Block 3 - hepatic glucose production (L9-10)

Question 1

HGP is a function of…

Answer 1

glycogen breakdown (glycogenolysis) and glycogen synthesis (glycogenesis)

Question 2

What are the overall effects of insulin and glucagon on HGP?

Answer 2

insulin - suppresses HGP
glucagon - increases HGP

Question 3

What are the 3 actions of insulin on HGP?

Answer 3

• activate glycogenesis (glycogen synthesis)
• inhibit glycogen breakdown (glycogenolysis)
• suppress gluconeogenesis

Question 4

How does insulin enhance glycogen synthesis?

Answer 4

• rapid activation of IR and IRS
• signals two pathways:
  –MAPK, p90-S6 kinase, activate PP1G
  –PI3K, PKB/Akt, inhibit GSK-3
• both pathways activate GS and increase glycogen synthesis, inhibiting HGP

Question 5

How does insulin inhibit glycogen breakdown?

Answer 5

• acts via IR/IRS/MAPK/p90-S6 kinase pathway
• activate PP1, which dephosphorylates and inhibits phosphorylase
• inhibition of glycogenolysis and reduced HGP

Question 6

How does insulin suppress gluconeogenesis?

Answer 6

• inhibition of GSK-3 and activation of p38 MAP kinase pathways
• suppress transcription of PEPCK and G9Pase
• reduce gluconeogenesis and HGP

Question 7

What are the 3 actions of glucagon on HGP?

Answer 7

• inhibition of glycogen synthesis (glycogenesis)
• activation of glycogen breakdown (glycogenolysis)
• activation of gluconeogenesis

Question 8

How does glucagon stimulate glycogenolysis?

Answer 8

• via the Gs/adenylate cyclase/cAMP pathway to activate PKA
• PKA phosphorylates and activates phosphorylase kinase, which phosphorylates and activates phosphorylase
• enhanced glycogen breakdown increases HGP

Question 9

How does glucagon activate gluconeogenesis?

Answer 9

• glucagon, via its GPCR, activates adenylate cyclase, producing cAMP and stimulating PKA
• activates PKA will migrate to the nucleus and phosphorylate CREB at the CRE site
• with CBP, this will increase gene transcription and the protein expression of PEPCK and G6Pase

Question 10

Regarding prolonged periods of exercise, when does gluconeogenesis peak?

Answer 10

right after exercise is ended

Question 11

What happens to overall HGP during prolonged periods of exercise?

Answer 11

it rises as the rate of glycogenolysis rises, then reaches a plateau and stays high until exercise is ended and glycogenolysis drops off too

Question 12

The glucagon:insulin ratio can be though of as the amounts of glucagon and insulin…

Answer 12

traveling through the blood and reaching the liver

Question 13

When is the glucagon:insulin ratio increased and decreased?

Answer 13

decreased after eating, increased during aerobic exercise

Question 14

What is the general response of HGP to a low or high glucagon:insulin ratio?

Answer 14

high ratio = increase HGP
low ratio = decreased HGP

Question 15

In the Metabolic syndrome, as insulin decreases, HGP…

Answer 15

increases

Question 16

What is the first step in how the metabolic syndrome causes increase HGP?

Answer 16

insulin usually decreases FFA, but when insulin is decreased, FFA is produced and released more, making it available to the liver

Question 17

How does FFA cause excess HGP?

Answer 17

• increase FFA is oxidized to ATP
• ATP availability drives gluconeogenesis and increases HGP

Question 18

What is the role of glucagon in excess HGP production?

Answer 18

• normally insulin suppresses glucagon secretion (less insulin = more glucagon secreted)
• also, basal SNS activity is increased in the Metabolic syndrome, leading to more stimulation of glucagon secretion

Question 19

How can insulin signaling at the hepatocyte be defective in the Metabolic Syndrome?

Answer 19

• increased activation of serine kinases (GSK-3, JNK, IKKB, PKC isoforms)
• increased serine phosphorylation or IR and IRS
• decreased tyrosine phosphorylation of IR and IRS
• upstream defects in IRS and PI3K lead to less transduction of insulin signaling downstream
• less insulin = less suppression of glucagon secretion = more HGP

Question 20

How does the glucagon:insulin ratio relate to the increase HGP in the Metabolic syndrome?

Answer 20

• ratio of glucagon:insulin is increased but does not indicate and increase in HGP…
• the ratio doesn’t reflect decreased insulin signaling (insulin resistance) in the hepatocytes
• so the ratio underestimates the increase in HGP in the Metabolic syndrome