3. Glucose Homeostasis And Glycogen Metabolism

Front 1

Why do we maintain blood glucose levels by using glycogen stores, when fat is the most efficient?

Back 1

Because fat metabolism is SLOW and it can't be converted to glucose!!!

Front 2

What is glycogen, and where is it mostly found?

Back 2

A branched polymer of glucose; most in skeletal muscle/liver.

Front 3

In terms of %by mass, what has a higher [glycogen]; sk musc or liver?

Back 3

Liver - 10%

Skeletal muscle only = 1-2%

Front 4

Which tissue STORES more glycogen?

Back 4

Skeletal muscle - by nature of the fact that there is just that much more tissue in the body.

Front 5

When does muscle glycogen decr?
When does liver glycogen decr?

Back 5

Muscle: during exercise
Liver: during fasting

Front 6

What molecule represents a major branch point in carb metabolism?

Back 6

Glucose

Front 7

What 4 pathways are available to the G6P branchpoint?

Back 7

1. Glycogen synthesis
2. Pentose Phosph Pathway (HMP)
3. Glycolysis
4. Gluconeogenesis (liver)

Front 8

How is the futile cycling of glycogenesis and glycogenolysis avoided?

Back 8

By having one unique set of enzymes for each direction - not the same. That makes regulation easier and more precise.

Front 9

What 3 hormones regulate glycogen metabolism?

Back 9

-Insulin
-Epinephrine
-Glucagon

Front 10

How do Insulin/Epi/Glucagon regulate glycogen metabolism?

Back 10

Insulin: stim glycogen formatn
Epineph: stim glycogen breakdown in muscle and liver
Glucagn: stim glycogen breakdown in liver only

Front 11

How do the tissues use the G-1-P product of glycogen breakdown?

Back 11

Muscle - for energy

Liver - to maintain blood glucose levels.

Front 12

What enzymes are affected by the hormones regulating glycogen metabolism

Back 12

Insulin: glycogen SYNTHASE

Epi/Glucagon: Glycogen PHOSPHORYLASE

Front 13

What is the blood's normal glucose range? Concentration?

Back 13

70-100 mg/dL
3.9-5.6 mM

Front 14

What are signs of hypoglycemia w/ a level lower than 60?

Back 14

Hunger, sweating, trembling

Front 15

What are signs of hypoglycemia w/ a level lower than 40?

Back 15

Lethargy, convulsions, coma

Front 16

What is the result of a very hypoglycemic state for a long period of time?

Back 16

Perm. brain damage and death.

Front 17

What diagnostic tool is used to indicate long-term excessive hyperglycemia?

Back 17

HgB A1C

Front 18

What specific tissues are HIGHLY DEPENDENT on maintaining blood glucose levels, and why?

Back 18

-RBC
-Brain
-Renal medulla
-They have little/no mitochondria

Front 19

Can RBCs use ketone bodies like the brain? Why?

Back 19

No; they have no mitochondria, where fat metabolism occurs.

Front 20

So the 3 sources of glucose in the body are:

Back 20

1. Diet
2. Glycogenolysis
3. Gluconeogenesis

Front 21

What is required for Glucose to traverse cell plasma membranes?

Back 21

Facilitated transport - no energy, but transporters b/c glucose is so large.

Front 22

What cells have GLUT 1 and 3? What is the function of GLUT1/3?

Back 22

Nearly all cells; allows for basal glucose uptake.

Front 23

Why are GLUT 1/3 good for basal uptake?

Back 23

Because they have a low Km (1mM) so they're nearly always saturated and operate well even at low blood glucose conc.

Front 24

Why is it good that Brain and RBCs have Glut 1/3?

Back 24

Because they always need glucose; you wouldn't want their function match the daily blood glucose fluctuations.

Front 25

What 3 tissues have GLUT2?

Back 25

-LIVER (v. important)
-Pancreatic B-cells
-Enterocytes - basolateral side

Front 26

How does GLUT2 operate when:
-Blood [Glu] is normal
-Blood [Glu] is low

Back 26

Normal: don't operate efficiently

Low: low operation
High: high operation

Front 27

So how is the operation of GLUT2 in the liver affected by blood glucose levels?

