Lecture 16 - Diagnosing and treating T1D

Question 1

What are the disease stages of T1D?

Answer 1

Clinical T1D requires number of factors and disease progression can be broken down into different stages

Length of time it takes to progress through these stages to clinical diagonsis is variable

Stage 1
>Normal blood sugar (normoglycaemia) + asymptomatic
> >2 autoantibodies

Stage 2
>Abnormal blood sugar (dysglycaemia) + asymptomatic
> >2 autoantibodies

Stage 3
>Clinical diagnosis
>Hyperglycaemia
> >2 autoantibodies

Stage 4
>Long standing T1D

Question 2

How is genetics a risk factor for T1D?

Answer 2

Risk increases with increasing number of FDRs (first degree relatives) and with increasing number of HLA risk alleles

HLA alleles
>protective
>risk
>high risk
>risk genes “identical by descent”

Question 3

Why do non-HLA associated alleles confer less risk?

Answer 3

Individual loci have relatively small contribution to genetic risk - difficult to use for predicting individual risk of developing T1D

Question 4

What are the biomarkers for predicting T1D risk

Answer 4

Probability of diabetes increases with increasing number of islet autoantibodies

> autoantibodies are not pathogenic, they are markers of the disease progress

Question 5

What are some examples of islet autoantibody specificities?

Answer 5

• Insulin –> produced by beta cells
• GAD65 –> expression not exclusive to beta cells
• IA-2 –> expression not exclusive to beta cells
• ZnT8 –> highly expressed in pancreatic endocrine cells, but also expressed in other tissues

Question 6

What is the T1D risk stratification?

Answer 6

Low Risk
>single islet AB
>low affinity
>older age
>unsusceptible HLA genotype

Intermediate Risk
>Single islet Ab
>high affinity
>Proinsulin reactive IAA, middle or C-terminal reactive GAD65
>young age
>HLA DR3 or DR4

High Risk
>2 or 3 IAbs
(IA2A, ZnT8A)
>Young age
>Low first-phase insulin (post-prandial rise)
(HLA risk genotype)

Very High Risk
>4 IAbs
>Abs to IA2b epitopes
>high titer
>Multiple IgG subclasses responses
>Young age at initiation
>Impaired glucose tolerance
>(HLA risk genotypes)

Question 7

Why is T1D progression more rapid in younger children?

Answer 7

Get diabetes at young age, progress more quickly than if you get it at older age
disease process more rapid and more active as a whole in younger people
Rapid onset of T1D in some people after checkpoint inhibitor drugs for cancer (drugs that take the breaks off the immune system)

Question 8

Why do we need more biomarkers for T1D risk?

Answer 8

To prevent T1D, we need to be able to predict which individuals will develop disease before Stage 1

Question 9

What are some examples of additional biomarkers for T1D?

Answer 9

• Can measure T cells in the peripheral blood
  o Beta-cell specific T cells are not always detectable in the peripheral blood especially at early and late stages of the disease
• Can measure levels of insulin & C-peptide in the blood
  o Radioimmunoassay – use of a radiolabelling and specific antibodies to measure insulin & C-peptide concentrations
• Use of a continuous glucose monitor
• Help better determine the disease stage and estimate the time of T1D onset

Question 10

How is T1D first diagnosed?

Answer 10

STAGE 1 AND STAGE 2:
* Asymptomatic: rare to identify someone at these early stages
o Requires various lab tests:
 Sequence HLA to determine genotype
 Autoantibody detection
 Glucose tolerance test
 Assay to test insulin first-phase response
 T-cell response assays
STAGE 3
* Clinical presentation
o Acute:
 Sudden and severe symptoms due to diabetic ketoacidosis: nausea, vomiting, dehydration, unconsciousness
o Sub-acute:
 Polydipsia, polyuria, weight loss, lethargy & fatigue over a longer period of time (weeks to months)

Question 11

What are some diagnostic tests to confirm T1D?

Answer 11

Increased blood glucose concentration –> hyperglycaemia, random >/= 11.1mmol and fasting >/= 7.0mmol

Autoantibodies –> islet autoantibodies detected in serum –> positive for >/= 1 autoantibodies

Increased blood protein glycation –> glycated haemoglobin (HbA1c) –> random blood test >/=6.5%

Question 12

Can C-peptide be used as a potential biomarker?

Answer 12

C-peptide specific CD4+ T cells are detectable in the peripheral blood at T1D onset

> Responses detectable in peripheral blood of >60% of people with T1D
presumably would also have T cells in their pancreas recognising this antigen
potential biomarker for T1D but the issues in rolling this out is that the assay isn’t straightforward to do, needs to be more user friendly

Question 13

What is the current treatment for T1D?

Answer 13

Exogenous insulin

Optimal glycaemic control requires:
* Multiple blood glucose measurements per day: >4x
* Multiple-dose insulin regimen to mimic physiological insulin release
* Need to be aware of hypoglycaemia events
o Ingestion of a quick-acting glucose source

Question 14

How is glucose monitoring and insulin delivery performed?

Answer 14

1. Glucose monitoring
   a. Hand-held device (finger pricks)
   b. Continuous glucose monitoring device
2. Insulin delivery
   a. Syringes or insulin pens
   b. Insulin opump
3. Different types of insulin
4. Lollies

Question 15

What is the caveat in the clinical course of T1D?

Answer 15

Heterogeneity
Not all individuals follow this sequence

some infants have multiple AAbs at first assessment
some aab+ve inviduals have impaired first-phase insulin secretion before abnormalities detected in GTT
> significant variation in beta-cell mass among those with multiple aab and low first phase insulin response
wide variation in residual beta cell mass and immune infiltration of islets in organ donor species

Question 16

What are the different types of insulins?

Answer 16

Rapid-acting
Short-acting
*Taken before a meal to treat increased glucose concentration after eating

Intermediate-acting
Long-acting
*Treats increases in blood glucose when rapid-acting insulin stops working

Available as mixtures (e.g., rapid-acting with intermediate-acting or long-acting insulin)
Type and amount of insulin depends on blood glucose levels, physical activity, illness

Question 17

How to determine how well a patient is controlling their glucose levels?

Answer 17

• Measure HbA1c:
  o Provides a 3-month average plasma glucose concentration
  o Higher HbA1c percentage corresponds to higher average blood glucose levels
  o Continuous glucose monitor
  o Regular high HbA1c or blood glucose levels = increased risk for long-term complications