Module 6: Insulin, glucagon and hypoglycemia

Question 1

What is the structure of insulin

Answer 1

51 amino acids form 2 protein chains, A and B, that are joined together via 2 intermolecular disulfide bonds. The A chain also contains an intramolecular disulfide bond.
- disulfide bonds occur on cysteine side chains

Question 2

How is insulin synthesized?

Answer 2

A single gene transcribed and translated encodes for preproinsulin which is then cleaved to proinsulin (inactive precursors). Proinsulin is cleaved, forming mature insulin and c-peptide (for proper folding of insulin).

Question 3

Where is insulin stored? how is it released? What’s it’s half-life? How is it degraded?

Answer 3

• Stored in cytosolic granules
• released by exocytosis
• half-life of 6 mins (short)
• degraded by insulinase in the liver

Question 4

What 3 factors stimulate the secretion of insulin?

Answer 4

1. Glucose: after eating, the plasma glucose concentration increases therefore stimulating secretion
2. Amino acids: after eating protein-rich meal, there’s a rise in amino acid in plasma therefore stimulating secretion
3. Gastrointestinal hormones: After eating food, intestinal hormones are released which stimulate secretion

Question 5

What factors inhibit insulin secretion?

Answer 5

1. Fasted state: when blood glucose level is low the body needs glucose
2. physiological stressors (infections, stress) fight or flight state:
   - mediated by catecholamines epinephrine and norepinephrine.
   - These cause a rapid mobilization of energy-yielding fuels.
   - glucose-stimulated insulin overriden and glucose is taken from liver while fatty acids are taken from adipose

Question 6

What is the metabolic effect of insulin on carbohydrate metabolism?

Answer 6

Affects 3 tissues: liver, adipose, and muscle
- In liver: glucose production decreases via inhibition of gluconeogenesis and glycogen degradation
- in liver and muscle: glycogen synthesis increases
- in muscle and adipose: glucose uptake increased by increasing the number of glucose transporters in membrane

Question 7

What is the metabolic effect of insulin on lipid metabolism?

Answer 7

Adipose tissue releases fatty acids via 2 mechanisms:
1. Decrease of TAG breakdown by inhibiting hormone sensitive lipase activity
2. Increase TAG synthesis by increasing glucose transport and metabolism in fat cells
- lipoprotein lipase activity increases therefore there’s more free fatty acids from lipoproteins (VLDL and chylomicrons)

Question 8

What is the metabolic effect of insulin on protein metabolism?

Answer 8

There’s an increase of amino acids uptake therefore an increase of protein synthesis and increase in amino acid degradation

Question 9

Describe the mechanism of action of insulin

Answer 9

1. insulin binds to an alpha subunit, activating receptor
2. tyrosine in tyrosine kinase domain found on bottom of ß subunit autphosphorylates. This initiates signal transduction
3. Signal stops when receptor dephosphorylates

• Has an off-switch mechanism because the system needs to be in equilibrium

Question 10

What is signal transduction?

Answer 10

A series of phosphorylation reactions on insulin receptor substrate proteins

Question 11

describe insulin-dependent glucose transport.

Answer 11

Muscle and adipose tissues have increased glucose uptake in response to insulin secretion.
- mediated through increased glucose transporters in cell membrane
- insulin binds to IR causing intracellular glucose transporters to move to cell membrane
- insulin-dependent transport of glucose into cell increases
- when insulin lvls are low, glucose transporters internalize until more insulin is detected

Question 12

What is the structure of glucagon?

Answer 12

A single peptide of 29 amino acids.

Question 13

How is glucagon synthesized?

Answer 13

A single gene transcribed and translated encodes for preproglucagon which undergoes a series of proteolytic cleavages converting it to glucagon.

Question 14

Where is glucagon stored and secreted from/by?

Answer 14

by the alpha-cells of the pancreatc islets of langerhans

Question 15

What is the most important role of glucagon?

Answer 15

to maintain blood glucose levels by activating glycogen degradation and gluconeogenesis

Question 16

What 3 factors stimulate the secretion of glucagon?

