PSIO 303 Block 3 Signalling Terms

eNOS causes…

NO release

vasodilation in smooth musc

more glucose and insulin delivery

insulin receptor works…

insulin to alpha

beta trans-autophos

other tyr get phos to interact (IRS)

IRS

docking protein

tyr positive activity

ser negative activity

glucose transport pathway

P13K binds to IRS

makes PIP3

PIP3 recruits PDK and PKB

PKB inactivates (phos) protein AS160 which stops vGLUT4 form fusing

now vGLUT4 fuses, more glucose inside skel musc.

PKB does…

phos GSK3 - inactivates GSK3 - keeps from stopping glycogen synthesis

phos AS160 - allows vGLUT4, more glucose inside

activates mTOR - causes insulin resistance

GSK3

normally phos GS (inactivates)

normally STOPS glycogen synthesis

normally promotes PEPCK and G6Pase transcription

GS

glycogen synthase

inactivated by GSK3 phos

GLUT1

beta cells

alpha cells

everywhere

GLUT2

B cells

doesn’t leave the membrane

GLUT 4

skeletal musc and adipocytes

NE in SNS effects

bind to alpha 2 adrenergic receptor (Gq)

inhibit adenylate cyclase

less cAMP

less PKA

less insulin

more glucagon

PNS effects

Ach binds to receptor (Gq)

stimulate PLC

form DAG IP3

DAG stim PKC

IP3 stim CA release

both increase insulin

GLP-1 effect

release more insulin

low [gluc] alpha cell behavior

activates Na channel

depolarization

Ca channel in opens

vGlucagon fuse and secrete

high [gluc] alpha cell behavior

inhibit Na

no potential

Ca closed

no vGlucagon fuse

normal [gluc] alpha cell behavior

SNS activation with exercise

more NE, activate alpha 1, increased Ca, vGlucagon fuse and secrete

glucagon influenced by…

increase with low glucose

increase with high NE

decrease with high glucose

decrease with low NE

compensatory hyperinsulinemia with acute glucose elevation

more glucose transport

more ATP

more K channels close

depolarization

more Ca entry

more exocytosis

more insulin

compensatory hyperinsulinemia accute FFA elevation

more FFA delivery

more ATP

more K channels close

depolarization

more Ca entry

more exocytosis

more insulin

long term high FFA and glucose

oxidative stress

less atp

less K channels close

less depolarization

less Ca

LESS INSULIN

sulfonylureas effect

bind to Katp

keep it closed

DIRECT depolarization

increased insulin no matter what

islet dysfunction causes…

low insulin

high glucagon

SNS on glucagon in alpha cells

more NE

more Ca from ER

more glucagon secretion

glucagon effect on HGP

INCREASES

activates glycogenolysis and gluconeogenesis

inhibits glycogenesis

insulin effect on HGP

SUPPRESSES

inhibit glycogenolysis and gluconeogenesis

activate glycogenesis

how does insulin enhance glycogenesis?

1. MAPK and p90-S6 kinase activate PP1G

2. P13K and PKB/Akt inhibit GSK3

both pathways activate GS

P13K and PKB enhance glycogenesis by…

inhibiting GSK3 so that it can’t inhibit GS

visceral adiposity then ___ and ____

insulin resistance and hyperinsulinemia

insulin inhibits glycogenolysis through

MAPK and p90-S6 kinase activate PP1

PP1 dephos and inhibits phosphorylase

inhibits glycogenolysis

PP1 does…

inactivates phosphorylase (B)

cannot become active (A) to turn glycogen into glucose

ALSO activates GS to increase glycogenesis

insulin suppressing gluconeogenesis

inhibits GSK3

activates p38 MAP kinase which

suppresses PEPCK and G6Pase transcription

reduces gluconeogenesis

PEPCK and G6Pase

gluconeogenic ENZYMES

suppression of them causes suppression of glucose synthesis

glucagon on glycogenolysis

G_s > adenylate cyclase > cAMP > activates PKA

PKA phos. and activates phosphorylase kinase

phosphorylase kinase activates phosphorylase

glycogenolysis increases, increases HGP

PKA on glycogenolysis

activates phosphorylase kinase

activates phosphorylase

increases glycogen breakdown

glucagon on gluconeogenesis

G_s > adenylate cyclase > cAMP > activates PKA

PKA phosphorylates CREB at CRE

CREB and CBP increase PEPCK and G6Pase transcription

increase gluconeogenesis

CREB and CBP

increase PEPCK and G6Pase

increase gluconeogenesis

glucagon inhibits glycogenesis

PKA pathway

PKA phos and deactivates glycogensynthase

PKA

activates phosphorylase kinase to increase glycogenolysis

phos. CREB to increase gluconeogenesis

phos. GS to deactivate glycogen synthase

HGP in MS

low insulin in adipocytes

low insulin makes increase in FFA

more ATP

drive gluconeogenesis

increase HGP

MS beta cells affect on alpha

less insulin coming from B so can’t suppress A glucagon

more A glucagon

MS SNS

enhanced

more A glucagon

stress kinases (4)

IKKBeta p38MAPK, JNK, GSK-3Beta

increased by ROS and oxidative stress

increases serine phos. of IR/IRS

causes insulin resistance and less GLUT4 transport

dyslipidemia

excess FFA

exacerbates insulin resistance

GPCR adenylate cyclase

Gs activats

Gi deactivates

GPCR phosphodiesterase

Gt activatesG

GPCR PLC

Gq activates

cleave PIP2 into DAG and IP3D

DAG

activate PKC, stim insulin secretion

IP3

stimulate Ca release

adiponectin

+ adipocyte

regulate insulin sensitivity

globular form has action

Adiponectin receptor pathway

Adipo1 recruits APPL1

activate TSC1/2

engages P13K and PKB to increase glucose transport

activate AMPK, p38 MAPK to increase GLUT4 glucose transporth

how adiponectin increases insulin sensitivity?

deactivates mTOR

causes less serine phos of IRS, causing less insulin resistance

mTOR

activated by PKB

activates S6K which serine phos IRS

causes insulin resistancean

angiotensinogen path in liver

renin converts to ANGI

ACE converts to ANGII

ANGII causes insulin resistance and oxidative stress species and vasoconstrictionA

ANGII

from ANGI by ACE

vasoconstriction!!!

insulin resistance in skel. musc.

ROS

renin

more SNS, more renin

converts angiotensinogen to ANGI