5Obesity - Obesity and Diabetes (Part 3) Flashcards
How is endocrine signalling from the adipose tissue linked to diabetes?
In diabetes we get disfunction in the signalling from adipose tissue
We sense signals from adipose tissue:
Adipose tissues release small amounts of FFAs and inflammatory cytokines = this is normal and required for tissue homeostasis
However, in obesity the adipose tissue mass expands but the lean body mass (the mass of the other organs) does not = concomitant increase in the levels of the FFAs and inflammatory cytokines = amount release is far greater than is needed in the liver, pancreas and muscle tissues. This leads to:
Liver = glucose output increases
Muscle = glucose uptake decreases = muscle signals to liver that it is starving = leading to liver producing more glucose via gluconeogenesis
Circulating blood glucose increase
As disease progresses, if lipid gets into pancreas = lipo-apoptosis of beta cells
How does obesity delay the onset of diabetes?
Obesity does not cause diabetes = in many ways it protects against diabetes = prevents it for a very long time = obesity is a way of avoiding diabetes
What can ectopic fat deposition lead to?
Ectopic fat deposition can lead to apoptosis = isolating it to adipose tissue is actually protective
How does the Randall Hypothesis describe insulin resistance?
Insulin resistance in these terms = decreased muscle uptake of glucose.
Glucose enters the muscle via GLUT4 = insulin causes GLUT4 to go the surface of the cell
Goes through glycolysis to produce pyruvate = goes to mitochondria and is used in the citric acid cycle
LCFA enter cell via CD36 = then converted to LCF acyl coA = goes to mitochondria via CPT-1 = undergoes beta-oxidation
What did Randall hypothesise regarding which fuel source the body would use?
Randall hyporthesised that the body would use whichever fuel source was in greatest supply = in obesity this is LCFA = production of citrate
Citrate is an inhibitor of GLUT4 and PFK1 = inhibit glycolysis
Acetyl CoA can also inhibit pyruvate dehydrogenase = build up of pyruvate
These processed will inhibit glucose uptake and glucose utilisation
Glucose-6-phosphate is never seen in high concentrations however this is probably due to the fact that it can be used for other pathways
What is the mechanism of inhibition of glucose utilisation by fatty acid oxidation?
Mechanism of inhibition of glucose utilization by fatty acid oxidation.
The extent of inhibition is graded and most severe at the level of pyruvate dehydrogenase (PDH) and less severe at the level of 6-phosphofructo-1-kinase (PFK) and glucose uptake.
PDH inhibition is caused by acetyl-CoA and NADH accumulation resulting from fatty acid oxidation, whereas PFK inhbition results from citrate accumulation in the cytosol.
The mechanism of inhibition of glucose uptake is not clear. These effects reroute glucose toward glycogen synthesis and pyruvate to anaplerosis and/or gluconeogenesis.
How does insulin signalling work?
Insulin binding causes phosphorylation of 3 bound tyrosine residues
There are three major pathways:
Cell growth/gene expression = not susceptible to insulin resistance
Glucose transport = does impinge on glucose transport but is mainly unaffected
Glycogen synthesis = most affected by insulin resistance
PI3 Kinase pathway is the most susceptible to insulin resistance:
Insulin binding to insulin receptor causes phosphorylation of tyrosine residue = this leads to binding of IRS1 = IRS1 is also phosphorylated on a tyrosine residue
IRS1 recruits PI3 kinase = PI3 kinase produces PIP3 which activates PDK1 = phosphorylates two targets = Protein kinase C zeta and Protein kinase B/AKC = stimulates glucose transport and stimulates glycogen synthesis
PKC zeta is an atypical protein kinase C
What are the features of the insulin signalling pathway?
Insulin interacts with the α-subunits of its receptor, leading to an increase in the autophosphorylation and the tyrosine kinase activity of the β-subunits.
The docking proteins Shc and IRS-1 interact with the Tyr960 in the juxtamembrane domain of the receptor while APS (adaptor protein with a PH and SH2 domain) interacts with Tyr1158/1162 in the catalytic domain.
Those interactions allow the tyrosine phosphorylation (pY) of these proteins which in turn bind and activate several signalling proteins.
Recruitment of the Grb2–SOS complex to tyrosine-phosphorylated Shc activates the MAPK cascade, which is involved in cell growth and regulation of gene expression.
