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Inflammation block > Insulin action & insulin resistance // T2DM > Flashcards

Insulin action & insulin resistance // T2DM Flashcards

1
Q

What are the cellular effects of insulin in terms of what insulin promotes ?

A
  • Glycogen synthesis ( liver & muscle)
  • Glucose uptake ( muscle& adipose)
  • Fatty acid synthesis ( liver)
  • DNA replication
  • Gene expression ( also inhibitory)
  • Protein synthesis
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2
Q

What are the inhibitory cellular effects of insulin

A
  • Glycogenolysis ( liver & muscle)
  • Lipolysis ( adipose)
  • Cell apoptosis
  • Gene expression ( also promoted)
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3
Q

Outline the mechanism of action of insulin

A
  • Insulin binds the receptor
  • The receptor is autophosphorylated
  • IR catalyses tyrosine phosophorylation of insulin receptor substrates IRS
  • IRS-1 activates several signalling pathways
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4
Q

What is the PI3-K pathway involved in?

A

The phosphatidyl inositol 3 OH kinase pathway is involved in protein, carbohydrate & fat metabolism

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5
Q

What is the MAP pathway involved in

A

The Mitogen activated protein kinase pathway is involved in cell growth & differentiation through ras

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6
Q

What is the function of ras proteins

A
  • Ras proteins function as binary molecular switches that control intracellular signaling networks.
  • Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, cell proliferation, cell differentiation, cell adhesion, apoptosis, and cell migration
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7
Q

Outline what happens after IRS-1 binding & phosphorylation & subsequent activation of PI3-K

A
  • An increase in the glucose transporter (Glut 4) molecules on the plasma membrane of insulin-sensitive tissues eg muscle & adipose tissuse
  • Glut 4 is transporter from cellular vesicles to the cell surface
  • This leads to increased uptake of glucose from blood
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8
Q

What can premature activation of protein kinase B lead to ?

A

Insulin resistance

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9
Q

Explain how Akt/PKB is activated

A
  • Activation of AKT/ protein kinase B follows the binding of insulin to its receptor
  • IRS bind the phosphorylated receptor with their SH2( src homology) domain& are themselves phosphorylated & activated
  • The phosphorylated IRS phosphorylates and activates PI3-Kinase
  • Which is attracted to the membrane by virtue of its PH (pleckstrin homology) domain
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10
Q

What is the difference between the whereabouts of GLUT4 transporters in the presence of insulin compared to in the absence of insulin?

A
  • GLUT4 transporters are in vesicles in the interior of the cell in the absence of insulin
  • In the presence of insulin the vesicles take the transporters to the plasma membrane
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11
Q

Explain the effect of insulin on gene expression through RAS & MAPK

A
  • The adaptor protein SHC docks at the phosphorylated tyrosine furthest away from the membrane
  • It activates the anchored protein Ras by phosphorylation
  • There follows a cascade of ras phosphorylating & activating raf
  • This then phosphorylates & activates MEK kinase
  • Which phosphorylates & activates MAPK
  • Which phosphorylates specific transcription factors
  • Leading to effects on gene expression & cell differentiation & proliferation
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12
Q

What is ras

A
  • An oncogene product, a small GTPase
  • It is a signal transduction protein
  • It activates a number of pathways
  • MAP kinase pathways are particularly important
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13
Q

Outline the termination of the insulin signal

A
  • Sustained insulin action would be detrimental to the system
  • A number of mechanisms to end the signalling
  • Protein phosphatases & phosphoinositide phosphatases inhibit at several points in the signalling pathway
  • Phosphorylation of IRS on serine/threonine sites is another mechanism for switching off
  • Emerging as an important link in the aetiology of insulin resistance
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14
Q

Explain insulin resistance and the consequences of it

A
  • Condition in which normal amounts of insulin are inadequate to maintain normal concentrations of blood glucose
  • Both insulin & glucose are high
  • Often associated with obesity
  • Reduces glucose uptake in muscle cells so reduces glycogen synthesis and storage
  • In liver cells it reduces glycogen storage
  • Both result in a high conc of glucose
  • High plasma levels of insulin and glucose due to insulin resistance often leads to metabolic syndrome and type 2 diabetes
  • In fat cells it reduces the effects of insulin
  • Results in lipolysis & increased FA conc. in the blood
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15
Q

