Skildum: glucose Metabolism Review

Question 1

The insulin receptor acts as a….

Answer 1

TK receptor

Question 2

A 44 y/o M ate a 1200 calorie meal taht was 50% carb, 30% fat and 20% protein. He then fasted for 30 hrs. What is the source of C for his blood glucose.

Answer 2

FA beta oxidation

Fasted entering into starved

Question 3

What is the most important source of blood glucose?

Answer 3

LIVER

supplies fasted and starved states through gluconeogenesis and glycogenolysis

Question 4

What regulates glucose homeostasis?

Answer 4

Insulin and glucagon

Question 5

What acts in opposition to insulin?

Answer 5

glucagon
catecholamines
cortisol
GH

Question 6

What leads to an INCREASE in glycogenolysis, gluconeogenesis, and lipolysis but a DECREASE in liver glycolysis?

Answer 6

Decrease in blood glucose>
glucagon release>
promotes GENERATION of glucose from storage forms

Question 7

What leads to an INCREASE in glycogen synthesis, TG synthesis, FA synthesis and liver glycolysis?

Answer 7

Increase in blood glucose>
insulin release>
acts on tissues to REDUCE generation of glucose

Question 8

What promotes hepatic gluconeogenesis?

Answer 8

Glucagon

Question 9

What is required for gluconeogenesis?

Answer 9

PEP-CK

G6Pase

Question 10

Why is PEP-CK impt?

Answer 10

gluconeogensis w/ ALANINE or LACTATE

*you can do gluconeogenesis w/out if glycerol is available

Question 11

Why is G6Pase impt?

Answer 11

allows glucose to EXIT the hepatocyte

or else glucose would be trapped in the liver

Question 12

What PROMOTES gluconeogensis?

Answer 12

PKA phosphorylates PFK-2

Question 13

What happens when PKA phosphorylates PKF-2 and how does this ultimately promote gluconeogenesis?

Answer 13

PKA phosphorylates PFK-2 →
activates phosphatase function & inactivates kinase function
→ decreases F-2,6-BP*
→ promotes gluconeogenesis & downregulates glycolysis

Question 14

What is an allosteric inhibitor of F-1,6-BPase and allosteric activator of Phosphofructokinase-1?

Answer 14

F-2,6-BP

Question 15

Describe how how high concentrations of glucose cause Beta cells to secrete insulin.

Answer 15

1. As extracellular glucose concentrations increase → glucose enters cells
2. Glucose converted to pyruvate & goes thru TCA to make ATP
3. ATP blocks K+ channels → depolarization
4. VG Ca2+ channels open → [Ca2+] in cytoplasm
5. Ca2+ dependent proteins mediate fusion of insulin containing vesicles w/ plasma membranes → insulin release

Question 16

Describe the insulin signaling pathway that promotes glucose storage.

Answer 16

Insulin binds receptor TYROSINE KINASE
→ Phosphatidyl inositol 3-kinase makes phosphatidyl inositol-3,4,5-trisphosphate.
→ PDK1 and PKB are recruited to the plasma membrane.
→ PDK1 phosphorylates PKB, activating it.
→ PKB phosphorylates Protein Phophatase-1 & Glycogen synthase kinase-3

• Phosphorylated PP1 is ACTIVATED
• Phosphorylated GSK-3 is INACTIVATED

Net effect: ACTIVATE GLYCOGEN SYNTHASE

Question 17

What is the dominant mediator of metabolism in the FASTED state?

Answer 17

Glucagon

Question 18

How does glucagon signal for the formation of PEP-CK and G6Pase?

Answer 18

Glucagon →
activates PKA → phosphorylates CREB →
activates transcription of PGC1a (transcriptional co-activator) →
liver →
CREB + PGC1a activate transcription of PEP-CK and G6Pase

**both are required for gluconeogenesis

Question 19

How does insulin block hepatic gluconeogenesis?

Answer 19

Insulin →
activates PKB (Akt) → blocks transcription factor FOX01 by phosphorylating it>
NO production of genes necessary for gluconeogenesis

Question 20

What is FOX01 required for?

Answer 20

FOX01 required for gene transcription of G-6-Pase & PEP-CK

Question 21

What hormone controls metabolism in the FED state?

