Insulin action & insulin resistance // T2DM Flashcards
What are the cellular effects of insulin in terms of what insulin promotes ?
- Glycogen synthesis ( liver & muscle)
- Glucose uptake ( muscle& adipose)
- Fatty acid synthesis ( liver)
- DNA replication
- Gene expression ( also inhibitory)
- Protein synthesis
What are the inhibitory cellular effects of insulin
- Glycogenolysis ( liver & muscle)
- Lipolysis ( adipose)
- Cell apoptosis
- Gene expression ( also promoted)
Outline the mechanism of action of insulin
- Insulin binds the receptor
- The receptor is autophosphorylated
- IR catalyses tyrosine phosophorylation of insulin receptor substrates IRS
- IRS-1 activates several signalling pathways
What is the PI3-K pathway involved in?
The phosphatidyl inositol 3 OH kinase pathway is involved in protein, carbohydrate & fat metabolism
What is the MAP pathway involved in
The Mitogen activated protein kinase pathway is involved in cell growth & differentiation through ras
What is the function of ras proteins
- 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
Outline what happens after IRS-1 binding & phosphorylation & subsequent activation of PI3-K
- 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
What can premature activation of protein kinase B lead to ?
Insulin resistance
Explain how Akt/PKB is activated
- 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
What is the difference between the whereabouts of GLUT4 transporters in the presence of insulin compared to in the absence of insulin?
- 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
Explain the effect of insulin on gene expression through RAS & MAPK
- 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
What is ras
- An oncogene product, a small GTPase
- It is a signal transduction protein
- It activates a number of pathways
- MAP kinase pathways are particularly important
Outline the termination of the insulin signal
- 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
Explain insulin resistance and the consequences of it
- 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
What are the causes of insulin resistance
- 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
What is the role of adipose tissue in development of insulin resistance
- 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
Outline the characteristics of the obese state that are key in development of insulin resistance & what they interfere with
- Chronic inflammation
- Oxidative stress
- Hyperinsulinaemia
- Lipotoxicity
They interfere with:
- Insulin secretion
- Insulin signalling pathways
- Glucose transport
- Insulin receptor numbers & binding affinity
State the ‘good’ adipose derived metabolites/hormones/cytokines
- LEPTIN: increases insulin sensitivity, but the obese are often leptin resistant
- ADIPONECTIN: which increases insulin sensitivity is decreased in obesity
State the ‘bad’ adipose derived metabolites/hormones/cytokines
- 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
Explain the role of inflammation in obesity
- 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
Explain the role of oxidative stress in obesity
- 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
What is the role of lipotoxicity in obesity?
- 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
What is metabolic syndrome
- Abdominal ( central) obesity ( waist measurement rather than/ as well as BMI)
- High blood pressure
- High blood glucose
- High serum triacylglycerols
- Low HDL conc.
What causes metabolic syndrome?
- 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
What is the link between T2DM & metabolic syndrome
- 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
