EXAM3_L29_Metabolic_Signaling Flashcards
How does Glucagon signaling work/increase PKA activity?
GalphaS GPCR increases cAMP-> Increases PKA activity
What two ways does insulin decrease PKA activity?
- protein phosphatase-1 (dephosphorylates PKA substrates)
2. insulin-responsive cAMP phosphodiesterase (less cAMP, less PKA)
What does insulin and glucagon do to PKA activity respectively?
Insulin- decreases PKA (two ways)
Glucagon- increases cAMP thus PKA activity
Insulin signaling via IRS1- Two events when insulin binds RTK:
UPON INSULIN SIGNAL: (insulin binds RTK):
- IRS1 binds GRB2 > MAPK (cell division, survival)
- IRS1 bind PI3K> AKT (increase glucose uptake GLUT4)
akt-also alters metabolic enzyme activities
What is the assumption of a defective IRS-1 signaling pathway?
- Consequence of obesity
- can result in insulin resistance and diabetes
What is the newly phosphorylated domain of IRS-1?
what two things bind to this domain?
- SH2 domain (src homology 2)
- can bind to : GRB2 or PI3K
GRB2 >SOS> MAPK pathways
PI3K (pi3 kinase)>activates AKT pathway
What are the 4 counterregulatory Hormones?
What do they do?
Oppose action of insulin by mobilizing fuels into blood
- Glucagon
- Cortisol
- Epinephrine
- Norepinephrine
What hormones are stress released in response to neuronal signals?
What is the signal pathway for these from the brain?
Cortisol (adrenal cortex)
Epinephrine (adrenal medulla)
Norepinephrine (adrenal medulla)
Hypothalamus>Pituitary>ACTH>Adrenal Gland
When you exercise, or experience HYPOGLYCEMIA, hypoxia, or hemorrhage what neurotransmitter will be released? What affects will it have on IG ratio?
Epinephrine- catecholamine (from tyrosine)
- Decreases IG ratio
- increases and mobilizes fuel/energy into blood
Cortisol is a glucocorticoid derived from Cholesterol (adrenal cortex) - why is that significant?
Cortisol binds receptors INSIDE THE CELL
-steroid diffuses right through plasma membrane
Cortisol functions differently in Adipose, Muscle, and Liver
What does it do in each?
Adipose- lipolysis (provides energy for liver gluconeogenesis)
Muscle- Decreases GLUT4 uptake of glucose
Liver- Gluconeogenesis (increase glucose production)
Why do Dietary Amino Acids stimulate Insulin High glucose and low glucose states?
High glucose state- AA’s convert to glucose> insulin
Low glucose state- AA’s from high protein diet can be made into glucose and stimulate a little insulin to prevent muscle breakdown
Is fat ever used to make glucose?
NOPE
What affects of glucagon in muscle, liver, adipose?
LIVER ONLY (only gasGPCR receptors on Liver Cells)
- mobilizes nutrient molecules,
- glycogenolysis (glycogen breakdown for export)
- gluconeogenesis for export (using AA’s as C source not FA’s)
Glucagon receptors are only found on Liver cells
(for liver glycogen breakdown) and will not affect the stored glycogen in muscle cells.
How is Muscle glycogen used then?
Epinephrine stimulates glycogenolysis of muscle glycogen to be used ONLY FOR THE MUSCLE ITSELF
What is muscle glycogen used for?
Only used for its own glycogenolysis>glucose
NEVER USED FOR BLOOD GLUCOSE HOMEOSTASIS!
How does epinephrine affect Muscle, Adipose, Liver, Pancreas?
Muscle- glycogenolysis (glycogen>glucose) MUSCLE USE
Liver- glycogenolysis (glycogen>glucose) for EXPORT
Adipose- FA’s mobile for use
Pancreas- Increases alpha cell (glucagon secretion)
inhibits beta cell (insulin secretion)
What does the liver use for energy?
What does it never use?
Beta oxidation of FAT
NEVER USES GLYCOGEN (exported to brain & RBCs)
How are blood glucose levels maintained when fasting?
Gluconeogenesis (from aa’s to glucose)
Glycogenolysis (glycogen to glucose) while supplies last
Stress or Low IG ratio in Liver?
glucagon and Epinephrine:
- gluconeogenesis
- glycogenolysis
- ketone bodies
High IG ratio in Liver?
Insulin:
glycogenesis
lipogenesis
Where are ketone bodies only made?
KB Made in Liver (can’t be used in liver) Used by other cells only
High IG ratio in Adipose?
Insulin:
LIPOGENESIS
Glucose Uptake (GLUT4)
FFA synthesis in liver stored TAGs in adipose
-(glucose>glycerol)
When will Lipolysis occur in adipose tissue?
ONLY EPINEPHRINE (stress only)
-TAGs of adipose mobilized into FFA’s in circulation
Stress( HYPOGLYCEMIA, Hypoxia, exercise, Hemorrhage, pain)
Low IG ratio in adipose?
No affect! -
- NO GLUCAGON RECEPTORS
- only has epinephrine receptors
(lipolysis will only occur during stress/epinephrine signaled
High IG ratio in muscle?
Insulin:
-AMPK> GLUT4 glucose uptake
-Glycogenesis* (store glucose as glycogen)
- this glycogen can only be used in the muscle
- only used when epinephrine/stress induced
note: AMPK glucose is metabolized, and not stored
How much glucose goes to the muscles after a meal?
80%
Low IG ratio in muscle?
NO EFFECT!
- no glucagon receptors on muscles (only has epi receptor)
-glycogenolysis occurs via epinephrine/stress only!
What is important about glucose that enters the muscle as AMPK?
It is metabolized and not stored as glycogen!
Stress to muscle cells?
exercise, hemorrhage, HYPOGLYCEMIA, Hypoxia, Pain)
Epinephrine
Insulin stimulates glucose uptake in the muscles via GLUT4.
When insulin is low or signal impaired, GLUT4 can still be stimulated by what pathway?
AMPK (activated protein kinase) pathway
small rise in AMP has what effect compared to ATP?
an AMP increase has much bigger increase in activity than equivalent amount of ATP increase
What does Adenylate Kinase do?
takes 2 ADPs and makes an ATP
AMP increases AMPK by what two ways?
- Allosteric activates AMPK (5x greater activity)
2. Stim phosphorylation of AMPK (100x greater activity)
What is Metformin?
Most common Type II Diabetes medication
- Allows GLUT4 to uptake glucose in the muscles
- increases AMP and> AMPK activation
- AMPK benefits independent of insulin signaling
What are the benefits of metformin on blood glucose levels?
- increases uptake of glucose in the muscle (GLUT4)
- stops gluconeogenesis in liver
*Independent of insulin signaling
What are the benefits of metformin on blood lipid levels?
promotes beta oxidation rather than storage
- Reduces TAGS in circulation
- improves insulin sensitivity
