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ER Week 2 > Mechanisms and Genetics of Diabetes > Flashcards

Mechanisms and Genetics of Diabetes Flashcards

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1
Q

WHat are the two general type sof diabetes and what are two additional groups?

A

TD1
TD2
Gestational
Maturity Onset Diabetes of the Yount

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2
Q

How are the MODY inherited?

A

they’re rare, atosomal cominal monogenetic disorders

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3
Q

What types of genes are mutated in MODY?

A

single genes taht disrupt pancreatic geta cell function

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4
Q

What are the 6 differet versions of MODY?

A 
1 	hepatocyte nuclear transcription factor (HNF)-4α
		 2    glucokinase
		 3 	HNF-1α
		 4 	insulin promoter factor-1 
		 5	HNF-1β
		 6 	NeuroD1
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5
Q

What is the mechanism for Type 1 diabetes?

A

insulin is not made because the beta cells are detroyed by an autoimmune process

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6
Q

What are the 2 generally ways Type 1 diabetes can occur?

A
  1. T cell receptors recognizing self antigens of beta cells are not weeked out because of a genetic defect in the immune system
  2. Specific viral infections lead to inflammatory response and the epitopes of the virus mimic the beta cell proteins

both lead to an autoimmune response where the T cell expression the TCR that recognizes beta cell peptides are amplified and mount an immune response against the beta cells.

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7
Q

At what point do people with TD1 become symptomatic?

A

when they have lost aout 80% of their beta cells

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8
Q

What is the treatment for TD1?

A

insulin is the only recourse

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9
Q

What are the major genetic variants associated with T1D?

A

polymorphisms in MHCII genes

in particular, DR3/DQB1 and DR4/DQB1

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10
Q

Describe the role that MHCII molecules play in this pathogenesis?

A

1.

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11
Q

Why do we think the , DR3/DQB1 and DR4/DQB1 are probably associated to diabetes?

A

These particular versions have altered amino acids in the binding site

we think they’re less stable or less effective in binding peptides, so the T cells that can bind Beta cells are more likely to survive and enter circulation

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12
Q

What’s the proof that MCHII alleles are not the whole story?

A

twin concordance is only 40-60%

MHCII polymoerphiss accounr fr oly 40-50% of genetic risk

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13
Q

What does the most current research focus on for TD1?

A

identifying individuals at the earliest stage of the autoimmune process (aided by the fact that a number of td1 specific antibodies have been discovered)

blocking autoimmune process to prevent beta cellddestruction

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14
Q

What are three current clinical trials aimed at preventing dibetes in close relatieves with T1D autoantibodies?

A
  1. teplizumab (antiCD3 - alteres T cell immune response
  2. oral insulin (acts as a decoy for those antibodies to chew on instead)
  3. Abatacept (activates CTL4 leading to T cell inhibition)
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15
Q

What is the etiology for T2D?

A

excess nutrition at the cellular level (hyperglycemia, high FA) leads to inflammation, dysregulated lipid metabolism, and cellular stress

over time, this leads to insulin resistance

The body can then either compensate or progress to relative insulin insufficiency

when that happens, you get beta cell destruction and absolute insufficiency over time.

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16
Q

What is the twin concordance for T2D?

A

70-90%

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17
Q

What are the genes associated with T2D?

A

well, we’ve found many genes associated with beta cell fuction that confer a small risk, but we don’t have the whole answer

TF7L2
ppar gamma
K+channel
zinc transporter
IRS
calpain 10
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18
Q

Where in the body does the insulin resistance occur?

A

many tissues - adipose, skeletal muscle and liver in particular

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19
Q

What are the two main cellular processes tha contirbut to insulin resistance?

A

inflammation and dysregulation of lipid metaoblism

20
Q

Does insulin resistance = T2D?

A

not necessarily

the insulin resistance contributes to beta cell fucntion loss and the T2D is that

21
Q

What is the first stage in the development of insulin resistance from infalmmation in adipose tissue?

A
  1. non-pathogenic - intiial increase in size due to increased uptake of glucose, and storage of TGs
22
Q

What’s the second phase?

