Feed-fast

Question 1

The control of fuel metabolism in tissues is mediated by

Answer 1

1. Nervous system
2. Level of plasma hormones
3. Availability of circulating substrate.

Main hormones are insulin and glucagon. Catecholamine (epinephrine and norepinephrine) play a supportive role

Question 2

Insulin is released as?

Answer 2

Preproinuslin. Pre means contains signal sequence guide it to rough ER for modification. Delta cells secrete hormone somatostatin

Question 3

What are the structures of preproinsulin, proinsulin and insulin

Answer 3

• preproinsulin: contains N-terminal signal sequence + A chain + B chain + connecting C-peptide
• proinsulin: A chain + B chain + connecting C-peptide
• insulin: contains A chain + B chain

Question 4

Insulin secretion is stimulated by what?

Answer 4

Glucose, amino acids and fatty acids and gastrointestinal peptide hormones (GLP-1) and GIP both released after glucose reaches intestine that’s why it’s better to feed patients glucose rather than inject it bc intestines make insulin more sensitive to glucose

Question 5

What happens to preproinsulin after it becomes proinsulin

Answer 5

Proinsulin taken to Golgi apparatus and cleaved C-peptide bond to form insulin. Both insulin and C-peptide are released by exocytosis so C-peptide plasma level is a good indicator of insulin secretion

Question 6

Insulin secretion is inhibited by?

Answer 6

Scarcity of dietary fuels (starvation) and by physiological stress. In emergency, catecholamines are released, they make glucose and fatty acids available + they inhibit glucose stimulated secretion of insulin REGARDLESS OF GLUCOSE LEVEL. So in emergency CNS controls pancreatic B cells rather than glucose level

Question 7

Insulin how does it affect ketogenesis

Answer 7

It inhibits it. Also, insulin increases glucose uptake by GLUT-4 which is insulin dépendent. Insulin dephosphorylates both glycogen synthase and glycogen phosphorylase and the synthase becomes the active one

Question 8

How does insulin affect target cell

Answer 8

Insulin contains two domains, alpha and beta. The intracellular Beta domain contains tyrosine kinase activity. Auto phosphorylation —> activation of receptor. And we have IRS (insulin receptor substrate) it gets phosphorylated and activated

Question 9

Does insulin inhibit or promote hormone sensitive lipase?

Answer 9

It inhibits it. Insulin wants fatty acids to be released by lipoprotein lipase and taken up by the cells. Also, insulin stimulate both entry of amino acids into the cell and protein synthesis

Question 10

Catecholamines promote secretion of

Answer 10

Glucagon. Also glucagon is released as preproglucagon and it’s made of a single polypeptide. Glucagon along with norepinephrine, cortisol and growth hormone oppose the effects of insulin.

Question 11

Effect of glucagon on lipid metabolism?

Answer 11

Inhibit fatty acid synthesis by phosphorylation and inactivation of Acetyl-CoA carboxylase by AMPK. Decrease in malonyl-CoA promote fatty acid beta oxidation. It also promotes hormone sensitive lipase

Question 12

Effect of glucagon on protein metabolism

Answer 12

Stimulate protein degradation and increase uptake of amino acids by liver to be used for gluconeogenesis

Question 13

Mechanism of glucagon and its receptors

Answer 13

Glucagon receptor is G-protein coupled. THESE RECEPTORS NOT FOUND IN SKELETAL MUSCLE. Glucagon binds to receptor, adenylyl cyclase convert ATP to cAMP. This activates cAMP dependent protein kinase A which phosphorylates the enzymes PFK-1 and fructose bisphosphatase (this one becomes active)

Question 14

What are the four regulatory mechanisms of the feed-fast cycle

Answer 14

1. Substrate availiablitly (fastest)
2. Allosteric regulation (takes minutes)
3. Covalent modification (takes hours)
4. Induction and repression of enzyme synthesis (genetic control) (takes days)

Question 15

Increased glycogenolysis and fatty acid oxidation in skeletal muscles is not stimulated by glucagon

Answer 15

It’s stimulated by epinephrine. Also the feed-fast cycle is the constant shift from absorptive state (fed state) to fasting state and vice versa

Question 16

Role of fructose 2,6 bisphosphate

Answer 16

• if PFK II active —> increase fructose 2,6 bisphosphate—> PFK I is active so glycolysis
  -if PFK II is inactive—> decrease fructose 2,6 bisphosphate—> fructose 1,6 bisphosphatase is activated so gluconeogenesis

