Glucose Metabolism Flashcards
Which is a more important source of blood glucose: dietary carbohydrate or liver stores?
liver stores
Mutations in glucokinase cause what autosomal dominant disease?
maturity onset diabetes of the young type 2
What part of the insulin signalling pathway is disrupted with a glucokinase mutation?
the glucose desn’t get phoshprylated to glucose-P (which is necessary for the glucose to be oxidized to ATP and without that ATP you don’t get the K channel to close, etc. etc)
We know the insulin receptor is a tyrosine kinase. What does it do?
It dimerizes and auto-phosphorylates in order to be able to phosphorylate phosphatidyl inositol 3-kinase (PI-3kinase) to make PIP.
What does that PIP do?
It binds to PDK1 and PKB (Akt) and recruits them to the plasma membrane
What does activated PDK1 do?
it phosphprylates and activates PKB (that’s why they need to be help close to each other by PIP)
What does PKB do?
is phosphorylates more intracellular targets to modulate metabolism
such as…phosphorylating and inactivaging glycogen synthase kinase 3 (so it’s unable to inhibit glycogen synthase) and phosphorylating and activating protein phosphatase 1
turns on glucogen synthase
How does activated PKB (Akt) block the expression of key gluconeogenesis genes?
It will block the transcription factor FOX01 - phosphorylates it so it can’t enter the nucleus
What are those glucoenogenesis genes that FOX01 will trigger?
G6-Pase and PEP-CK
Describe the signalling pathway for glucagon
Glucagon activates it’s GPCR
- activates adenylate cyclase
- increase levels of cAMP
- cAMP activates protein kinase A
- PKA phosphorylase the transcription factor CREB
What does the transcription factor CREB activate transcriptoin of?
lots of things, but in particularly - PGC1alpha,
What is PGC1alpha?
It’s a transcriptional coactivator that is neessary for the transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase)
How does PEP-CK promote gluconeogenesis?
It is the cytoplasmic enzyme that converts oxaloacetate to PEP, so you need if if you’re using alanine or lactate as a substrate for gluconeogensis (not necessary if you’re using glycerol)
How does G-6-Pase promote gluconeogenesis?
It’s located near the plasma membrane and is responsible for removing the phosphate from glucose so that it can exit the hepatocyte through the GLUT 2 transporter
without it, any glucose the cell made would just be stuck inside
What bifunctional anzyme is phosphorylated and activated by PKA besides CREB?
Phosphofructokinase-1
What does PFK-2 do?
- phosphorylates fructose 6 phosphate to make fructose 2,6,bisphosphate
- Dephosphotylates fructose 2,6bisphsphate to make fructose 6 phosphate
so it will convert them back and forth
Which direction will the reactoin go if PFK-2 is phosphorylated?
phosphorylation inhibits the kinase activity and activates the phosphatase activity, so decreases the pool of fructose 2,6-bisphosphate
What does fructose 2,6, bisphosphate do?
it allosterically inhibits fructose 1,6, bisphosphatase and allosterically activates the liver isoform of phosphofructokinase 1
Does glucagon signal an increas or decrease in fructose 2,6-bisphosphate?
a decrease
What does this disease in F26B do?
it inhibits glycolysis and promotes gluconeogenesis
Normally, PGC1alpha-dependent transcription of PEPCO and G6Pase requires what additional coactivator?
TORC2
aka CRTC2
How does metformin affect this system?
It will activate LKB1, which activates AMPK, which phosphorylates TORC2 to inhibit it’s nuclear localization, thus preventing transcription of the gluconeogenesis genes
What does metformin do to the ATP production by the mitochdonria?
decreases it, which means concentration of AMP goes up, which then inhibits adenylate cyclase so you lose the cAMP activation of PKA etc. etc.
basically disrupts the signalling that would take place with glucagon
Normally the inner mitochondrial membrane is impermeable to protons, meaning they can only cross back to the matrix thorugh ATP synthase. What do mitochondrial uncouplers do?
they dissipate that proton gradient without generating ATP
What are some exampes of uncouplers?
UCP2 (an endogenous one that punches holes in the membrae)
dinitrophenol and salicylates can just diffuse back and forth and dissipate the protons along the way
How is this uncoupler discussion relevant to a a lecture on glucose metabolism?
Clinical studies are currently looking to see if extended release uncouplers could be a diabetes treatment
in theory, uncoupling would mean the body couldnt use glucose efficiently, so it would need to use more in order to make enough ATP. This would take care of hyperglycemia
essentially improving glucose tolerance
What does testosterone do to insulin receptor expression?
increases it
also does other things to basically enhance cellular responsiveness to insulin…
increase GLUT4, increase glycogen synthase activity, inhibit glycogen phosphorylase
How do increased adipose tissue and testosterone interact in relation go insulin effects?
increased adipose tissue will increase the ativity of aromatase
aromatase will convert testosterone to estradiol
estradiol directly inhibits the hypothalamic pituitary-testis axis, which further decreases testosterone levels
the lower testosterone means you don’t have the same sensitivity to insulin. furthermore, without the testosterone inhibition, lipoprotein lipase can be active and will promote the uptake of triglycerides, further increasing adipose tissue deposition
snow ball effect
What cells support the developing spermatocytes?
sertoli cells
What do the sertoli cells do for the spermatocytes in terms of energy sources?
sertoli cells will ferment the glucose to pyruvate
most of that pyruvate will be further converted to lactate, which is then given to the spermatocytes for oxidation
What transporter will export the lactate from the sertoli cell and what will take it up into the spermatocyte?
MCT4 out of the sertoli
MCT2 in2 the spermatocyte
What cell does something similar to the developing oocyte in females?
cumulus cells