A

pro-inflammatory: secretion of monocyte chemoatrractatn protein 1 by adipocytes

23
Q

What’s the third phase?

A

inflammation = recruitment of macropahges, which secrete TNFalpha

24
Q

What does the TNFalpha do?

A

It binds to the TNFR on the adipocyte cell surface

this activates the serine threonine kinase called JNK

JNK phosphorylates and inactivates the Insulin receptor syngaling pathway1

25
Q

What does inactivation of IRS do?

A

it makes insulin signaling ineffective

so the insulin still binds to the receptor, but cannot stimulate translocation of Glut4 and uptake of glucose doesn’t happen

26
Q

So what happens to the free fattya cids in response to this action of TNFalpha?

A

it leads to greatly increased released of free fatty acids

under normal circumstances, the excess fattya cids would be taken up and converted to TGs

27
Q

So what does TNFalpha action do to TG formation?

A

decreases it - you have more free fatty acids instead of TH formation

28
Q

What’s the consequence of those elevated free fattya cids?

A

they promote systemic insulin resistance in peripheral tiseus like skeletal muscle

(also help maintain the insulin resistance that started in the adipocytes)

29
Q

When there are normal levels of circulating FFAs, what will insulin do to skeleal muscle?

A

insulin binding activates insulin receptor

insulin receptor activates the IRS1 and downstream signalling

promtoes GLUT4 into the membrane

glucose enters the cells

30
Q

When there are igh levels of free fatty acids, what happens?

A

1 FFAs compelx with Fetuin A which bind TLR4

  1. TLR4 signalling activates JNK
  2. This phosphotylates the iRS to inhibit insulin signaling
  3. GLUT4 not translocated
  4. No glucose taken up
  5. Hyperglycemia
31
Q

How do you get insulin resistance in hepatocytes?

A
  1. FFA binds to TLR4
  2. IRS phosphorylation

also 1. FFAs taken up by the cells are metabolized to form DAG,
2. DAG activates protein kinase C and phosorylase IRS1

  1. FFAs taken up by the cella re metabolized to form ceramide, which inactivates Akt

so insulin signalling is inhibited

32
Q

How do hepatocytes take up glucose?

A

GLUT2

33
Q

Is GLUT2 regulated by glucose signaling?

A

no

34
Q

Insulin resistance leads to ____ storage and ____ production of glucose

A

decreased storage

increased production

35
Q

What is the frontline drug for T2D?

A

metformin because it limits excess lguconeogenesis

36
Q

What is the MOA for metformin?

A

inhibition of complex 1 of mitochdonrial electron transport chain

37
Q

What kinase is activated after metformin?

A

AMP kinase

so it decreases gluconeogenesis

38
Q

Pancreatic beta cells response to initial hyperglicemia is what?

A
  1. increase in inulin output
  2. relative insufficency due to insulin resistance
  3. destruction due to inflammation
39
Q

What are the two general apopotocis mechanisms for this?

A
  1. hyperglycemia nd FFA leading to oxidative stress and ER stress
  2. Oxidatie stress and ER stress apoptotic pathways.
40
Q

What does excess nutrients cause in all this?

A

overload of the electron transport chain in mitochondria, excess proton gradient

41
Q

Describe endoplasmic reticulum stress?

A

the ER does protein folding and secretion

If you have excess neutrients cause overload of the ER protein capacity

ER stress then activates the unfolded protein response which can lead to apotpsis

42
Q

How do we thin oxidative stress causes this?

A

probalby activates the inflammasome complex, which basically acts to activate the proapotostic cytokine 1beta.

43
Q

1

A

1

44
Q

1

A

1

45
Q

What are advanced blycation end products?

A

they are non-enzymatically modified proteins with sugars or lipids on them - omr in hyperglycemia enviornmetns

These will accumulate in vessels walls

46
Q

What do these AGE products bind to>

A

soluble form binds to receptors for AGE - RAGE

47
Q

What does activated RAGE do?

A

binds to macrophages ROS to promote release of inflammatory cytokines

ER Week 2 (10 decks)

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