What are the causes of insulin resistance

A
  • Insulin receptors are down regulated because of the high conc. of circulating insulin
  • Interference with the signalling pathway
  • Inflammation also contributes to insulin resistance
  • (possible hypothesis) a number of these adipose tissue produced hormones & metabolites may inhibit IRS activation
  • The switching off mechanisms may be activated
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16
Q

What is the role of adipose tissue in development of insulin resistance

A
  • Plays a crucial role in development of insulin resistance
  • It produces a number of metabolites/hormones/cytokines which modulate metabolism
  • Visceral adipose tissue mainly implicated in insulin resistance
  • Obesity= a well known risk factor for insulin resistance which can lead to T2DM
17
Q

Outline the characteristics of the obese state that are key in development of insulin resistance & what they interfere with

A
  • Chronic inflammation
  • Oxidative stress
  • Hyperinsulinaemia
  • Lipotoxicity

They interfere with:

  • Insulin secretion
  • Insulin signalling pathways
  • Glucose transport
  • Insulin receptor numbers & binding affinity
18
Q

State the ‘good’ adipose derived metabolites/hormones/cytokines

A
  • LEPTIN: increases insulin sensitivity, but the obese are often leptin resistant
  • ADIPONECTIN: which increases insulin sensitivity is decreased in obesity
19
Q

State the ‘bad’ adipose derived metabolites/hormones/cytokines

A
  • FFS & DAG: can impair insulin sensitivity by interfering with IRS activation
  • TNF-alpha: interferes with IRS activation (it is secreted by adipose tissue in obesity)
  • Resistin: some studies show it’s bad & some irrelevant
20
Q

Explain the role of inflammation in obesity

A
  • Adipose expansion in obesity recruits monocytes which become macrophages
  • They secrete proinflammatory cytokines eg TNFalpha and IL-6
  • They lead to increased secretion of FFA ( usually insulin esterifies the FFAs but now it does the opposite & they are released) & ceramide
  • decreased secretion of adiponectin
  • TNFalpha causes ser phosphorylation through JNK kinase which terminates insulin signal prematurely ( the association between inflammation & insulin resistance appears to be through phosphorylation in the wrong place)
  • Anti-inflammatory therapies show decrease in IR but not cure, so inflammation can’t be the only factor
21
Q

Explain the role of oxidative stress in obesity

A
  • In obesity the oversupply of FA and glucose to the mitochondria leads to ROS ( reactive oxygen species) overproduction
  • They interfere with PI3K activity
  • Treatment of IR patients with antioxidants ascorbic acid & tocopherol had mixed results
22
Q

What is the role of lipotoxicity in obesity?

A
  • There is an increased flux of FFA & TAG & ceramide in obesity associated with IR
  • Interfere with phosphorylation of IRS causing premature signal termination
  • Exercise in T2D patients reduced ceramide & DAG, but trained athletes had high ceramide and no IR
  • also had higher ROS & no IR
  • Thiazolidinediones which inhibit lipolysis showed some improvement in insulin sensitivity
23
Q

What is metabolic syndrome

A
  • Abdominal ( central) obesity ( waist measurement rather than/ as well as BMI)
  • High blood pressure
  • High blood glucose
  • High serum triacylglycerols
  • Low HDL conc.
24
Q

What causes metabolic syndrome?

A
  • Possibly obesity or insulin resistance
  • Could be consequences of another metabolic derangement
  • A number of markers of systemic inflammation markers including CRP are often increased
  • Cause not well known/understood
25
Q

What is the link between T2DM & metabolic syndrome

A
  • T2DM is considered a complication of metabolic syndrome
  • In a patient with impaired glucose tolerance or impaired fasting glucose who also has the characteristics of metabolic syndrome the risk of developing T2DM is twice as high

Inflammation block (27 decks)

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