Insulin & Counterregulatory Hormones

Question 1

Storage of glucose

Answer 1

Processes that generate ATP decrease

Insulin

Question 2

Mobilization of glucose

Answer 2

Needed when we need energy

Glucagon
Epinephrine

Question 3

Insulin

Answer 3

Promote fuel storage

Increase in blood glucose –> insulin signals to tissues –> cells take up excess glucose from blood –> used to make TAG or stored as glycogen

Question 4

Insulin

Released from…

Answer 4

B-cells of the pancreas in response to high blood glucose

Question 5

Insulin
All actions ultimately increase glycogen synthesis

Answer 5

(1) increases glucose transport into cells

(2) decreases cAMP → glycogen synthesis

(3) increase phosphoprotein phosphatase 1 (PP1)

(4) decrease glycogen synthase kinase 3 (GSK3)

Question 6

Glucagon

Answer 6

Mobilize stored fuels

Decrease in blood glucose –> glucagon signals to hepatocytes –> production and restoration of glucose

Question 7

Glucagon

Released from…

Answer 7

a-cells of pancreas in response to hypoglycemia

Glucagon binds GPCR on liver cells –> increase cAMP –> increase PKA –> Glycogen breakdown–> supplies glucose to tissues

Question 8

Epinephrine

Answer 8

Mobilize stored fuels

Decrease in blood glucose –> epinephrine signals to (1) muscle cells to breakdown glycogen & (2) liver to make more glucose

Question 9

Epinephrine

Released in response to ..

Answer 9

Stress

Question 10

Epinephrine

Muscle

Answer 10

Epinephrine binds B-adrenergic receptors → increase cAMP → increase PKA → glycogen breakdown → glucose monomers into glycolysis → generate ATP

Question 11

Epinephrine

Liver: direct v. indirect

Answer 11

D: epinephrine bind a- & B- andrenergic receptors –> increase Ca++, increase cAMP –> glycogen degradation

I: promotes release of glucagon from pancreas

Question 12

Cortisol

Answer 12

Signals stress, including low blood glucose (counterbalance insulin)

Question 13

Cortisol acts on..

Answer 13

Adipose: increase release of fatty acids from TAG –> FAs are fuel & glycerol for gluconeogenesis

Muscle: breakdown of muscle proteins –> amino acids for gluconeogenesis

Liver: stim gluconeogenesis –> glucose stored as glycogen or exported to tissues for fuel

Pancreas: Decrease insulin, increase glucagon

Question 14

Liver: Glycogen metabolism is controlled by

Answer 14

Insulin & glucagon (acting in opposition)

Synth by pancreas in response to conc. of glucose in blood

Increase glucose (fed) –> increase insulin, decrease glucagon

Decrease glucose (fasted) –> decrease insulin, increase glucagon

Question 15

Muscle

control is exerted by…

Answer 15

Insulin & Epinephrine

Question 16

Increase blood glucose

Answer 16

1. Glucose binds GLUT2 –> glucose enters cell –> phosphorylated to G6P (now trapped in cell) –> citric acid cycle –> oxidative phosphorylation –> increase in ATP –> ATP closes ATP-gated K+ channels –> decrease K+ efflux –> depolarization –> open Ca++ channels –> increase Ca++ w/in cell –> insulin exocytosis

Question 17

Feedback loop –> limits insulin relase

Answer 17

Insulin lowers blood glucose by stimulating glucose uptake by tissues

Reduced blood glucose detected by B-cells

Less glucose –> slows down cascade –> decrease in signal to release insulin (through glucokinase rxn)

Question 18

Sulfonylurea drugs

Use:
MOA:

Answer 18

U: oral medication for type II diabetes

M: binds to & closes K+ channels –> stim insulin release

Question 19

Regulation of glycogen phosphoylase

Function
Regulated

Answer 19

F: breaks down glycogen –> glucose 1-phosphate

Catalyze phosphoolysis of glycogen –> bound cleavage by substitution of a phosphate

R: hormonally (phosphorylation/dephosphorylation) & allosterically

Question 20

Hormonal regulation of glycogen phosphorylase

Answer 20

Phosphorylation –> activates glycogen phosphorylase (glycogen breakdown)

PKA activated –> phosphorylates phosphorylase kinase making more active –> phosphoylation of glycogen phosphoylase –> breakdown glycogen–> GLUCOSE

Question 21

Glucagon (liver) & epinephrine (muscle)

