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Flashcards in Immunological Mechanisms of Diabetes Deck (79)
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1

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

True

2

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

3

What race has a 10 fold higher prevalence of T2D — 50% of which occurring at age 20?

Pima indians

4

Other than the proven genetic component of developing T2D, what are some behavioral/environmental factors contributing to T2D?

Sedentary lifestyle
High fat diet
Pollution (pesticides, herbicides, traffic-related pollutants PM and NO2)

5

Pesticides and herbices disturb ____ metabolism and induce insulin _____

Glucose; resistance

6

Risk factors that contribute to development of T2D

Body fat - particularly abdominal fat
Insulin resistance
Ethnicity (greater risk in african american, hispanic, and native american children)
Onset of puberty

[these risk factors appear to act in additive fashion)

7

High correlations between percentage body fat and _____ _____are found in obese children

Fasting insulin

8

What are levels of the following like in a person with healthy pancreatic beta cells:

Serum insulin
Serum glucose
Serum FFA
Serum IL-1B
Serum IL-1Ra

Low Serum insulin
Low Serum glucose
Low Serum FFA
Low Serum IL-1B
High Serum IL-1Ra

9

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

10

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

11

_____ is characterized by chronic activation of inflammatory pathways

It is increasingly recognied that inflammation in this condition are causally linked to insulin ______

Obesity; resistance

12

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

FFA

Gluconeogenesis

13

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

14

Adipose tissue obesity is a chronic _____ disease leading to a predominance of _____-like macrophages

Inflammatory; M1

15

What mediators are released by lean, insulin-sensitive adipocytes to favor the development of anti-inflammatory M2 macrophages?

Short-chain FA
IL-13
IL-4

16

What mediators are released by obese, insulin-resistant adipocytes to favor the development of pro-inflammatory M1 macrophages?

Long- and Medium-chain FAs
Chemokines
MCP-1
TNF-alpha

17

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

Adipocytes; M1

18

What mediators are released from M1 macrophages to perpetuate the diabetic disease state set up by obese, insulin-resistance adipocytes?

TNF-a
IL-1B
IL-6
Resistin
NO

[further induce insulin resistant state]

19

Besides the mediators released by obese, insulin-resistant adipocytes, what 2 things activate M1 macrophages?

LPS
IFN-y

20

The ______ pathway leads to islet inflammation and beta cell dysfunction

Palmitate-TLR-4

21

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

Palmitate; islets

TLR4/MyD88; chemokines

M1

22

T1D is characterized by _______-mediated destruction of pancreatic beta cells resulting in insulin _______

Immune; deficiency

23

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

Ketoacidosis; ketones

Autoantibody; HLA

24

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

Insulitis

25

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

Decreases

Increases

Increases

26

T/F: T1D patients and their relatives are at increased risk for other autoimmune diseases like thyroid autoimmunity and Addison disease

True

27

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

HLA; 6

Insulin

AIRE

CTLA-4

28

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]

29

HLA alleles ____ and _____ are high-risk for developing T1D; the former are found in more than 90% of individuals with T1D

DQ2/DQ8; DR3/DR4


[typically found in those who develop T1D early in life]

30

Heterozygous genotypes _______ are most common in children diagnosed with T1D prior to age 5 (50%)

DR3/DR4