Back 27

They are directly proportional - the liver only takes up glucose after a meal when levels are high.

Front 28

What allows for the liver to only take up glu at high blood concentrations?

Back 28

Its HIGH Km = 15-20 mM

Front 29

What tissues have GLUT 4?

Back 29

Skeletal muscle
Fat cells

Front 30

Why do we want muscles/fat to have GLUT4?

Back 30

B/c it is insulin responsive - they only take up glucose to store it when there is extra.

Front 31

What is the Km of GLUT4?

Back 31

Intermediate - 5 mM

Front 32

What is insulin's effect on GLUT4?

Back 32

It increases its microvesicular transport to the plasma membrane of muscle/fat.

Front 33

So what GLUT transporters will be functioning when the blood is at 5 mM?

Back 33

Glut 1/3 (brain/RBCs)
Glut 4 (sk. muscle/fat)
-B/c 5 is on the high end
-But not high enough for liver

Front 34

What tissues have GLUT5 and for what?

Back 34

Apical side of enterocytes - for FRUCTOSE uptake

Front 35

What is the sodium glucose transporter related to GLUTs?

Back 35

SLGT-1

Front 36

Where is SLGT-1 located? What is its function?

Back 36

-On apical side of enterocytes
-Functions for Glucose and Galactose uptake from the intestines into enterocytes.

Front 37

How is SLGT-1 distinct from the other GLUT transporters?

Back 37

It requires energy and transport is irreversible.

Front 38

What makes the transport of Glucose/Galactose thru SLGT-1 favorable?

Back 38

Na gradient establishd by ATP pump

Front 39

So what transporters are on enterocytes?

Back 39

SLGT-1 -> Apical
GLUT-5 -> Apical
GLUT-2 -> Basolateral

Front 40

When would GLUT2 on enterocytes be functional?

Back 40

After a meal b/c its Km is so high!! (same as in liver)

Front 41

What is expressed by tumors as they outgrow their blood supply?

Back 41

HIF-1 (hypoxia-inducible transcription factor)

Front 42

What does HIF-1 do?

Back 42

Induces GLUT1 and GLUT3 so the tumor cells get a basal glucose uptake (more efficient)

Front 43

What is the metabolically active form of glucose? Why?

Back 43

Glucose-6-phosphate -> this is the only kind that stays within cells; plain glucose is freely reversible and equilibrated across cell membranes.

Front 44

What 2 enzymes achieve G6P?

Back 44

-Hexokinase
-Glucokinase

Front 45

Where is HEXOKINASE found?

Where is GLUCOKINASE found?

Back 45

Hexo = all cells

Gluco = liver & pancreatic Bcell

Front 46

Why is it good for all cells to have Hexokinase?

Back 46

B/c it has a VERY LOW KM -> traps glucose very efficiently

Front 47

What does Hexokinase require for function? What inhibits it?

Back 47

-Requires Mg-ATP
-G6P (its product) inhibits it

Front 48

Why is it good that only liver and pancreatic B-cells have GLUCOKINASE?

Back 48

B/c Glucokinase has a much HIGHER KM -> ~10mM; only traps glucose when levels are high.

Front 49

What are the 3 important differenes between glucokinase and hexokinase?

Back 49

Glucokinase has
1. Higher Km
2. Cooperative binding curve
3. No product inhibition

Front 50

How does glucokinase behave?

Back 50

When liver glu levels high, it traps glucose continuously until levels decrease - regardless of how much G6P builds up.

Front 51

Recap; why is it good for SLGT-1 to be dependnt on ATP?

Back 51

Because if ATP in the body is high, there will be less glucose uptake - no need for it!
..thats a stretch...

Front 52

Fates of G6P; what will it do
-After a meal?
-Between meals?

Back 52

After a meal G6P -> glycogen

Between meals G6P goes to
a. PPP pathway -> NADPH
b. Gluconogenesis -> LIVER
c. Glycolysis -> sk muscle

Front 53

Describe glycogen again:

Back 53

Branched polymer of glucose with 1. a-1,4 linear glycosidic bonds
2. B-1,6 branchpoint linkages

Front 54

How much glucose does 0.01 uM of glycogen equal?

