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Endo/Repro: Week 2 > Scott: Mechanism and Genetics of Diabetes > Flashcards

Scott: Mechanism and Genetics of Diabetes Flashcards

1
Q

What is maturity onset diabetes of the young?

A

Rare, autosomal dominant , monogenetic disorders

Caused by mutations in single genes that disrupt pancreatic β cell function.
Give clues to important functions in β cells.

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2
Q

What is the etiology of T1D?

A

Insulin is not made because pancreatic beta cells are

destroyed by an autoimmune process.

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3
Q

What is hte autoimmune process that leads to the destruction of beta cells?

A 
Genetic defect>
TCR that recognize self NOT weeded out>
Viral infection>
viral epitope mimics B cell protein>
TCR (that wasn't weeded out) that recognize B cells are amplified>
IR against cells>
80% destroyed>
individuals become assymptomatic
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4
Q

How do viral infections lead to an inflammatory response?

A

Epitopes of some viruses mimic beta cell proteins

viruses promote inflammatory cytokine production

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5
Q

What are the major genetic variants associated with T1D?

A

polymorphisms in MHCII genes

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6
Q

How are T cells that can initiate an autoimmune response usually eliminated?

A

USUALLY during T cell development, MHCII proteins present “self” peptides. T cells expressing TCR that STRONGLY binds MHCII + self are targeted for apoptosis.

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7
Q

What is tolerance and how does it relate to MHCII?

A

Tolerance requires that individual’s MHCII proteins can bind self antigens.

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8
Q

What influences an individual’s immune response and tolerance?

A

Different MHCII alleles encode MHCII proteins w/ different peptide binding capabilities

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9
Q

What MHCII polymorphisms are strongly associated w/ T1D?

A

DR3/DQ1*0201

DR4/DQ1*0302

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10
Q

Why are DQB1 alleles associated with diabetes?

A

altered AA site binding site>
weaker interaction with peptides

*Most high risk variants of MHCII can’t bind pancreatic B cell peptides strongly so T cells carrying TCR for these peptides aren’t weeded out during development

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11
Q

Can T1D be prevented?

A

Current research aims to identify individuals at an earlier stage of the AI process and BLOCK it to prevent B cell destruction

*Current clinical trials aim at prevetening diabetes in close relatives w/ T1D autoantibodies

(Teplizumab)

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12
Q

What is the MCC of T2D in individuals of european descent?

A

Obesity

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13
Q

Does genetics play a role in T2D?

A

Twin concordance 70-90%
One parent Increases chances
Two parents 40%

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14
Q

What is the precursor to T2D?

A

insulin resistance–decreased ability to respond to insulin

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15
Q

How does insulin resistance develop?

A

Insulin resistance develops through processes like inflammation and dysregulation of lipid metabolism in:

adipose
skeletal muscle
liver

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16
Q

When does T2D occur?

A

ONLY if beta cell fxn is lost

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17
Q

What are the several stages of chronic inflammation in adipose tissue that leads to insulin resistance?

A
  1. initial increase in size of adipocytes> increased uptake of glucose and TG storage
  2. Pro-inflammatory secretion of MONOCYTE CHEMOTRACTANT protein
  3. Inflammatory recruitment of MPHAGES
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18
Q

How does the secretion of TNFa lead to insulin resistance in adipocytes?

A

TNFa binds to TNFR on adipocyte cell>
activates serine threonine kinase (JNK)>
JNK phosphorylates and inactivates IRS>
inactivation of IRS makes insulin signaling ineffective (INSULIN RESISTANCE)

19
Q

What happens to insulin in adipose tissue that is “insulin resistance”?

A

insulin still BINDS to receptor but can’t stimulate translocation of Glut4 and uptake of glucose

20
Q

How does TNFa promote SYSTEMIC insulin resistance?

A

Increases the release of FFA>

promotes IR in skeletal and peripheral tissue

21
Q

What happens in adipose tissue under conditions of excess nutrition and inflammation?

A

Favors free FA release over TG formation>

Decreased glucose uptake

Activation of HSL

TNFa inhibits PPARy activity

22
Q

What plays a major role in skeletal muscle insulin resistance?

