Lecture 16 - Diagnosing and treating T1D Flashcards
What are the disease stages of T1D?
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
How is genetics a risk factor for T1D?
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”
Why do non-HLA associated alleles confer less risk?
Individual loci have relatively small contribution to genetic risk - difficult to use for predicting individual risk of developing T1D
What are the biomarkers for predicting T1D risk
Probability of diabetes increases with increasing number of islet autoantibodies
> autoantibodies are not pathogenic, they are markers of the disease progress
What are some examples of islet autoantibody specificities?
- 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
What is the T1D risk stratification?
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)
Why is T1D progression more rapid in younger children?
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)
Why do we need more biomarkers for T1D risk?
To prevent T1D, we need to be able to predict which individuals will develop disease before Stage 1
What are some examples of additional biomarkers for T1D?
- 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
How is T1D first diagnosed?
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)
What are some diagnostic tests to confirm T1D?
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%
Can C-peptide be used as a potential biomarker?
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
What is the current treatment for T1D?
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
How is glucose monitoring and insulin delivery performed?
- Glucose monitoring
a. Hand-held device (finger pricks)
b. Continuous glucose monitoring device - Insulin delivery
a. Syringes or insulin pens
b. Insulin opump - Different types of insulin
- Lollies
What is the caveat in the clinical course of T1D?
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