Answer 16

1. Low blood glucose: decrease in plasma glucose concentration (overnight or prolonged fast)
2. Amino acids: If eating protein rich meal low in carbohydrates; glucagon released to prevent over response to insulin
3. Catecholamines: increase glucagon secretion during periods of physiological stress, regardless of blood glucose levels. (elevated lvls of epinephrine/norepinephrine

Question 17

What 2 factors inhibit glucagon secretion

Answer 17

1. elevated blood glucose levels
2. Insulin
   - After glucose or carbohydrate-rich meal

Question 18

What are the metabolic effects of glucagon on carbohydrate metabolism?

Answer 18

glucagon stimulates breakdown of liver glycogen and increases gluconeogenesis.
- intravenous administration of glucagon results in rapid rise of blood glucose

liver glycogen NOT muscle

Question 19

Briefly describe the metabolic effects of glucagon

Answer 19

Largely catabolic
- breaks down stores of energy
Primary target: liver

Question 20

What are the metabolic effects of glucagon in lipid metabolism?

Answer 20

Increases fatty acid oxidation and formation of ketone bodies from acetyl CoA

Question 21

What are the metabolic effects of glucagon in protein metabolism?

Answer 21

glucagon increases uptake of amino acids from blood by the liver
- to increase carbon skeletons available for gluconeogenesis
- plasma lvls of amino acids are decreased

Question 22

Describe the mechanism of action of glucagon.

Answer 22

1. glucagon binds to specific glucagon receptor in cell membrane of liver cells
2. Adenylyl cyclase activates and converts ATP to cAMP (leads to an increased concentration of cAMP)
3. cAMP activates cAMP-dependent protein kinase
4. cAMP-dependent protein kinase phosporylates specific protein which results in:
   - increased glycogen degradation
   - increased gluconeogenesis
   - increased ketone body synthesis
   - increased uptake of amino acids
   - decreased glycogenesis

Question 23

What is cyclic AMP (cAMP)

Answer 23

a second messenger for glucagon’s metabolic action

Question 24

What is hypoglycemia?

Answer 24

Low blood glucose
- blood glucose lvl equal to or 70 mg/dl

Question 25

What are the 2 classes of symptoms associated with hypoglycemia?

Answer 25

Adrenergic
- elevated epinephrine: fight or flight hormone
- Fear, tremors, sweating

Neuroglycopenic
- from decreased brain glucose
- impaired brain function, confusion, seizures, coma, death (lol)

Question 26

Why is hypoglycemia a medical emergency?

Answer 26

The brain needs continuous supply of glucose or you die

Question 27

What systems does your body have to prevent and correct hypoglycemia?

glucoregulatory systems?

Answer 27

1. Pancreatic alpha-cells release glucagon
2. receptors in hypothalamus respond to low glucose
   - triggers secretion of catecholamines, cortisol and growth hormone

Question 28

What are the main counterregulatory hormones? Why are they called this?

Answer 28

Glucagon, catecholamine’s, cortisol, and growth hormones
- they oppose action of insulin

Question 29

What are the 4 types of hypoglycemia? List from most common to least

Answer 29

1. insulin-induced
2. postprandial hypoglycemia
3. fasting hypoglycemia
4. alcohol-related hypoglycemia (not ranked)

Question 30

What is insulin-induced hypoglycemia?

Answer 30

occurs in diabetics being treated with insulin
- patient may administer too much insulin (body doesn’t know exogenous insulin vs insulin exhausted by meal)
- Mild case: oral glucose administration
- severe case: glucose given subcutaneously or intramusculary
- most common type

Question 31

What is postprandial hypoglycemia

Answer 31

caused by exaggerated insulin released following a meal (pancreas exaggerates insulin)
- transient hypoglycemia with mild adrenergic symptoms
- Treatment: small frequent meals
- 2nd most common type

Question 32

What is fasting hypoglycemia?

Answer 32

low blood glucose during fasting
- occurs in individuals with damage (hepatic damage, pancreatic cancer)
- severe symptoms: neuroglycopenic symptoms, comas, seizures
- least common type

Question 33

What is alcohol-related hypoglycemia?

Answer 33

sub-class of fasting hypoglycemia
Occurs when patient hasn’t eaten and consumed lots of alcohol
- Ethanol needs to be metabolized so it decreases gluconeogenic substrates to regenrate NAD
- low gluconeogenic substrate = slow gluconeogenesis = less glucose production = hypoglycemia