Type 1 Diabetes (4) Flashcards
Diagnosing and treating Type 1 Diabetes
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
> >2 autoantibodies
Stage 2
>Abnormal blood sugar
> >2 autoantibodies
Stage 3
>Clinical diagnosis
> >2 autoantibodies
Stage 4
>Long standing T1D
Risk factors for T1D: Genetic Predisposition
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"
Alleles for genes encoding MHC molecules and insulin confer the highest risk of T1D
HLAII
>DQ2, OR >3.6
>DQ8, OR >11.4
>DQ2, DQ8, OR >16.6
HLA alleles confer most risk
Non-HLA associated loci confer less risk
Individual loci have relatively small contribution to genetic risk - difficult to use for predicting individual risk of developing T1D
Biomarker for T1D: Development of Islet Autoantibodies
Probability of diabetes increases with increasing number of islet autoantibodies
> we want better biomarkers to be better able to dollow progression of diabetes and monitor responses to therapy, and get mechanistic clues about T1D
> autoantibodies are not pathogenic, they are markers of the disease progress
Which proteins are these autoantibodies binding?
> focused on insulin as the primary antigen in T1D
>Insulin >GAD65 >IA-2 >ZnT8 >others include ICA512, IA-2, PHOGRIN
> most of these other antigens are made in other parts of the body, insulin by beta cells, but all important autoantigens but insulin and proinsulin have a primary most important role
T1D risk stratification: Islet autoantibody and HLA genotype
Low Risk >single islet AB >low affinity >older age >nonsusceptible 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 epitobes >high titer >Multiple IgG subclasses responses >Young age at initiation >Impaired glucose tolerance >(HLA risk genotypes)
Disease progression is 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 disease risk?
To prevent T1D, we need to be able to predict which individuals will develop disease before Stage 1
> only 30% individuals who have a single islet autoantibody progress to clinical disease
need to identify additional biomarkers that will increase the accuracy of predicting who will develop T1D
Other potential biomarkers for T1D?
Research using samples from at-risk or recently diagnosed individuals:
- Transcript analysis of whole blood samples or peripheral blood mononuclear cells
- responses in a standardized reporter cell line exposed to serum
- metabolomic analysis of serum
> new biomarkers from these studies have yet to be definitively identified and replicated in independent patient cohorts
C-peptide as 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
assay isnt straightforward to do, needs to be more user friendly to be rolled out into routine clinical practice
Predicting the development of T1D
Genetic Markers
>Family history
>HLA DR-DQ genotype
(genetics for primary prevention particularly, mutigene scores to increase predictability)
T1D-relevant immune markers
>Autoantibodies to insulin, GAD, IA-2, ZnT8
Progression-associated immune and/or metabolic markers >antibody affinity and epitopes >IVGTT insulin secretion and sensitivity >OGTT >fasting blood sugar >HbA1c >T-cell memory markers *need more of these so that we can predict who will develop disease and when exactly
Disease development
Development of T1D
> want to prevent diabetes
focused on period before clinical diabetes develops
where there is already an established autoimmune response
maybe even earlier before autoimmune response(primary prevention) and secondary prevention
> more than any other common autoimmune disease, childhood and early adult T1D is now partially predictable in genetically susceptible individuals by careful use and analysis of genetic and immunological biomarkers
Predicting development of T1D
For individuals w/wo family history of T1D, who are identified to have multiple islet cell antibodies,
it is no longer a question of IF they will develop disease, but WHEN it will occur
-2018
Other risk factors: Environment
Concordance rate in identical twins is between 30-70% so there are environmental factors
- not sure what they are
> infectious microbes/gut microbiome
sunlight/vit D
diet
many candidate environmental agents have been implicated but non confirmed
>poor predictive value
