Lecture 6: Glucose Homeostasis/glycogen Metabolism

Front 1

What is the normal level of plasma glucose? What are the consequences of too high/low

Back 1

Normal=70-100mg/100ml (3.9-5.6mM)
too low=<60 sxs of hypoglycemia, <40 big trouble
too high= non specific glycosylation, vascular damage, diabetes sxs

Front 2

which tissues relpy on plasma glucose

Back 2

brain, RBC, renal medulla
(note cornea, lens, retina, testies, leukocytes, and white muslce have few mitochondria so they rely heavily on plasma glucose as well)

Front 3

Which tissues express GLUT 1 and 3? What is the metabolic role of this transporter? What is the aprox. Km of this transporter and why is this significant

Back 3

Expressed in nearly all tissues, resonsible for basal glucose uptake. Km of 1 is less than normal glucose levels (3.9-5.6) so they are always saturated. Especially important for brain and RBCs

Front 4

Which tissues express GLUT 2? What is the metabolic role of this transporter? What is the aprox. Km of this transporter and why is this significant

Back 4

expressed in liver, pancreatic B cells, and basolateral side of intestinal cells. Km is 15-20 which is higher than normal levels of fasting glucose. These transporteres are used to take in glucose after a meal to store in the liver or trigger release of insulin. Ensures that liver doesn't hog glucose when levels are low

Front 5

Which tissues express GLUT 4? What is the metabolic role of this transporter? What is the aprox. Km of this transporter and why is this significant

Back 5

Expressed in skeletal muscle and fat in an insulin dependent manner. Km~5mM which is upper end of fasting glucose (3.9-5.6) Allows these tissues to replenish glucose/glycogen stores when blood glucose is high but brain and rbc's still get first dibs, these are upregulated by insulin

Front 6

Which tissues express GLUT 15? What is the metabolic role of this transporter?

Back 6

Expressed on apical side of intestine cells, functions in fructose uptake

Front 7

Which tissues express SGLT1? What is the metabolic role of this transporter?

Back 7

Expressed on apical side of intestinal cells, responsible for glucose and galactose uptake, coupled to sodium transport which drives the sugars in.

Front 8

What two glucose transporters do intestinal cells express? How do they work together?

Back 8

SGLT1 is expressed on the luminal surfaces and helps to absorb glucose,galactose, and salt from food
GLUT2 is expressed on the capilary side and helps transport glucose, galactose, and fructose into the blood after a meal

Front 9

Why is it necessary to convert glucose into glucose 6-phosphate

Back 9

The GLUT transporters are freely reversible and would transport glucose out of the cell if the levels inside were high. Changing glucose to glucose-6-phosphate "traps" glucose in the cells.

Front 10

Why do most cells use hexokinase to convert glucose to glucose-6-phosphate but liver cells use glucokinase

Back 10

hexokinase has a low km for glucose ensuring that all of the glucose that gets into the cell is traped and available for use. In the liver however, not all glucose is used in liver cells. When the liver is trying to restore blood glucose levels, it must be able to release glucose into the blood without "retrapping it". The higher Km of glucokinase ensures that the liver only traps glucose when blood glucose is high

Front 11

Why is it important that hexokinase is subjected to product inhibition by glucose-6-phosphate but gluokinase is not?

Back 11

Hexokinase is expressed in most cells and is used to trap glucose. If it were not product inhibited the cell could trap tons of glucose and overload itself. In contrast, the liver wants to use any extra glucose to make glycogen, if G-6-P inibited glucokinase, this would not be possible.

Front 12

What affect would insulin have on glucokinase

Back 12

Insulin would increase glucose kinase expression. Glucokinse converts glucose to glucose-6-phosphate which is trapped in the liver. This gives the liver a chance to make glycogen which is what we want to do when blood glucose is high
remember: glucokinase is the liver's version of hexokinase

Front 13

What are the two different bonds used in glycogen

Back 13

1. Chain links = a 1,4
2. branches = a 1,6

Front 14

why is it necessary to store glucose as glycogen

Back 14

glycogen gives an osmotic advantage because it turns ~400mM of glucose into 0.01uM of glycogen, if the cells tried to store that much glucose, they would explode!!

Front 15

Which enzyme is responsible for initiating glycogen breakdown (removing a molecule from the chain)

Back 15

glycogen phosphorylase-breaks the a1,4 bonds that are >4 units away from a branch point

Front 16

What molecule is released from glycogen after glycogen phosphorylase breaks the a1,4 bond? What step must occur inorder for this molecule to become useful

Back 16

Glucose-1-phosphate is released. It must be changed into glucose-6-phosphate by phosphoglucomutase to participate in further metabolism
In the liver, G6P can be converted back to glucose by glucose-6-phosphatase and used to maintain blood sugar. This does not happen in muscle.

Front 17

Which tissues express glucose-6-phosphatase (the final enzyme in glycogen breakdown)

Back 17

Liver only. this allows the liver to export glucose into the blood. This enzyme is not present in skeletal muscles because the G6P is used directly to fuel the cell. Muscles do not participate in maintenece of blood glucose levels (for the most part)

Front 18

What is the role of debranching enzyme in glycogen breakdown

Back 18

Glycogen phosphorylase can only cleave a1,4 bonds up to 4 residues away from a branch. Debranching enzyme 1)transfers a block of 3 glucose units to the end of an outer branch and 2) hydrolyses the remaining unit to release free glucose (10% of total units released)

Front 19

Why does glycogen synthesis use different enzymes from glycogen breakdown even though the breakdown reactions are reversible

Back 19

1) The glycogen phosphorylase rxn is driven towards breakdown by the high Pi/G-1-P ratio (thermodynamic advantage)
2) allows for seperate control

