Zeidi Insulin pathways and signaling

Question 1

Insulin “big picture” stuff

Answer 1

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

Question 2

when are the 3 disulfide bonds added to insulin?

Answer 2

in the ER lumen

Question 3

what glucose transporter is used in the liver?

how is it trapped in the cell?

Answer 3

GLUT2 and glucokinase phosphorylates it, trapping in hepatocyte

Question 4

how does glucose “cause” the release of insulin?

Answer 4

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

Question 5

Ras dependent PW “big picture”

Answer 5

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

Question 6

Ras independent PW “big picture”

Answer 6

ultimates leads to GLUT4 (muscle and adipose tissue) and glycogen synthase synthesis, allowing glucose into the cell and converted into storage form

Question 7

the Ras independent PW activates what protein?

Answer 7

PI3 and PKB

Question 8

RTK: what sets the stage for the RAS and RAS-indepedent PWs?

Answer 8

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

Question 9

Ras dependent details

Answer 9

GRB2 which activates RAS

Question 10

Ras independent details

Answer 10

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)

Question 11

insulin resistance

Answer 11

quantifiable parameter; measured as amount of glucose cleared from blood in response to a dose of insulin

Question 12

possible causes of insulin resistance

Answer 12

failure of GLUT4 to insert in membrane of adipose and muscle cells

also, 75 different mutation in insulin receptor identified

Question 13

biochemical cause of insulin resistance (2)

Answer 13

Ser/thr kinases phosphorylate serine residues instead of tyrosine in the IR region of the IRS: this inhibits activation and signaling

IRS1 effectively disabled

Question 14

what activates Ser/Thr Kinases?

Answer 14

activated by cytokines, free fatty acids, DAG

Question 15

under ged conditions, insulin

Answer 15

glycogen synthesis, stimulating glycolysis, and inhibiting the activity and synthesis of enzymes for gluconeogenesis

Question 16

insulin resistance, glucagoon, epindephrine, and cortisol

Answer 16

in the absence of insulin signals, glucagon is produced

glucagon promotes glycogen catabolism to increase blood sugar levels, as well as inhibiting glycogen synthesis

epinephrine promotes glucagon synthesis and therefore glycogen breakdown

once glucagon is exhausted, cotisol (steroid based) stimulates gluconeogenesis by inducing enzymes involved in pathway