Immune Mechanisms of Diabetes Flashcards
T2D and obesity behavioral and environmental triggers
LO1
Microbiome
- delivery mode
- antibiotic usage
- diet: processed foods
Diet
- total calorie intake
- macronutrients
- micronutrients
- vitamins
- high fat diet
Energy Expenditure
- basal metabolism
- exercise
- sedentary behavior
- ambient temperature
Early life influences
- maternal disease
- placental function
- maternal nutrition
- postnatal growth
Other
- particulate matter
- NO2
- pesticide
- sleep debt
- endocrine disruptors
- chronic inflammation
T2D and obesity genetic risk factors
LO1
- ethnicity: greater risk for african american, hispanic, and native american
- Pima Native Americans: 10 fold higher prevalence than general population
- offspring with 1 T2D parent: 40% risk
- offspring with 2 T2D parents: 70% risk
- monozygotic twins: 34%
- dizygotic twins: 16%
What are the differences in LEAN adipose tissue vs OBESE adipose tissue?
LO2
LEAN: more Treg cells, Th2 cells, NK T cells, M2 macrophages, and eosinophils –> more IL-4, IL-13, IL-10, and adiponectin (all antiinflammatory)
OBESE: more Th1 cells, M1 macrophages, CD8+ T cells, B cells, dendritic cells, mast cells, and neutrophils due to increased migration from blood –> more leptin, elastase, IFN gamma, TNF alpha, IL1beta, and IL-6 (all inflammatory)
What is the effect of IL-6 in T2D?
LO3
acute inflammatory response; role in adipose inflammation and insulin resistance well documented
What is the effect of IL-6 on the pancreas?
LO3
increase GLP-1
What is the effect of IL-6 on the intestine?
LO3
increase GLP-1
What is the effect of IL-6 on adipose tissue?
LO3
increase lipolysis and AMPK
What is the effect of IL-6 on muscle?
LO3
increase GLUT4 translocation and lipolysis
What is the effect of IL-6 on the liver?
LO3
increase acute-phase response, SOCS-3, and insulin resistance
What does use of IL-6 in clinical settings increase the patient’s risk for?
LO3
risk of inflammation, cancer, and rheumatoid arthritis
What is the process for FFA induction of adipose inflammation?
LO2
- long chain FFA palmitate is a ligand for TLR4 present on adipocytes
- receptor/ligand binding leads to pro-inflammatory cytokine and chemokine production
- recruitment and differentiation of M1 macrophages
- inflammatory state leads to sustained beta cell dysfunction
What are the innate immune responses that increase in obesity?
LO3
M1 macrophages
Mast cells
What are the innate immune responses that decrease in obesity?
LO3
M2 macrophages
eosinophils
What are the adaptive immune responses that increase in obesity?
LO3
B2 cells
CD8+ T cells
INF gamma Th1 cells
What are the adaptive immune responses that decrease in obesity?
LO3
Treg
What cytokines increase in obesity?
LO3
TNF alpha
IFN gamma
IgG2c antibodies
Th1 response
What cytokines decrease in obesity?
LO3
IL-4
IL-10
IL-13
Th2 response
What are histological changes in T2D?
LO3
islet hyalinization: central hyaline deposits replace dead beta cells in late stages
Describe T1D
LO4
- true autoimmunity
- T cell mediated –> Type IV hypersensitivity
- T cell mediated destruction of of beta cells resulting in insulin deficiency
- autoantibody production used as markers of beta-cell destruction
- strong HLA associations
- prone to ketoacidosis
- insulitis: lymphocytic infiltrate within islets
What is insulitis?
LO4
lymphocytic infiltrate within islets
What are complications of T1D?
LO4
- kidney failure
- cardiovascular disease
- diabetic retinopathy
- foot ulcers
Describe the mechanism of T1D
LO4
- genetic predisposition and environmental factors lead to autoantigen formation on insulin-producing beta cells and circulate in the blood stream and lymphatics.
- Processing and presentation of autoantigen by antigen presenting cells.
- Activation of Th1 lymphocytes –> IFN gamma and IL-2
- IFN gamma –> activation of macrophages with release of IL-1 and TNF alpha
- IL-2 –> activation of autoantigen specific T cytotoxic CD8 cells
- Activation of Th2 lymphocytes –> IL-4 –> activation of B lymphocytes to produce islet autoantibodies and antiGAD65 antibodies
- all lead to destruction of beta cells with decreased insulin secretion
Genetics of T1D: familial clustering and concordance
LO5
- mother: 2-3% lifetime risk
- father: 5-6% lifetime risk
- both: 30% lifetime risk
- sibling: 6% lifetime risk
- general public: 0.4% risk
- monozygotic twins: 30-50%
- dizygotic twins: 10%
patients and relatives at increased risk for other autoimmune diseases
What are genes associated with T1D?
LO5
HLA alleles DQ2/DQ8 and DR3/DR4
INS-insulin gene
AIRE
CTLA-4