Association between PI 3-kinase (PI3K) and IRS-1 increases the amount of PtdIns3P that activates PDK1 and its effectors, the Ser/Thr kinases PKB and atypical PKCζ. These kinases are involved in the stimulation of glucose uptake.
PKB is also involved in insulin-induced glycogen synthesis by phosphorylating and inactivating glycogen synthase kinase-3.
The interaction between tyrosine-phosphorylated APS and the CAP–Cbl complex allows the tyrosine phosphorylation of Cbl by the insulin receptor.
Phosphorylation of Cbl mediates glucose transport by a pathway independent of PI 3-kinase and dependent on the activation of the small GTPase TC10. MEK, MAPK/extracellular-signal regulated kinase kinase.
What is the fate of free fatty acids?
When FFAs enter the cell the main thing that they will be used for is beta oxidation.
However, they also have other uses:
Can produce Ceramide
Can also produce triglyceride
Depends not only on the amount of fat but also on the type of fat:
Saturated fat = Messes up cell membrane fluidity and is not very well esterified doesn’t get turned into triglyceride = produces Di-acyl glyceride = potent signalling molecule
Unsaturated = produces triglyeride easily
Having unsaturated fat with saturated fat helps more of it to become triglyceride
Why can ceramide, DAG and glucosamine interfere with insulin signalling?
Ceramide, DAG and glucosamine are all signalling molecules in their own right = build up of these ancillary products are problematic = interfere with insulin signalling
How does LCACoA induce insulin resistance?
LCACoA comes in start to produce Ceramide, DAG and Hexosamines
These can all activate protein kinase C (PKC)
Ceramide activates CAPP (PP2A) and CAPK
These can lead to insulin resistance
How does free fatty acid accumulation cause alternate phosphorylation of IRS?
Major parts of IRS-1 include:
PI3K binding site = Ser 612 and 632
Phospho-tyrosine binding domain = Ser307
FFA accumulation causes alternate phosphorylation of IRS
Insulin usually activates JNK = which can then phosphorylate Ser307 = this inhibits the binding of IRS1 to the insulin receptor and targets IRS1 for degradation = classic feedback inhibition = allows transient signal/ transient uptake of glucose = if glucose was taken into muscle continuously blood glucose levels would fall = brain is entirely dependent on glucose for survival = you would die
FFA can hijack this pathway = FFAs themselves - in particular palmitate can activate JNK = scientists don’t know why
FFA in excess will also lead to a build up of diacyl glycerol (DAG) = which activates protein kinase C theta = which can directly phosphorylate Ser 307
Insulin usually causes tyrosine residues (Tyr608 and Tyr628) in the PI3 kinase binding site to become phosphorylated = allowing IRS to recruit PI3k
FFA can activate protein kinase C theta which can phosphorylate Ser 612 and Ser 632 = this inhibits PI3 kinase binding and inhibits the ability to phosphorylate tyrosine 608 and 628 = leading to an overall reduction in the interaction of IRS1 with PI3 kinase
A combination of these two factors will inhibit the transduction of the insulin signalling
What is the argument against the theory that free fatty acid accumulation can lead to insulin resistance via alternate phosphorylation of IRS1?
Argument against this theory is that if you look at muscle samples from people who are insulin resistant you don’t see phosphorylation of Ser 307, Ser612 and Ser632
However, can only see this in cells for very short periods of time = very hard to reproduce in humans
If done in cell culture = you do see it
This is probably happening to a degree along with Randall’s Hypothesis and all these factors converge to cause Type II diabetes
What can lead to the synthesis of ceramide?
FFA converted to Palmitoyl CoA = Palmitoyl CoA converted to Ketosphinganine = Ketosphinganine converted to Sphinganine = Sphinganine converted to Dihydroceramide = Dihydroceramide converted to Ceramide
In addition, TNF-alpha and sphingomyelinase also increase the conversion of sphingomyelin to ceramide
TNF-alpha is a pro-inflammatory cytokine
What can a build up of glucosamine cause?
Glucosamine can lead to a build-up of UDP-GlcNAc; an excess of FFA will cause more Fructose 6-phosphate from the glycolysis pathway to be converted to GLcN-6P by GFAT and this will eventually also end up as UDP-GlcNAc
UDP-GlcNAc = allows glycosylation of proteins
