Integration of Metabolism

Question 1

What 4 major tissues play a role in energy metabolism

Answer 1

• Liver, adipose, muscle, brain
• each specialized in storage, use of specialized fuels
• form a network in which one tissue provides substrates to another
• communication mediated by nervous system

Question 2

Integration of energy metabolism is controlled by which two peptide hormones?

Answer 2

• Insulin and glucagon
• Secreted in response to changing substrate levels in blood

Question 2

Catecholamines play a supporting role

Answer 2

• Epinephrine and norepinephrine- secreted in response to neutral signals from brain

Question 2

Changes in conc. of two hormones allow what?

Answer 2

Body to store energy after eating, or make stored energy available during fasting, injury or fight or flight

Question 3

Insulin vs. Glucagon

Answer 3

Insulin: inc. glucose ox., glycogen synthesis, fat synthesis, protein synthesis
Glucagon: inc. glycogenolysis, gluconeogenesis, ketogenesis

Question 4

Insulin

Answer 4

Most important hormone controlling energy use by tissues

Question 5

What are the metabolic effects of insulin?

Answer 5

Anabolic
- well fed state
- promotes storage of energy
- promotes synthesis of glycogen, fat and protein

Question 6

Where is insulin synthesized

Answer 6

peptide hormone synthesized is the b-cells of islets of langerhans in the pancreas

Question 7

Structure of Insulin

Answer 7

• Insulin is composed of 51 amino acids in two protein chains (A and B chain)
• The two chains are joined by 2 intermolecular disulfide bonds
• The A chain also contains an intramolecular disulfide bond
• mostly a-helical

Question 8

Synthesis of Insulin

Answer 8

• Involves 2 inactive precursors: preproinsulin and proinsulin
• Precursors are sequentially cleaved to form mature insulin and c-peptide
• C-peptide is essential for protein folding

Question 9

Where is Insulin stored

Answer 9

• Stored in cytosolic granules and released by exocytosis when glucose levels are high

Question 10

Plasma half life of insulin

Answer 10

• 6 mins (short)
• Rapid turnover once released = rapid changes in circulated changes

Question 11

Stimulation of Insulin Secretion

Answer 11

1. Glucose
2. Amino Acids
3. Gastrointestinal hormone
   (mirror images for spike of glucose corresponding to spike in insulin)

Question 12

1. Glucose

Answer 12

Inc. plasma glucose conc. is the most important signal for increased insulin secretion

Question 13

2. Amino Acids

Answer 13

Eating protein causes rise in plasma a.a, inducing insulin secretion (fatty acids have similar effect)

Question 14

3. Gastrointestinal Hormones

Answer 14

Ingestion of food causes the release of intestinal hormones that stimulate insulin secretion

Question 15

Inhibition of Insulin Secretion

Answer 15

1. Decreased food ingestion (lower blood glucose)
2. Periods of physiological stress - injury or infection
   - mediated by norepinephrine and epinephrine
   - catecholamines cause rapid mobilization of energy-yielding fuels
   - can override glucose-stimulated insulin release in emergency situations

Question 16

Metabolic Effects of Insulin

Answer 16

• Insulin promotes nutrient storage in glycogen, TAG and protein and inhibits their mobilization
  1. Effects on Carbohydrate metabolism
  2. Effects on lipid metabolism
  3. Effects on protein synthesis

Question 17

1. Effects on Carbohydrate metabolism

Answer 17

Most pronounced in liver, muscle, adipose
- In liver and muscle glycogen synthesis is increased
- in muscle and adipose glucose uptake is increased by inc. the number of glucose transporters in the membrane
- In liver glucose production is decreased through inhibition of glycogen degradation and gluconeogenesis

Question 18

2. Effects on lipid metabolism

Answer 18

• In adipose tissue release of FA is decreased by two mechanisms (inhibiting hormone sensitive lipase activity resulting in decreased TAG breakdown and increasing TAG synthesis by inc. glucose transport and metabolism in fat cells resulting resulting in inc. glycerol 3-P levels)
• Activity of lipoprotein lipase is inc. resulting in more FFA from lipoproteins (VLDL/chylomicrons) available for TAG formation