Back 54

400 mM -> provides a great advantage of storing LOTS of glucose w/out osmolar signific.

Front 55

Are there reducing ends on glycogen?

Back 55

1 - tied up with glycogenin

Front 56

What is the major storage tissue for glycogen?

Back 56

liver

Front 57

how many steps are involved in glycogen breakdown? What are they?

Back 57

Four steps:
1. Phosphorylation
2. Mutation
3. Hydrolysis
4. Debranching

Front 58

What are the four enzymes in glycolysis?

Back 58

1. Glycogen phosphorylase
2. Phosphoglucomutase
3. Glucose-6-Phosphatase
4. Debranching enzyme

Front 59

What occurs in the phosphorylation step one?

Back 59

Phosphoryltic cleavage to produce Glu-1-PO4 and Glycogen (minus one residue)

Front 60

What is the active site residue of Glycogen phosphorylase, adn how does it act?

Back 60

PLP - pyridoxal phosphate; acts as a general acid/base catalyst, which is an atypical use of PLP.

Front 61

Where on glycogen can Glycogen Phosphorylase act?

Back 61

-ONLY at residues at least 4 away from branchpoints
-only at a-1,4 linkages

Front 62

So what is the cofactor of Glycogen Phosphorylase?

Back 62

PLP

Front 63

What happens to Glucose-1-PO4 in step 2?

Back 63

Phosphoglucomutase converts it to G6P so it can be further metabolized.

Front 64

What happens in the mechanism of mutation of G1P?

Back 64

Exchange of PO4 from enzyme to G1P to make G1,6-bisphosphate; then it gives a PO4 back to the enzyme to result in G6P

Front 65

What cell compartment contains phosphoglucomutase?

Back 65

Cytosol

Front 66

What is the enzyme for Step 3 and where is it found?

Back 66

G6Phosphatase -> only in LIVER lumenal side of ER membrane.

Front 67

What happens to G6P during step 3 of glycogenolysis? (3 steps)

Back 67

1. G6P transport to ER
2. Hydrolysis produes Glucose + Phosphate
3. Glucose transported back to cytosol, then bloodstream.

Front 68

What must you remember about Step 3's enzyme Glucose-6-Phosphatase?

Back 68

IT IS ONLY FOUND IN LIVER.

Front 69

Why is a debranching enzyme needed for glycogenolysis?

Back 69

Because Glycogen Phosphorylase only acts on a-1,4 linkages, not the B-1,6 linkages at branchpoints.

Front 70

What is the name of the product resulting after Glycogen Phosphorylase cleaves all the outermost residues of glycogen?

Back 70

Limit Dextrin

Front 71

What is the mechanism of Debranching Enzyme?

Back 71

1. Move 3 residues from a-1,6 branchpoint to main chain.
2. Cleave remaining a-1,6 residue.
Now normal processing can go.

Front 72

When G6Phosphatase releases free glucose into the cytosol (step 3), how does it not just get rephosphorylated and trapped?

Back 72

Liver cells only have glucokinase - it only traps it when the Glu concentration is high. (not the case when breaking DOWN glycogen)

Front 73

In general what do we call debranching enzyme?

Back 73

Bifunctional:
1. Transferase
2. a(1-6)-Glucosidase

Front 74

Is glycogen synthesis just the reverse of breakdown? Why/why not?

Back 74

In VITRO, yes.
In VIVO, No; b/c the ratio of Phosphate to G1P is normally HIGH; favors glycogenolysis

Front 75

Are ALL the enzymes of glycogen synthesis different from glycogen breakdown?

Back 75

No; both processes use the same phosphoglucomutase.

Front 76

How many enzymes are used in glycogen synthesis? What are they?

Back 76

Five:
1. Phosphoglucomutase
2. UDP-Glucose Pyrophosphorylase
3. Glycogen synthase
4. Glycogenin
5. Branching Enzyme

Front 77

What is the first step of glycogen synthesis?

