Immunological Mechanisms of Diabetes Flashcards
What causes T2D in general?
chronic inflammation in both adipose tissue and pancreas both genetic and lifestyle factors contribute to it
associated with obesity
In a normal person, what immunological things does insulin do?
promotes release of IL1Ra (anti-inflammatory)
inhibits IL-1beta (inflammatory)
How does obesity contribute to T2DM?
characterized by chronic activation of inflammatory pathways –> inflammation causally linked to insulin resistance
What inflammatory mediators are present in chronic obesity?
M1 macrophages
Th1 cells
CTLs
Neutrophils
What immune mediators that are anti-inflammatory are predominant in lean people?
M2 macrophages
Treg cells
Th2 cells
eosinophils
What Free fatty acids predominate in T2D pts?
Normal, lean ppl?
long and medium-chain FAs = bad
short-chain FAs = good
How are M1 macrophages activated in T2D ppl?
LPS IFN-gamma –> M1 –> TNFalpha, IL-1beta, IL-6, resistin, NO, etc –> insulin resistant
How are M2 macrophages acitvated and what do they do to lean ppl?
IL-4, IL-3 –> M2 –> IL-10 –> promotes insulin sensitivity via short chain FFAs, IL-13 and IL-4
What type of fat is bad in obese people and what does it do?
visceral fat
induces inflammatory cascades –> leukocyte-endothelial interaction –> coupled angiogenesis and adipogenesis and adipocyte dell death
What is MCP-1?
factor that helps recruit and activate macrophages
seen in obesity
What things contribute to beta cell death in T2D?
high serum IL-1beta
low serum IL-1Ra
glucotoxicity
lipotoxicity
What is the significance of palmitic acid?
long-chain FFA released by obese adipose tissue –> TLR4/MyD88 –> chemokines –> m1 macrophages recruited and inflammation ensues –> beta cell dysfunction
What are the genetics of T2D?
multifactorial disease related to 52 common risk variants
40% of dev if 1 parent has T2D
70% of developing if 2 parents have it
How is pollution related to T2D?
chronic exposure to organic land pollutants –> disturbs glucose metabolism and induces insulin resistance
chronic exposure to traffic-related pollutants (particulate matter and NO2) –> assoc w/ higher rates of T2D
What is the link btw gut microflora and insulin resistance?
increase in the firmicutes/bacteroidetes ratio linked to insulin resistance
recent studies w/ fecal transplants show butryate-producing intestial bacteria protect against T2D
What is the immune cause of T1D?
autoauntibodies that attack beta islet cells
cytotoxic T cells also attack insulin
Type IV hypersensitivity
When was insulin first used to treat a Type 1 diabetic?
Jan 11, 1922
nobel prize to Frederick Grant Banting and John James Richard Macleod
What is insulitis?
infiltration of islets by mononuclear cells and CD8 T cells
What are some phys contributions from the bone marrow and thymus toward T1D?
defective thymic selection
potential for self-Ags presented in incorrect register of MHC binding
Aire and VNTR expression in thymus
defects in lymphocyte precursors
genetic susceptibility
What are some phys contributions of beta cells toward T1D? (7)
expression of class 1 MHC
production of cytokines and chemokines
free-radical sensitivity
ptential to present high quantities of self-Ag via MHC II
susceptibility to viral tropism and inability to resolve inflammation
limited replication potential
rate of immune destruction influenced by metabolic activity
What is the concordance rate for T1D in monozygotic twins?
30-50% = suggests non-genetic influences
What are some key environmental factors being studied in T1D?
incidence is increasing abt 3% each year
evidence linking the environment ant T1D in himans is indirect
350 fold variation in indicence of T1D in different countries
What are the most significant pre and post-natal triggers for T1D?
pre: maternal enteroviral infection, older maternal age
post: enteroviral infection, infant weight gain, serious life events
What are the main promoters of progression of T1D?
overweight or increased height velocity
puberty
insulin resistance
psychological stress