Question 19

3. Effects on protein synthesis

Answer 19

• Insulin stimulates entry of a.a into the cells
• Stimulates protein synthesis

Question 20

Signal Transduction Pathway

Answer 20

Ways signals from outside the cell can change the overall activity of the cell
- External signal received by receptor, amplifies signal, transduction in pathways, results in respone

Question 21

Insulin Receptor

Answer 21

• Insulin binds to specific receptor in cell membrane (can’t cross membrane on own)
• Insulin receptor is found on most tissues, including liver, adipose and muscle
• binding to receptor is firsts step that leads to cascade of rxns ultimately leading to diverse array of biological responses to insulin signal

Question 22

Mechanism of Action

Answer 22

• Binding of insulin to the a-subunit activates the receptor, changing its shape
• Initiates signal transduction by autophosphorylation of Tyr on receptor - locks in active site

Question 23

Insulin mechanism of action

Answer 23

- Signal transduction is a series of phosphorylation rxns of insulin receptor substrate proteins - Signal stops when receptor is dephosphorylated

Question 24

Insulin-Dependent Glucose Transport

Answer 24

- Muscle and adipose tissues experience inc. glucose uptake in response to insulin - Mediated through inc. glucose transporters in the cell membrane in response to insulin - Binding of insulin to insulin receptor causes intracellular glucose transporters to move to the cell membrane - Inc. insulin dependent transport of glucose into cell - Dec. insulin leads to internalization of glucose transporters untl more insulin is detected

Question 25

Glucagon

Answer 25

- Peptide hormone secreted by a-cells of the pancreatic islets of Langerhans - Glucagon (epinephrine/norepniphrine) oopose actions of insulin

Question 26

Most important role of glucagon

Answer 26

Maintain blood glucose levels by activating glycogen degradation and gluconeogenesis in the liver

Question 27

Structure of Glucagon

Answer 27

Glucagon is a signle peptide of 29 a.a - similar to insulin it starts as preproglucagon and is converted to glucagon by a series of proteolytic cleavages

Question 28

Stimulation of Glucagon Secretion

Answer 28

1. Low blood glucose 2. Amino Acids 3. Catecholamines

Question 29

1. Low blood glucose

Answer 29

Dec. in plasma glucose conc. is primary stimulus for glucagon release, during overnight or prolonged fast, glucagon prevents hypoglycemia

Question 30

2. Amino Acids

Answer 30

Derived form protein rich meal. Glucagon prevents hypoglycemia that would other wise occur as a result of inc. insulin secretion

Question 31

3. Catecholamines

Answer 31

Elevated levels of epinephrine/norepinephrine increase glucagon secretion - During periods of physiological stress, regardless of blood glucose level, glucagon is elevated in anticipation of inc. glucose use

Question 32

Inhibition of Glucagon Secretion

Answer 32

Elevated blood glucose - Insulin (both elevated after glucose or carbohydrate-rich meal)

Question 33

Metabolic Effects of Glucagon

Answer 33

1. Carbohydrate metabolism 2. Lipid metabolism 3. Protein metabolism - effects are catabolic and promote the maintenance of blood glucose - primary target is liver

Question 34

1. Carbohydrate metabolism(G)

Answer 34

glucagon stimulates breakdown of liver glycogen (not muscle) and inc. gluconeogenesis - intravenous administration of glucagon results in rapid rise of blood glucose

Question 35

2. Lipid Metabolism(G)

Answer 35

glucagon increases ox. of fatty acids and formation of ketone bodies from acetyl CoA

Question 36

3. Protein metabolism(G)

Answer 36

glucagon increases uptake of a.a from the blood by liver - Inc. C skeleton available for gluconeogenesis - Plasma levels of a.a are decreased

Question 37

Glucagon mechanism of action

Answer 37

- Glucagon binds to specific glucagon receptor in the cell - Activates adenylyl cyclase in cell membrane (inc. conc. of cAMP a second messenger for glucagon's metabolic action)

Question 38

What does cAMP do?

Answer 38

activates cAMP-dependent kinase which phosphorylates specific protein that results in - Inc. glycogen degradation - Inc. gluconeogenesis - Inc. Ketone body synthesis - Inc. uptake of amino acids - Dec. glycogenesis