Glucose Metabolism Review - Skildum

Question 1

What is the hormonal control of glucose metabolism?

Answer 1

↑Blood glucose => Insulin release => ↑Glycogen synthesis, ↑FA synthesis, ↑Triglyceride synthesis, ↑Liver glycolysis

↓Blood glucose => Glucagon release => ↑Glycogenolysis, ↑Gluconeogenosis, ↑Lipolysis, ↓Liver glycolysis

Question 2

What are the molecular signaling and transcriptional pathways of glucagon?

Question 3

What are the molecular signaling and transcriptional pathways of insulin?

Question 4

The insulin receptor acts as a _______?

A. G protein coupled receptor

B. Receptor tyrosine kinase

C. Ligand activated transcription factor

D. Ligand gated cation channel

E. Jak/STAT receptor

Answer 4

B. Receptor tyrosine kinase

Question 5

A 44 year old male ate a 1,200 calorie meal that was 50% carbohydrate, 30% fat and 20% protein. He then fasted for 30 hours. What is the source of carbon for his blood glucose?

A. Fatty acid beta oxidation
B. Dietary carbohydrates
C. Liver glycogen
D. Protein catabolism
E. Muscle glycogen

Answer 5

D. Protein catabolism

Question 6

What is a more important source of glucose: dietary carbohydrates or liver produced glucose?

Answer 6

The liver is a more important source of blood glucose than dietary carbohydrate. The liver supplies glucose through glycogenolysis and gluconeogenesis.

Question 7

What hormones act in opposition to insulin?

Answer 7

Glucagon, catecholamines, cortisol and growth hormone act in opposition to insulin.

Question 8

How is insulin secretion/release from pancreatic beta cells initiated?

Answer 8

1. Glucose enters the cell (GLUT2) and is oxidized (to pyruvate), producing ATP.
2. ATP inhibits a potassium channel, causing depolarization of the cell.
3. A voltage gated calcium channel opens, and calcium concentrations in the cytoplasm increase.
4. Calcium dependent proteins (calmodulin) mediate fusion of insulin containing vesicles with the plasma membrane.

Question 9

What is MODY2 (Maturity Onset Diabetes of the Young type 2) caused by?

Answer 9

Autosomal dominant inherited mutations in pancreatic glucokinase => Inappropriate insulin release

Question 10

What are the actions of insulin directly after it is released? Interactions?

Answer 10

Insulin activates a receptor tyrosine kinase on target cell.

Phosphatidyl inositol 3-kinase (PI-3kinase) => makes phosphatidyl inositol-3,4,5-trisphosphate (docking site).

PDK1 and PKB (a.k.a. Akt) are recruited to the plasma membrane (bind to docking site).

PDK1 phosphorylates PKB, activating it.

PKB phosphorylates intracellular targets to modulate metabolism.

Question 11

How does insulin signaling promote storage of glucose?

Answer 11

signaling cascad that phosphorylates Glycogen Synthase Kinase-3 (becomes inactive) => can’t REPRESS glycogen synthase => MAKE GLYCOGEN!

Question 12

How does insulin block hepatic gluconeogenesis?

Answer 12

Transcriptional regulation:

Insulin activates PKB (Akt), which blocks the transcription factor FOX01 (which controls expression of Glucose 6-phosphatase and PEP-CK) => blocks expression of key gluconeogenesis genes

Question 13

How does hepatic gluconeogenesis get stimulated during the fasted state?

Answer 13

Protein kinase A (PKA) is activated by glucagon signaling through cAMP. PKA phosphorylates the transcription factor CREB.

CREB activates transcription of PGC1a, a transcriptional coactivator.

In the liver, transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) is activated by CREB and PGC1a. Both enzymes are required for hepatic gluconeogenesis.

Question 14

How is hepatic gluconeogensis blocked during the fed state?

Answer 14

In the fed state, insulin is the dominant hormone that controls metabolism.

The insulin receptor causes activation of protein kinase B (Akt). Akt phosphorylates the transcription factor Fox01, inactivating it. Genes necessary for gluconeogenesis are not expressed.

Question 15

What two enzymes are required for hepatic gluconeogenesis?

Answer 15

Glucose-6-phosphatase (GSPase) and phosphoenolpyruvate carboxykinase (PEPCK)

Question 16

How does glucagon regulate Phosphofructokinase 1/2?

Answer 16

Glucagon => ↑cAMP => ↑PKA =>

Protein kinase A (PKA) => phosphorylates PFK-2 (PFK/FBPase 1), the bifunctional enzyme that:

1. Phosphorylates fructose 6-phosphate the make fructose 2,6-bisphosphate (kinase)
2. Dephosphorylates fructose 2,6-bisphosphate to make fructose 6-phosphate (phosphatase).

Phosphorylation by PKA inhibits the kinase activity and activates the phosphatase activity, decreasing the pool of fructose 2,6-bisphosphate.

A drop in F2,6BP levels promotes gluconeogenesis and inhibits glycolysis.

A rise in F2,6BP levels suppresses gluconeogenesis and stimulates glycolysis.

Question 17

Diabetes mellitus results from what two etiologies?

Answer 17

insulin deficiency OR glucagon excess

Question 18

Why do people with Type 1 diabetes mellitus tend to be thin or slim?

(according to Dr. Skildum)

Answer 18

Don’t store excess calories normally and have constant lipolysis

Question 19

How does Metformin work?

Answer 19

Metformin activates LKB1, which phosphorylates and activates AMPK.

AMPK phosphorylates TORC2, preventing its nuclear localization => can’t activate CREB to activate transcription

This prevents transcription of gluconeogenesis genes and lowers blood glucose.

ALSO Metformin inhibits mitochondrial electron transport => decreases ATP => increases AMP => activates PK => sensitizes cell to insulin signaling

Question 20

A 16 year old male is brought to the emergency room after swallowing two bottles of aspirin tablets. His oral temperature is 103°. Why?

A. COX-2 promotes gluconeogenesis

B. Arachidonic acid is required for IL-6 synthesis

C. Salicylate is a mitochondrial uncoupler

D. COX-1 inhibition increases PGE2 production

E. Acetylation of NADH dehydrogenase blocks electron transport

Answer 20

C. Mitochondrial uncoupler

Question 21

Disorders in glycosylation can present as a failure to develop secondary sex characteristics during puberty. This is because . . . ?

A. steroid hormones are glycated.

B. peptide hormones are glycosylated.

C. glycogenolysis is activated only in the fasted state.

D. human milk oligosaccharides are fermented by gut bacteria.

E. transferritin activates a G protein coupled receptor.

Answer 21

B. peptide hormones are glycosylated.

Question 22

How does insulin receptor signaling inactivate gluconeogenesis?

A. Akt phosphorylates FOX01

B. PI3K cleaves PIP2 into DAG and IP3

C. PGC1a activates PEP-CK transcription

D. PP1 dephosphorylates glycogen synthase kinase

E. cAMP activates PKA

Answer 22

A. Akt phosphorylates FOX01

Question 23

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

A. Alanine

B. Glycerol

C. Palmitate

D. Phosphatidyl inositol

Answer 23

B. Glycerol