Block 3 - insulin signaling and insulin resistance in skeletal muscle (L5-6) Flashcards
What are the two critical stages of glucose regulation?
delivery of glucose - through the vascular system to skeletal muscle
transmembrane transport of glucose - from extracellular space into the cytoplasm of a skeletal muscle cell
What three factors determine the vascular delivery of glucose to skeletal muscle?
- output of blood from the heart (cardiac output)
- degree of vasodilation in the vascular bed supplying the skeletal muscle (vascular resistance)
- number of capillary contacts to the skeletal muscle (capillary density)
How does insulin mediate vasodilation?
- insulin stimulates eNOS to produce NO
- NO diffuses to SMC and causes relaxation and vasodilation
- increased capillary recruitment
- greater capillary surface area
- increase delivery of glucose and insulin
What are the downstream effects of insulin receptor activation?
- stimulation of glucose transport
- enhanced glucose storage as glycogen
- increased synthesis and decreased breakdown of proteins
- upregulated lipid synthesis
- alterations in the expression of numerous genes in the nucleus
Describe the stimulation of glucose transport AFTER IRS is activated
- PI3K binds to IRS
- PI3K forms PIP3 from PIP2
- PIP3 recruits PKB and PDK to the membrane
- PDK phosphorylates and activates PKB
- PKB phosphorylates (inactivating) a protein the stops GLUT4 from fusing with the membrane
- GLUT4 inserted into the membrane and more glucose transport
Describe how insulin stimulates glycogenesis in skeletal muscle
- PKB/Akt phosphorylates GSK3, inactivating it, no longer phoshphorylates glycogen synthase (GS)
- since GS is inactive when phosphorylated, it is now stimulated the glycogen synthesis is promoted
Describe how the insulin receptor is deactivated
- insulin disengages or receptor is internalized
- conformational changes are reversed
- tyrosine phosphatases (PTP1B) removes the phosphates from the IRS and IR
- signaling pathway ends, causing GLUT4 to return to intracellular sites in vesicles and glucose transport drops to base rates
Where are GLUT2 and GLUT4 located?
GLUT2 - basolateral membranes of the liver, pancreatic B cells, intestine, and kidney
GLUT4 - skeletal and cardiac muscle, adipocytes, and specific hypothalamic neurons
How many transmembrane domains does a GLUT molecule have?
12
How do the kinetics of GLUT2 and GLUT4 compare?
GLUT2 - rate increases with increases in glucose conc, because GLUT2 is nowhere near being saturated (super high Kt)
GLUT4 - rate is constant over range of glucose conc, increases only occur by recruiting more GLUT4
How does insulin resistance effect glucose delivery to skeletal muscle?
less activation of eNOS
less synthesis of NO
less NO delivered to smooth muscle
less vasodilation (vasoconstriction)
impaired delivery of glucose to skeletal muscle cells
What is the relationship between tyrosine/serine phos. and IR/IRS activity?
more tyrosine phos = more IR/IRS activity
more serine phos = less tyrosine phos and less IR/IRS activity
How does dyslipidemia lead to the PKCtheta isoform? What are the effects?
dyslipidemia, increased lipolysis, increase plasma free fatty acids (FFA), increased DAG accumulation in the plasma membrane (needed to bring PKCtheta close to PDK), increase PKCtheta activation
PKCtheta increases IRS phosphorylation of Ser307
decrease in glucose transport
inhibition of PKCtheta abolishes phos of Ser307, increases glucose transport
How can stress effect IR/IRS?
stress - inflammatory factors and oxidative stress
inflammatory factors: increase CRP, IL6, and other factors
oxidative stress: increase reactive oxygen species, increase IKKB, p38MAPK, JNK, GSK-3B, and other serine kinases
serine kinases increase IRS serine phos/IRS degradation and insulin resistance
When insulin is present, inhibiting of GSK-3B leads to…
increased glucose uptake (increased insulin sensitivity)
