Flashcards in Immunological Mechanisms of Diabetes Deck (79)
T/F: In the past T2D was thought to be solely d/t insulin resistance, but now this is combined with decreased insulin production and destruction/decrease in production of beta cells
T2D is a multifactorial disease. How have twin studies proved this?
Offspring of a parent with T2D have 40% lifetime risk, increasing to 70% if both parents have T2D.
Environment also important, because in twin studies show 34% concordance rate in monozygotic
What race has a 10 fold higher prevalence of T2D — 50% of which occurring at age 20?
Other than the proven genetic component of developing T2D, what are some behavioral/environmental factors contributing to T2D?
High fat diet
Pollution (pesticides, herbicides, traffic-related pollutants PM and NO2)
Pesticides and herbices disturb ____ metabolism and induce insulin _____
Risk factors that contribute to development of T2D
Body fat - particularly abdominal fat
Ethnicity (greater risk in african american, hispanic, and native american children)
Onset of puberty
[these risk factors appear to act in additive fashion)
High correlations between percentage body fat and _____ _____are found in obese children
What are levels of the following like in a person with healthy pancreatic beta cells:
Low Serum insulin
Low Serum glucose
Low Serum FFA
Low Serum IL-1B
High Serum IL-1Ra
What type of macrophages are found in adipose tissue of healthy people, and what is the important cytokine produced?
What do they secrete into serum?
M2 (alternative) macrophages — anti-inflammatory IL-10
Secrete IL-R1a, which is soluble in serum
What changes occur in the macrophages of adipocytes and kupffer cells (liver macrophages) in diabetic conditions? How does this perpetuate the diabetic disease state?
They take on M1 phenotype - produce pro-inflammatory IL-1
Inflammation is perpetuated by decreased secretion of IL-1R antagonist in serum, so that more and more inflammation occurs
This eventually reaches the pancreatic beta cells which will be killed by necrosis
_____ is characterized by chronic activation of inflammatory pathways
It is increasingly recognied that inflammation in this condition are causally linked to insulin ______
In lean, insulin-sensitive individuals, normal insulin secretion is sufficient to:
Induce robust uptake of glucose from circulation by _____ and ______ tissue
Inhibit _____ release from adipose tissue
Suppress hepatic ______
Skeletal m; adipose
The adipose tissue macrophages and kupffer cells in a healthy individual have an alternative bias, resulting in expression of _____ receptor antagonist and suppression of ______
The resulting serologic state is characterized by relatively low concentrations of insulin, glucose, FFAs, and inflammatory mediators, and high levels of regulatory cytokines
IL-1 (IL1-Ra); IL-1B
Adipose tissue obesity is a chronic _____ disease leading to a predominance of _____-like macrophages
What mediators are released by lean, insulin-sensitive adipocytes to favor the development of anti-inflammatory M2 macrophages?
What mediators are released by obese, insulin-resistant adipocytes to favor the development of pro-inflammatory M1 macrophages?
Long- and Medium-chain FAs
The IL-10 secreted by M2 macrophages activates _____ to secrete more anti-inflammatory mediators that promote further M2 production, while simultaneously inhibiting the action of ____ macrophages
What mediators are released from M1 macrophages to perpetuate the diabetic disease state set up by obese, insulin-resistance adipocytes?
[further induce insulin resistant state]
Besides the mediators released by obese, insulin-resistant adipocytes, what 2 things activate M1 macrophages?
The ______ pathway leads to islet inflammation and beta cell dysfunction
A long chain FA _______ induces beta cell dysfunction in vivo at least partly by activating inflammatory processes in _____
Beta cells sense this molecule via the ______ pathway and recruit inflammatory monocytes to islets by producing ______
The recruited monocytes differentiate into _____ macrophages that play a pivotal role in beta cell dysfunction
T1D is characterized by _______-mediated destruction of pancreatic beta cells resulting in insulin _______
Patients with T1D are prone to ______, a dangerously high level of ____ in the blood
Most cases are characterized by _______ markers of beta-cell destruction and strong _____ associations
Type 1 diabetes is a _______mediated autoimmune disorder; its onset is associated with infiltration of the islets of langerhans by ______ cells and ______ cells
This infiltrate is termed _______
T-cell; mononuclear; CD8 T
Factors contributing to T1D occur at interface between genetics and environment
Islet cell mass ______
MHC I ______
Th1/Th2 ratio ______
All leading to increased beta cell death
T/F: T1D patients and their relatives are at increased risk for other autoimmune diseases like thyroid autoimmunity and Addison disease
About 18 genes of varying potency are associated with susceptibility to T1D. Of these, the most significant are:
The ____ region — the MHC gene on chromosome ____ responsible for Ag presentation
The _____ gene on chromosome 11 — Ag for autoimmune response
Regulators of insulin gene expression in the thymus = ______
The _____ gene on chromosome 2 = regulation of autoimmune response
Central tolerance to insulin is established in the ______ when insulin-Ags are presented within ______ MHC
Thymus; class II
[high-avidity recognition of peptide-MHC complexes on thymic APCs leads to negative selection and apoptotic cell death]
HLA alleles ____ and _____ are high-risk for developing T1D; the former are found in more than 90% of individuals with T1D
[typically found in those who develop T1D early in life]