**_🧪Endocrinology🧪 - Type 1 Diabetes Mellitus Flashcards
What is type 1 diabetes?
An autoimmune condition where insulin secreting beta-cells are attacked and destroyed
What are the consequences of T1DM?
Partial/complete insulin deficiency, leading to hyperglycaemia
Life-long insulin treatment
What is LADA?
Latent autoimmune diabetes in adults
Autoimmune diabetes leading to insulin deficiency can present later in life
What is diabetic ketoacidosis?
Cells (particularly hepatocytes) start making ketones as alternative fuel source due to lack of glucose (can’t enter from bloodstream), leads to ketoacidosis - acutely unwell patient
Usually sign of T1DM, but can also occur in T2DM
What is monogenic diabetes?
Some rare forms of diabetes result from mutations or changes in a single gene - called monogenic
Can present as T1/T2DM
What can trigger a presentation of diabetes?
Diabetes may present following pancreatic damage or another endocrine disease
What ages can T1DM present?
Usually childhood/early adulthood
Can present throughout entire adult life
Challenges arise trying to distinguish adult-onset T1DM vs much more common T2DM
How is Insulin produced?
Pro-Insulin is cleaved into insulin and C-peptide
What are the first stages of T1DM development?
Genetic predisposition, then there is a potential precipitating event
What is the series of events after a potential precipitating event?
Overt immunological abnormalities - normal insulin release
Progressive loss of insulin release - glucose still normal
Overt diabetes - C-peptide still present
No C-peptide present
What happens to the mass of beta-cells in the pancreases as each stage of the progression of T1DM occurs?
It continually declines
Why is the immune aspect of T1DM specifically highly clinically relevant?
Increased prevalence of other autoimmune disease
Risk of autoimmunity in relatives
More complete destruction of beta-cells (compared to infection etc…)
Immune modulation offers possibility of future novel treatments (none in existence yet)
What immunological defects lead to T1DM?
Presence of autoreactive CD4+ T lymphocytes
Exacerbation by pro-inflammatory cytokines
Defects in T-reg cells that fail to suppress the autoimmunity
How do autoreactive CD4+ cells lead to the destruction of beta-cells?
Auto-antigens presented to autoreactive CD4+ T lymphocytes
CD4+ cells active CD8+ cells
CD8+ cells travel to islets and lyse beta-cells
Exacerbated by release of pro-inflammatory cytokines
Are all beta-cells destroyed in all cases of T1DM?
No
Some people with T1DM have some beta-cells, small amount of insulin production
Not enough to negate need for insulin therapy however
Which HLA-DR alleles have an effect on genetic susceptibility to T1DM?
DR1-DR9
T1DM and T2DM are polygenic disorders, what does this mean?
Multiple tiny changes in a large number of genes
Which gene can often be used to measure genetic susceptibility?
HLA-DR allele
What does the DR1 mutation in the HLA-DR allele mean for risk level of T1DM?
Slight risk
What does the DR2 mutation in the HLA-DR allele mean for risk level of T1DM?
Protective
What does the DR3 mutation in the HLA-DR allele mean for risk level of T1DM?
Significant risk
What does the DR4 mutation in the HLA-DR allele mean for risk level of T1DM?
Significant risk
What does the DR5 mutation in the HLA-DR allele mean for risk level of T1DM?
Slight risk
What does the DR6 mutation in the HLA-DR allele mean for risk level of T1DM?
Neutral/protective
What does the DR7 mutation in the HLA-DR allele mean for risk level of T1DM?
Protective
Risk in African descent
What does the DR8 mutation in the HLA-DR allele mean for risk level of T1DM?
Neutral/slight risk