Back 77

mutation - phosphoglucomutase converts G6P -> G1P

Front 78

What is the 2nd step of glycogen synthesis?

Back 78

Conversion of G1P to an activated glucose

Front 79

How is Glucose activated for glycogen synthesis?

Back 79

By UDP-Glucose Pyrophosphorylase which adds a PO4 to G1P, and subsequent PPi hydrolysis to drive the reaction forward.

Front 80

What happens to Activated Glucose (UDP-Glucose)?

Back 80

Glycogen synthase adds them to pre-existing glycogen chains at least 4 residues long. Prevents adding to free glucose.

Front 81

When UDP is released from activated glucose during glycogen synthesis, what follows?

Back 81

It is immediately converted to UTP by ATP (if the cell's energy charge is high, which it should be if you're STORING glycogen)

Front 82

What enzyme catalyzes conversion of UDP to UTP?

Back 82

Nucleoside Diphosphate Kinase (NiDiKi)

Front 83

What is glycogenin and why is it important?

Back 83

An enzyme that has Tyr residues linked to glucose; it catalyzes addition of 7 more glu to itself, providing the substrate w/ >4 residues for Glycogen synthase.

Front 84

What is the glucose source for Glycogenin when it builds itself up?

Back 84

Activated glucose (UDP-glucose), same as for glycogen synthase.

Front 85

When does branching enzyme operate on glycogen synthesis?

Back 85

When linear polymers are at least 11 residues long; Moves a 7-unit chain to a C6 position if it's at least 4 residues away from a previous branchpoint.

Front 86

What regulates liver glycogen metabolism - determining whether synth or degradation occurs?

Back 86

Blood glucose levels.

Front 87

What factors stimulate glycogen synthesis?

Back 87

-Plentiful glucose
-Insulin
-ATP
-G6P

Front 88

What factosr stimulate glycogen degradation?

Back 88

-Epi
-Glucagon
-AMP
-Ca2+

Front 89

How do these factors alter rates of glycogen synth/degradation?

Back 89

By regulating the ENZYMES:
-Glycogen synthase
-Glycogen phosphorylase

Front 90

How is Glycogen phosphorylase regulated? (2 ways)

Back 90

1. Allosteric regulation via metabolites
2. Covalent regulation via phosphorylation

Front 91

What are the states that Glycogen phosphorylase can exist in?

Back 91

T (inactive) vs. R (active)

b (inactive) vs. a (active)

Front 92

What are the b/a forms used to signify?

Back 92

Unphosphorylated = b

Phosphorylated = a

Front 93

What controls whether glycogen phosphorylase is b or a?

Back 93

Hormones - they act through phosphorylase kinase and phosphoprotein phosphatase 1.

Front 94

What allosteric regulators in muscle turn on Glycogen phosphorylase by causing conform change from T->R?

Back 94

ADP

Front 95

What allosteric regulators have the opposite effect and inactivate glycogen phosphorylase?

Back 95

ATP and G6P

Front 96

What mechanism is mostly regulating Glyc. phosph in
-Skeletal muscle?
-Liver?

Back 96

Skeletal muscle = allosteric regulation by metabolites (fast)

Liver = phosphorylation controlled by hormones.

Front 97

What 2 enzymes are responsible for regulating the phosphorylated state of glycogen phosphorylase?

Back 97

1. Phosphorylase kinase
2. Protein phosphatase 1

Front 98

What does Phosphorylase kinase do? What stimulates it?

Back 98

Phosphorylates Glycogen phosphorylase; stim by Glucagon/Epi (need glucose);
inhibited by glucose/insulin

Front 99

How is Phosphorylase KINASE regulated?

Back 99

By cAMP-dependent protein kinase (PKA)

Front 100

What is the role of Phosphoprotein Phosphatase 1?

Back 100

It dephosphorylates both Phosphorylase Kinase, and Glycogen phosphorylase, to inactivate them.

Front 101

How does Glycogen degradation get stimulated by hormones?

Back 101

Epinephrine starts the PKA cascade; PKA phosphorylates Phosphorylase b -> a; degradation is turned on.