A

elevated FFA

23
Q

What happens in skeletal muscle in the presence of excess FFA?

A 
FFA complex w/ FetuinA>
bind TLR4>
signals and activates JNK>
activated JNK phosphorylates IRS>
inhibits insulin signaling>
GLUT4 is not translocated>
glucose is not taken up>
leads to more glucose free in circulation
24
Q

What is the source of most of the excess glucose that contributes to T2D?

A

hepatocytes

25
Q

How do hepatocytes take up glucose? Is this regulated by insulin?

A

GLUT 2

NOT regulated by insulin

26
Q

What is the mechanism by which FFA in the hepatocytes lead to insulin resistance?

A

FFA bind TLR4>
IRS phosphorylation

FFA taken up by the cell are metabolized to form DAG> PKC> IRS

FFA taken up by the cell are metabolized to form ceramide which inactivates Akt

27
Q

What are the two mechanisms by which insulin resistance leads to decreased storage and increased production of glucose in the liver?

A
  1. inhibition of glycogen synthesis (decreased phosphorylation of GSK3, decreased activity of GS)
  2. Increased gluconeogenesis (translocation of FOXO1 to nucleus and trxn of gluconeogenesis enzymes)
28
Q

What is the main cause of elevated blood glucose in a pt w/ T2D?

A

unregulated liver gluconeogenesis

29
Q

Why is Metformin the front line drug for tx of T2D? What is the MOA of Metformin?

A

limits excess gluconeogenesis

Inhibits complex 1 of mitochondrial ETC> decreased energy change> increased AMP/ATP:

  1. Activation of AMPK> increased FA oxidation and decreased lipogenesis
  2. Inhibition of gluconeogenesis at SEVERAL steps
30
Q

How do the interactions among insulin resistance tissues affect insulin resistance?

A

amplifies hyperglycemia

31
Q

What is the pancreatic beta cell response to initial hyperglycemia?

A
  1. increase insulin output to overcome affects of decreased signaling
  2. relative insufficiency d/t insulin resistance
  3. in T2D destruction of beta cells d/t inflammatory process
32
Q

When does T2D develop?

A

When insulin secretion can’t keep up d/t:

  1. genetic susceptibility (SLC30A8)
  2. Apoptosis as a result of excess nutrients
33
Q

What mechanisms contribute to apoptosis of beta cells?

A

hyperglycemia and FFA>
oxidative and ER stress>
activates apoptotic pathways

34
Q

How does oxidative stress lead to beta cell dysfunction?

A 
excess nutrients>
overloads ETC>
excess H gradient>
transfer of e to copmlex III is inhibited>
electrons are transfered to O instead>
generates ROS>
increased ROS >
oxidative stess
35
Q

Why are beta cells highly susceptible to damage by ROS?

A

low levels of anti-oxidant enzymes

36
Q

How do excess nutrients cause ER stress?

A 
ER site of protein folding for insulin>
ER stress>
signaling pathways called UPR>
unfolded protein response>
initiates apoptosis
37
Q

What is the connection between ER stress and apoptosis?

A

Oxidative stress and ER stress activate the inflammasome complex

38
Q

What is hte inflammasome complex?

A

activates pro apoptotic cytokine IL1b>
IL1B binds to pancreatic B cell>
apoptosis

39
Q

What is responsible for many of the consequences of T2D?

A

ER/oxidative stess and advanced glycosylation end products (AGE)> leading to vascular damage

40
Q

What are three of the main end consequences of T2D?

A
  1. foam cells in arteries> plaques> CVS risk
  2. GC disruption of filtration barrier> end stage kidney disease
  3. Retinal capillary> increased permeability> angiogenesis> adult onset blindness
41
Q

What is AGE?

A

Advanced glycation end produc

42
Q

What is the mechanism of age?

A

Non-enzymatic modificiation of proteins by sugars and lipids that are formed in hyperglycemic environments>
accumulates in vessel walls>
vascular disease

43
Q

How do AGEs cause vascular disease?

A
  1. disrupt fxn by adding bulky non-functional modification by promoting crosslinking
  2. Soluble form binds to receptors> promotes formation of ROS> promotes release of inflammatory cytokines

Endo/Repro: Week 2 (11 decks)

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