Question 17

So when insulin is secreted it dephosphorylates PFK and bisphosphatase (makes PFK active) what does glucagon do

Answer 17

cAMP dependent protein kinase A phosphorylates and does the opposite job

Question 18

Most enzymes are active in their dephosphorylated form except…

Answer 18

1. Hormone sensitive lipase
2. Glycogen phosphorylase kinase
3. Glycogen phosphorylase
4. FBP II
5. AMPK

Question 19

In well fed state what does insulin do

Answer 19

Increase synthesis of Acetyl-CoA carboxylase and fatty acid synthase while in fast state glucagon induce phoshphonelolpyruvate carboykinase (PEPCK) for gluconeogenesis

Question 20

Liver usually does gluconeogenesis but with high glucose and high insulin it goes back to glycolysis, what else?

Answer 20

Increases glucose uptake by GLUT-2 which is insulin INDEPENDENT. Also with insulin and high glucose, liver activates glucokinase which has low affinity for glucose and high Km, but unlike other hexokinases it’s not inhibited by its product (glucokinase starts phosphorylating glucose and making glucose 6-P)

Question 21

With high insulin and high glucose what does liver do

Answer 21

Increased PPP because liver keeps making glucose-6-P so this activates PPP to make NADPH needed for lipid synthesis. Also with high glucose, PDH (pyruvate dehydrogenase complex) is dephosphorylated and active making acetyl-CoA needed for making lipids and for TCA cycle

Question 22

How does insulin inhibit fatty acid oxidation?

Answer 22

By activating acetyl-CoA carboxylase which makes high malonyl CoA so CPT-I is inhibited. Also insulin increased amino acid degradation into Acetyl-CoA that can be used for fatty acid synthesis

Question 23

Insulin increases TAG synthesis how

Answer 23

Dihydroxyacetone phosphate (from glycolysis) increases and DHAP can be converted into glycerol-3-P so increases fat synthesis.

Question 24

How is glycogen synthase activated by insulin

Answer 24

Insulin keeps making glucose into glucose-6-P and this activated glycogen synthase.

Question 25

Brain in the fed state?

Answer 25

Brain only uses glucose bc only it can pass through BBB by GLUT-1 which is insulin INDEPENDENT. brain can also use ketone bodies in prolonged starvation

Question 26

Glucose level should always be at

Answer 26

(70-99 mg/dl) and this is a main priority.

Question 27

In fasted state, gluconeogenesis is increased this means..

Answer 27

C-skeleton for glucose provided by amino acids, lactic acid and glycerol. Gluconeogenesis promotes PEPCK by glucagon. Also fatty acids start getting oxidized in fasted state, malonyl CoA decreases so CPT-1 is activated

Question 28

In fasting state, we break down fatty acids into Acetyl-CoA what do we do with this Acetyl-CoA

Answer 28

Acetyl-CoA activate pyruvate carboxylase for gluconeogenesis and inhibit pyruvate dehydrogenase complex

Question 29

Why is ketogenesis increases in fasting state?

Answer 29

High NADH from beta oxidation of fatty acids inhibit TCA cycle and this will shift Acetyl-CoA for ketogenesis making ketone bodies like (3-hydroxybutyrate and acetoacetate). Liver doesn’t use ketone bodies because it lacks thiophorase enzyme

Question 30

Activation of hormone-sensitive lipase is mediated by?

Answer 30

Epinephrine. In prolong fasting, skeletal muscles exclusively use fatty acids to spare ketone bodies for the brain. Acetyl-CoA is transaminated to alanine and transported for gluconeogenesis

Question 31

In the second week of fasting muscle proteolysis decreases, why?

Answer 31

Due to decrease need for gluconeogenesis because at this time brain depends more on ketone bodies instead of glucose

Question 32

Kidneys role in long term fasting

Answer 32

Renal cortex participate up to 50% of gluconeogenesis. Also it neutralizes excess acids due to elevated ketone bodies. How? Well glutamine is released from muscles metabolism and taken by kidneys and deaminated by renal glutaminase forming glutamate and ammonia. Glutamate becomes a-ketoglutarate by glutamate dehydrogenase and NH3 is formed. NH3 takes an H+ from ketone bodies and eliminated in urine as NH4+