Front 102

How is the simultaneous degradation and synthesis of glycogen prevented?

Back 102

When PKA phosphorylates Glycogen synthase it converts from a->b which is its inactive form.

Front 103

What is required of Glycogen Phosphorylase for it to be phosphorylated by PKA?

Back 103

It must be in the T - inactive state.

Front 104

What form does Glycogen Phosphorylase tend to be in in the liver?

Back 104

R state (active); because glucose is low (unless you just ate a meal).

Front 105

What happens to Glycogen Phosphorylase when glucose is high in the liver?

Back 105

It will be in the T (inactive) state, which can be dephosphorylated.

Front 106

Why is it good that the modified form of Glycogen phosphorylase (the phosphorylated a form) predominates in liver?

Back 106

Allows it to ignore the cell's energy status (ATP/GTP) and be regulated mainly by glucose levels.

Front 107

What is the mechanism of PKA's actn on Glycogen phosphorylase?

Back 107

1. Phosphorylates B-subunit
2. Binds Ca2+ to delta subunit

Front 108

Why does PKA phosphorylate Glycogen Phosphorylate w/ 2 steps?

Back 108

Because they're both needed for max enzyme activity.

Front 109

What protein is responsible for activating PKA via Cortisol or stress hormones?

Back 109

cAMP (cyclic AMP dependent protein kinase)

Front 110

What enzyme dephosphorylates both cAMP and Glycogen phosph.?

Back 110

Phosphoprotein phosphatase 1
(PP1)

Front 111

What is the effect of Epi and stress hormones on PP1?

Back 111

-PKA phosphorylatn of a molecule connecting PP1 to glycogen makes PP1 dissociate (partly inactive)
-PKA also phosphorylts an Inhibitor molecule, which binds PP1 to fully inactivate it.

Front 112

What is the net effect of inhibiting PP1?

Back 112

Both Glycogen phosphatase and Glycogen synthase are phosphorylated, so active and inactive respectively.

Front 113

How does INSULIN alter the activity of PP1?

Back 113

1. Activates Receptor Tyrosine Kinase
2. Phosphorylates PP1's glycogen connector at a different site activates Pp1.

Front 114

What is the net effect of activating PP1?

Back 114

It dephosphorylates Glycogen Phosphatase (inactive) and Glycogen synthase (ACTIVE).

Front 115

What 2 factors cause PP1 to dissociate from Glycogen and be activated?

Back 115

1. Insulin
2. GLUCOSE binding

Front 116

How does Epi/Cortisol stimulation of glycogenolysis differ in liver vs sk. muscle?

Back 116

Liver: HAS G6Pase; inhibits glycolysis, favors gluconeogen.

Sk. muscle: no G6Pase; favors glycolysis for energy.

Front 117

How does Insulin's effect on glycogenesis differ in liver vs. sk. muscle?

Back 117

It doesn't, still uses the same Receptor Tyrosine Kinase; BUT
GLUT2= liver glucose transportr
GLUT4= muscle transporter

Front 118

What does Ca2+ release from nerve impulse stimulation do to glycogen metabolism?

Back 118

Turns on PKA -> turns on Glycogen Phosphorylase -> turns on glycogen breakdown.

Front 119

What are the 4 most common glycogen storage diseases?

Back 119

1. Von Gierke's
2. Pompe's
3. Cori's
4. McArdle's

Front 120

Which one doesn't belong? why?

Back 120

Pompe's - caused by enzyme deficiency of pathway not discussed in lecture (hydrolysis of glycogen, not phosphorylase)

Front 121

Which storage disease is most common? What enzyme deficient?

Back 121

Von Gierke's - Glucose 6-Phosphatase

Front 122

What is the effect on liver glycogen storage in Von Gierke's?

Back 122

Normal glycogen structure, but storage in very high amounts.

Front 123

What are symptoms of Von Gierke's?

Back 123

-Failure to thrive
-Severely enlarged liver

Front 124

What enzyme is deficient in Cori's disease? What is the pathologic effect?

Back 124

Debranching enzyme; increased glycogen storage with shorter branches. Milder than Von Gierke's.