Front 20

What cofactor is necessary for the glycogen phosphorylase rxn

Back 20

pyridoxal phosphate = PLP=HPO4 2-
an abnormal use of PLP

Front 21

What is the sugar substrate of the UDP glucosepyrophosphorylase rxn? How is this molecule made

Back 21

the substrate is glucose 1 phosphate (not G6P) as glucose enters the liver cell it is converted to G6P by glucokinase, it is then converted to glucose 1 phosphate by phosphglucomutase

Front 22

Describe the UDP-gluocose pyrophosphorylase reaction

Back 22

Glycogen synthesis reaction. Glucose-1-phosphate reacts with UTP to make UDP- glucose, an "activated glucose" that can be added to a glycogen chain. This reaction is coupled to the hydrolysis of pyrophosphate which makes it irreversible.

Front 23

Describe the glycogen synthase reaction.

Back 23

UDP glucose is added to an a1,4 linkage of a pre-existing glycogen molecule that is at least 4 units long

Front 24

Why is it important that glycogen synthase uses UDP glucose as a substrate and only adds to glycogen chains that are at least 4 units long

Back 24

this prevents the addition of free glucose. If free glucose could be added to glycogen, then the liver would be inefficicent at releasin glucose back into the blood stream (futile cycling)

Front 25

What is the role of glycogenin

Back 25

Glycogenin catalyzes the start of glycogen molecules (glycogen synthase can only add UDP glucose to chains of 4 or more units). Glycogenin adds free glucose to tyrosine units and then links them to for an 8 unit chain

Front 26

What is the role of branching enzyme in glycogen synthesis

Back 26

When a1,4 chains reach at least 11 residues, BE moves 7 of those to a 6 position on a nearby chain (at least 4 away from an existing branch) Branching is essential because it creates more non-reducing ends where glycogen phosphorylase can break it down

Front 27

Ca2+ stimulates glycogen (synthesis/ breakdown)

Back 27

Breakdown, Ca2+ is a signal of muscle contraction which drains the muscle's energy supply. Glycogen must be broken down to supply more energy.
Ca helps to partially activated phosphorylase kinase which phosphorylates glycogen phosphorylase making it active.

Front 28

Describe the changes that glycogen phosphorylase would go through as blood glucose decreased

Back 28

In the fed state, glycogen phosphorylase is inactive so it is in the b-T form. As blood glucose decreased, glucagon is released and phosphorylase kinase is activated. This enzyme phosphorylates glycogen phosphorylase chainging into the aT-P state. the aT-P state then converts to the aR-P state which is active. The active glycogen phosphorylase can now begin to breakdonw glycogen and restore blood glucose levels.

Front 29

Describe the changes that glycogen phosphorylase would go through as blood glucose increased

Back 29

When blood glucose is low, glycogen phosphorylase is in the a-R-P state. The addition of glucose shifts the enzyme to the a-T-P state. Glucose also stimulates the release of insulin which turns on phosphoprotein phosphatase (PP1). PP1 removes the phosphate group from aT-P chaning it to bT. This form is inactive and glycogen phosphorylase no longer breaks down glycogen

Front 30

Describe the importance of AMP dependent regulation of glycogen phosphorylase in muscle tissue.

Back 30

High levels of AMP in muslce tissue signal low energy. AMP can cause glycogen phosphorylase to shift from the bT form to the bR form and become active. This allows for glycogen breakdown independent of hormonal regulation.

Front 31

Phosphorylase kinase is needed to activated glycogen phosphorylas. How is phosphorylase kinase activated?

Back 31

1. Phosphorylation by PKA
2. calcium
most active when both occur

Front 32

Phosphoprotein phosphatase inactivates glycogen phosphorylase by removing a phosphate group from the aT-P form. How else does PP1 prevent glycogen breakdown.

Back 32

PP1 removes a phosphate group from phosphorylase kinase which is necessary to convert the bT form of glycogen phosphorylase to the aT-P form

Front 33

Glycogen phosphorylase is (activated/inactivated) by phosphoyrlation

Back 33

activated
Hint:glucagon responses tend to involve phosphorylation

Front 34

Glycogen synthase is (activated/inactivated) by phosphorylation

Back 34

inactivated
Hint: glucagon responses tend to involve phosphorylation, insulin responses involve dephosphorylation

Front 35

How does the prescence of glucose lead to the inactivation of glycogen phosphorylase independent of hormone regulation.(In the liver)

Back 35

Glucose converts the active aRp form to the inactive aTp form.
Additionally, when PP1 is active, glucose helps by binding to glycogen phosphorylase and exposes Ser-P. PP1 removes the phosphate and converts aT-P to bT.

Front 36

In the fasted state, cAMP is high (because glucagon activates adenylate cyclase). What affect does this have on PP1 and glycogen metabolism

Back 36

cAMP inactivates phosphoprotein phosphatase. This stops PP1 from making the inactive form of glycogen phosphorylase and allow phorphorylase kinase to make the active form. This facillitates glycogen breakdown

Front 37

What affect will active PKA have on glycogen metabolism

Back 37

PKA activates phosphoyrlase kinase whihc activates glycogen phosphorylase. Active PKA leads to glycogen breakdown and inhibition of glycogen synthesis

Front 38

Describe how glyocgen breakdown increases in exercising muscle independent of hormonal regulation

Back 38

Ca2+ is released from nerve impulses and AMP increased. The increase in AMP shifts glycogen phosphorylase from the bT form to the bR form which is active. Additionally the Ca partially activates phosphorylase kinase which can change the bT form to the acitve aT-P form.