Answer 21

Increase cAMP –> increase PKA–> increases this process

During vigorous muscular activity –> epinephrine increases phosphorylation

Question 22

Hormonal regulation of Glycogen phosphorylase

Dephosphoylation

Answer 22

Inactivates phosphorylase kinase & glycogen phosphorylase

Insulin → PP1 → dephosphorylates & inactivates phosphorylase kinase & glycogen phosphorylase → glycogen synthesis

Predominates in resting muscle

Question 23

Calcium influence on Glycogen phosphorylase

Answer 23

Acts synergistically w/ hormones to stimulate glycogen breakdown

Question 24

Calcium influence on Glycogen phosphorylase

Increase calcium

Answer 24

–>Increase phosphorylase kinase → increase glycogen breakdown → glucose → glycolysis

Stimulates muscle contraction
○ Rate of glycogen breakdown linked to rate of muscle contraction
○ Glycogen breakdown provides fuel for glycolysis to generate more ATP required for muscle contraction

Question 25

In muscle ATP & G6P

Answer 25

Inactivate glycogen phosphorylase High ATP = high G6P → don’t need to breakdown glycogen → promote inactive form of glycogen phosphorylase

Question 26

In muscle AMP

Answer 26

Activates glycogen phosphorylase Breakdown ATP → AMP → signals need to fuel → promote glycogen breakdown

Question 27

In Liver Glucose

Answer 27

Inactivates glycogen phosphorylase ○ High glucose = don’t need more glucose Increase energy, increase blood glucose (fed state), inhibit glycogen breakdown

Question 28

Glucose 6 phosphate (G6P) a. in muscle b. in liver

Answer 28

G1P (end product of glycogen phosphorylase) → G6P a. G6P --> glycolysis E to support muscle contract b. G6P --> glucose + P --> blood Dephosphoylate glucose --> allows to exit hepatocyte Muscle & adipose do not have G6P, therefore do not contribute glucose to the blood

Question 29

Regulation of PP1

Answer 29

“PP1c is protective from glycogen breakdown” Function: dephosphorylates & inactivates glycogen phosphorylase a & phosphorylase kinase

Question 30

Regulation of PP1 in the muscle

Answer 30

Catalytic subunit PP1c is active when bound to glycogen at glycogen binding (GM) subunit Regulated by phosphorylation of GM

Question 31

Regulation of PP1 in the liver

Answer 31

PP1 bound to glycogen through GL GL not controlled via phosphorylation → binds phosphorylase a → both T & R strongly bind PP1 R-form: active T-form: inactive

Question 32

In the muscle Insulin regulation of PP1

Answer 32

Insulin-stimulated protein kinase → GM subunit phosphorylated once → active PP1c → decreased phosphorylation → glycogen synthesis

Question 33

In the muscle Epinephrine regulation of PP1

Answer 33

Stimulate PKA → GM subunit phosphorylated twice → inactive PP1c → increased phosphorylation → glycogen breakdown (active glycogen phosphorylase)

Question 34

GL R-form

Answer 34

Active Phosphoryl not accessible → sequesters PP1

Question 35

GL T-Form

Answer 35

Inactive Phosphoryl groups accessible to PP1 hydrolysis Conformational change → T form → phosphorylation sites accessible → PP1 dephosphorylated → phosphorylase B → PPI & glycogen can dissociate High glucose levels --> this is favored

Question 36

In the liver GL's allosteric effector

Answer 36

Independent of insulin --> therefore the cell can rapidly response to changes in blood glucose rather then waiting for insulin

Question 37

PP1

Answer 37

dephosphorylates & activates glycogen synthase In the liver, can dephosphorylate after G6P binds to allosteric site on glycogen synthase (better substrate for dephosphorylation)

Question 38

GSK3

Answer 38

Phosphorylates & inactivates glycogen synthase Casein kinase II (CKII) phosphorylates GSK3 → inactivation of glycogen synthase

Question 39

AMPK

Answer 39

Inactivates glycogen synthase Increase AMP (metabolic stress) → inhibit glycogen synthase

Question 40

Insulin

Answer 40

Activates glycogen synthase Promotes PP1; Inactivates GSK3

Question 41

Epinephrine

Answer 41

Increases phosphorylation & inactivates glycogen synthase in the muscle PKA → P1 & P2-GM → inactivate PP1 → decrease glycogen synthesis

Question 42

Von Gierke disease (glycogen storage type I)

Answer 42

AR Glucose 6-phosphatase deficiency - Inadequate conversion of G6-P → glucose in the liver - G6P cannot be dephosphorylated → released into the blood → pt requires supply of dietary glucose