Immune Mechanisms of Diabetes Flashcards
How does Obesity play an impact in generating Insulin resistance?
- Increase lipolysis
- increasea mcrophage accumulanteion
- Increase glucose production
- increase triacylglycerides
- inflammation
- decrease in efficiency of glucose uptake in Skel M
- decrese insulin secretion
- decrease b cell function
What are some Environemental triggers and risk factors that lead to T2DM and obesity?
Microbiome:
- Delivery mode
- Antibiotic usage
- Diet
Diet:
- Total calorie intake
- Macronutrients
- Micronutrients
- Vitamins
Energy expenditure:
- Basal metabolism
- Exercise
- Sedentary behavior
- Ambient temperature
Early life influences:
- Maternal disease
- Placental function
- Maternal nutrition
- Postnatal growth
Other:
- Sleep debt
- Endocrine disrupters
- chronic inflammation
- NO2
- Pesticides
What is the Genetic risk for T2DM
- Ethnicity of African america, hispanic, and Native american
- Off spring with a T2D parent 40%
- Off spring with both T2D parents 70%
- Monozygotic twins: 34%
- Dizygotic twins 16%
52 common risk factors associate with T2D
Obesity as an inflammatory state, what is happening?
- Increased Th1 cells
- M1 macrophages
- CD8 T cells
- B cells
- Dendritic cells
- Mast cells
- Neutrophils
IL-6!
How does IL-6 play a role in T2DM?
Acute inflammatory response
Role in adipose inflammation and insulin resistance
- increase GLP-1 in pancreas and intestine
- increase lipolysis
- increase AMPK
- increase GLUT4 translocation
- INcrease acute phase response
How does FFA impact inflammation?
Long chain FFA Palmitate is a ligand for TLR4 on adipocytes
- leads to receptor ligand binding leads to pro-inflammatory cytokine and chemokine production
- recruitment and differentiation of M1 macrophages
- Inflammatory state leads to sustained B cell dysfunction
what immune responses increase and decrease in obesity?
Increase:
- TNF-a
- IFN-y
- IgG2c antibodies
- TH1 response
Decrease:
- IL-4
- IL-10
- IL-13
- Th2 response
what is the relationship between insulin resistance and beta cell dysfunction
as their is an increase in insulin resistance there is an increase n beta cell dysfunction
What is Islet Hyalinization?
in Type II DM there are central hyaline deposits replacing the dead beta cellls in the islets of the pancreas
Pathology of T1DM?
- True autoimmunity
- T cell mediated (type IV)
- T cell mediated destruction of B cells resulting in insulin deficiency
- Autoantibody production used as markers of B cell destruction
- strong HLA associations
- Prone to ketoacidosis
What is the majority of risk for T1 DM
88% of the cases are Genetic
higher chance if Father has T1 DM
significantly high risk if both parents have Type 1 DM
What are the 4 big genes that are associated with T1DM?
- HLA
- INS insulin gene
- AIRE
- CTLA-4
what are the High risk HLA class II alleles?
DQ2/DQ8 and DR3/DR4
found on chromosome 6
DQ2/DQ8 found in more than 90 percent of individuals with T1DM
DR3/DR4 most common in children diagnosed prior to age 5
HLA class II that lack Asp57 of the beta chain are often found among individuals with T1DM
What are the Protective HLA class II haplotype?
DR2/DQ6 confers protection
Other Genes that are involved in autoimmunity
PTPN22:
- Tyrosine phosphate
- RA, T1DM, autoimmune thyroid disease
CTLA4:
-Many autoimmune syndromes
AIRE:
- necessary for thymic expression of self proteins
- Diabetes, adrenal, parathyroid
- Autoimmune polyendocrine syndrome
FAS:
-Splenomegaly, lymphadenopathy
FOXP3:
- Immune dysregulation
- Polyendocrineopathey, entropathy
