Flashcards in Zeidi Insulin pathways and signaling Deck (16):
Insulin "big picture" stuff
glucose upregulates preproinsulin mRNA transcription. afterwards it is cleaved to preinsulin in the ER lumen and then cleaved to insulin in the Golgi
there are two pools: rapidly ready release pool (less than 5% of total insulin supply) which can be released at the get-go, but 95% requires time to transcribe
Glucose increases insulin stability
when are the 3 disulfide bonds added to insulin?
in the ER lumen
what glucose transporter is used in the liver?
how is it trapped in the cell?
GLUT2 and glucokinase phosphorylates it, trapping in hepatocyte
how does glucose "cause" the release of insulin?
glucose metabolism creates an unswing in the ATP/ADP ratio, which inactivates something called the Katp channel. this leads to activation of Ca channels, whose sudden upsurge intracellularly causes readily release pools to bind to the membrane and release insulin
Ras dependent PW "big picture"
leads to phosphorylation of GRB2 ---> RAS protein activation, followed by Ras-Map PW--->
ultimately, it leads to glucokinase transcription, which increases glucose trapping in the cell
Ras independent PW "big picture"
ultimates leads to GLUT4 (muscle and adipose tissue) and glycogen synthase synthesis, allowing glucose into the cell and converted into storage form
the Ras independent PW activates what protein?
PI3 and PKB
RTK: what sets the stage for the RAS and RAS-indepedent PWs?
RTK receives insulin message causing autophosphorylation
insulin receptor substrate 1 (IRS1) recognizes the P site and binds, causing RTK to phosphorylate IRS-1 on its own tyrosine: SH2 domain proteins GRB and PI3 bind to IRS1
Ras dependent details
GRB2 which activates RAS
Ras independent details
PI3 which produces two compounds "phosphatidyl-bisphosphate and phsophatidyl-trisphosphate (PIP3)"
these crecuit protein kinase B to the membrane (PKB)
PKB is also known as Akt, it helps phosphorylate proteins and induces GLUT4's insertion into the membrane of muscle and adipose tissue
promotes glycogen synthesis by inhibiting glycogen synthase kinase 3 (GSK-3)
quantifiable parameter; measured as amount of glucose cleared from blood in response to a dose of insulin
possible causes of insulin resistance
failure of GLUT4 to insert in membrane of adipose and muscle cells
also, 75 different mutation in insulin receptor identified
biochemical cause of insulin resistance (2)
Ser/thr kinases phosphorylate serine residues instead of tyrosine in the IR region of the IRS: this inhibits activation and signaling
IRS1 effectively disabled
what activates Ser/Thr Kinases?
activated by cytokines, free fatty acids, DAG
under ged conditions, insulin
glycogen synthesis, stimulating glycolysis, and inhibiting the activity and synthesis of enzymes for gluconeogenesis