Answer 21

Insulin

Question 22

What is the mechanism for maturity onset diabetes of the Young Type 2?

Answer 22

Mutation in glucokinase →
less efficient kinase activity
→ β cell can’t rapidly increase ATP
→ don’t get glucose storage

Question 23

What happens when there is a lack of insulin or insulin signaling?

Answer 23

don’t get inhibition of glucagon release from pancreastic cells →
increased glucose uptake & hepatic gluconeogenesis→
water wants to leave cells to balance osmotic P →
bad sx: dehydration, coma, death

Question 24

How does the body deal with a pseudostarved state?

Answer 24

increased lipolysis→ increased FA in blood→
diabetic ketoacidosis if ketone bodies too great
→ bad sx: coma, death

Question 25

What happens in T1D?

Answer 25

no insulin> dietary fat doesn't get stored in adipose → TAG in blood→ Elevated KB, FA & glucose levels

Question 26

What happens in T2D?

Answer 26

Insulin made, but not signalling appropriately or made in small amts that isn't enough to respond to dietary glucose→ Don't get uptake of glucose into muscle cells → inappropriate gluconeogenesis.

Question 27

How does Metformin lower blood glucose?

Answer 27

activates LKB1→ phosphorylates and activates AMPK→ AMPK phosphorylates TORC2→ TORC2 can't localize to nucleus→ This prevents transcription of gluconeogenesis genes and lowers blood glucose.

Question 28

What complex doesn't dissociate leading to constant gluconeogenesis in T2D? How does Metformin conteract this?

Answer 28

TROC2-DREB Metformin PREVENTS TORC2 translocation to the nucleus

Question 29

How does metformin decrease hepatic gluconeogensesis?

Answer 29

blocks complex 1 in ETC→ activation of AMP-K → decreased hepatic gluconeogenesis

Question 30

What affect does Metformin have on F-2,6-BP ?

Answer 30

prevents generation of cAMP → which blocks PKA activation → higher levels of F-2,6-BP → acts as allosteric inhibitor of gluconeogenesis and allosteric activator of glycolysis

Question 31

What does Dinitrophenol do?

Answer 31

It's an Uncoupler that dissipates the proton gradient without generating ATP.

Question 32

What are some of hte SE of dinitrophenol? Why might it be a future diabetes tx?

Answer 32

dose dependent fever improves hepatic insulin sensitivity--> possible diabetes tx in future

Question 33

How does testosterone affect insulin?

Answer 33

It ENHANCES insulin's effects on glucose metabolism by: 1. increasing insulinR expression 2. Increasing GLUT4 expression and membrane translocation 3. Upregulation of key enzymes> store glucose as glycogen

Question 34

How does an increase in adipose tissue affect testosterone production?

Answer 34

increased adipose tissue → increased aromatase activity→ increased conversion of testosterone to estradiol in adipocytes→ negative feedback to hypothalamus → decreased testosterone production

Question 35

What is metabolic coupling?

Answer 35

occurs in many tissues of the body, where one cell type converts glucose to other substrate that is then passed on to the other cell type to be used.

Question 36

How is metabolic coupling used in spermatogenesis?

Answer 36

Sertoli cells are glycolytic, fermenting glucose to lactate → lactate is exported through MCT4, and taken up by spermatocytes through MCT2.→ The spermatocytes then oxidize the lactate.

Question 37

How is metabolic coupling used in oocyte maturation?

Answer 37

Cumulus cells are glycolytic, fermenting and providing the oocyte substrates for oxidative phosphorylation.

Question 38

A 16 y/o M is brought to the ER after swallowing two bottles of aspirin tablets. His oral temp is 104. Why?

Answer 38

Salicylate is a mitochondrial uncoupler

Question 39

Some tissues are comprise of different cell types that are metabolically coupled. In the brain, astrocytes ferment ________and provide ________to neurons.

Answer 39

``` GLUCOSE> pyruvate> LACTATE> MCT transporter> taken up by adjacent neuron ```

Question 40

How does insulin receptor signaling inactivate gluconeogenesis?

Answer 40

Akt phosphorylates FOX01

Question 41

A toxin inhibits PEP-CK. In the presence of this toxin, what can provide carbon for gluconeogenesis?

Answer 41

Glycerol