autoantibodies, and what does this mean?

Answer 16

10%

Progressing to T1D slowly

Question 17

What are some of the autoantibodies that can be detected in type 1 diabetes?

Answer 17

Insulin autoAbs
GAD autoAbs
IA-2 autoAbs

Question 18

What is the key self-antigen in the development of type 1 diabetes?

Answer 18

Insulin

Question 19

Are all the self-antigens recognised by autoantibodies in type 1 diabetes specific to beta pancreatic cells?

Answer 19

No - some are, some aren’t

Question 20

Does everyone with type 1 diabetes have all autoantibodies?

Answer 20

Not everyone has each autoAb but almost everyone does have them

Question 21

Why are autoantibodies in type 1 diabetes diagnostic of, but not disease causing?

Answer 21

Because Ags recognised intracellular > Abs can’t bind and block function

Question 22

How can babies get congenital autoimmunity?

Answer 22

Possibility of crossing placenta if mother has autoAbs

Wanes with half life of maternal Abs

Question 23

What is the relationship between the time course and disease process in type 1 diabetes?

Answer 23

Quite well > get sick very suddenly, but disease process going on for a long time

Question 24

Is there an age limit to developing type 1 diabetes?

Answer 24

No, but most common in childhood

Question 25

What is the risk of developing type 1 diabetes in monozygotic twins, where one sibling develops it in childhood?

Answer 25

In non-diabetic twin at start - Develop autoAbs - Increased risk of developing type 1 diabetes later in life

Question 26

What is the rate of loss of function in type 1 diabetes?

Answer 26

Unknown

Question 27

What are the stages proposed for type 1 diabetes?

Answer 27

``` Variable genetic and environmental risk Stage 1 - pre-symptomatic T1D - Beta cell autoimmunity - Normoglycaemia Stage 2 - pre-symptomatic T1D - Beta cell autoimmunity - Dysglycaemia - No symptoms Stage 3 - symptomatic T1D - Beta cell autoimmunity - Dysglycaemia - Symptoms ```

Question 28

What is APS-I syndrome?

Answer 28

Loss of thymic tolerance to peripheral Ags Because of mutations in AIRE gene Multiple autoimmune disorders - 18% have T1D

Question 29

What is immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX)?

Answer 29

Mutation of FoxP3 gene | 80% of children develop T1D

Question 30

What can reverse IPEX?

Answer 30

Bone marrow transplant

Question 31

Which gene associations are the strongest with type 1 diabetes?

Answer 31

HLA | Insulin - polymorphic expression in thymus

Question 32

Which two HLA are strongly associated with type 1 diabetes?

Answer 32

HLA-DQ2 and -DQ8

Question 33

What is the pathogenesis of type 1 diabetes?

Answer 33

1. Proinsulin-reactive T cells escape negative selection 2. Become activated due to high concentration/altererd Ag 3. Recognition of beta cells 4. CD8 T cell dominant destruction 5. Spreading to other specifications

Question 34

What are possible environmental triggers for autoimmunity?

Answer 34

``` UV Diet Drugs - not for T1D Hygiene hypothesis Infection ```

Question 35

What is wrong with the current treatment of type 1 diabetes?

Answer 35

Incapable of mimicking physiological glucose control > can't prevent complications Multiple injections per day

Question 36

What are the possible future therapies for type 1 diabetes?

Answer 36

``` Restore insulin production - Transplant/regenerate Abolish disease recurrence - Correct autoimmunity In meantime - Islet transplantation - Artificial pancreas ```

Question 37

What are some possible avenues of correcting autoimmunity?

Answer 37

``` Immunosuppression Immunomodulatory drugs Anti-inflammatory biologicals Ag specific Cell therapy ```

Question 38

Can hypoglycaemia unawareness be treated with islet transplantation?

Answer 38

Yes, with associated freedom from severe hypoglycaemic events

Question 39

What are the problems with islet transplantation?

Answer 39

``` Availability of organ doners Viability and function of islets Immunosuppression - needed for - Rejection - Recurrence of T1D Longevity of graft All-sensitisation Cost ```