Module 6: Insulin, glucagon and hypoglycemia Flashcards
What is the structure of insulin
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
How is insulin synthesized?
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).
Where is insulin stored? how is it released? What’s it’s half-life? How is it degraded?
- Stored in cytosolic granules
- released by exocytosis
- half-life of 6 mins (short)
- degraded by insulinase in the liver
What 3 factors stimulate the secretion of insulin?
- Glucose: after eating, the plasma glucose concentration increases therefore stimulating secretion
- Amino acids: after eating protein-rich meal, there’s a rise in amino acid in plasma therefore stimulating secretion
- Gastrointestinal hormones: After eating food, intestinal hormones are released which stimulate secretion
What factors inhibit insulin secretion?
- Fasted state: when blood glucose level is low the body needs glucose
- 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
What is the metabolic effect of insulin on carbohydrate metabolism?
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
What is the metabolic effect of insulin on lipid metabolism?
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)
What is the metabolic effect of insulin on protein metabolism?
There’s an increase of amino acids uptake therefore an increase of protein synthesis and increase in amino acid degradation
Describe the mechanism of action of insulin
- insulin binds to an alpha subunit, activating receptor
- tyrosine in tyrosine kinase domain found on bottom of ß subunit autphosphorylates. This initiates signal transduction
- Signal stops when receptor dephosphorylates
- Has an off-switch mechanism because the system needs to be in equilibrium
What is signal transduction?
A series of phosphorylation reactions on insulin receptor substrate proteins
describe insulin-dependent glucose transport.
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
What is the structure of glucagon?
A single peptide of 29 amino acids.
How is glucagon synthesized?
A single gene transcribed and translated encodes for preproglucagon which undergoes a series of proteolytic cleavages converting it to glucagon.
Where is glucagon stored and secreted from/by?
by the alpha-cells of the pancreatc islets of langerhans
What is the most important role of glucagon?
to maintain blood glucose levels by activating glycogen degradation and gluconeogenesis
What 3 factors stimulate the secretion of glucagon?
- Low blood glucose: decrease in plasma glucose concentration (overnight or prolonged fast)
- Amino acids: If eating protein rich meal low in carbohydrates; glucagon released to prevent over response to insulin
- Catecholamines: increase glucagon secretion during periods of physiological stress, regardless of blood glucose levels. (elevated lvls of epinephrine/norepinephrine
What 2 factors inhibit glucagon secretion
- elevated blood glucose levels
- Insulin
- After glucose or carbohydrate-rich meal
What are the metabolic effects of glucagon on carbohydrate metabolism?
glucagon stimulates breakdown of liver glycogen and increases gluconeogenesis.
- intravenous administration of glucagon results in rapid rise of blood glucose
liver glycogen NOT muscle
Briefly describe the metabolic effects of glucagon
Largely catabolic
- breaks down stores of energy
Primary target: liver
What are the metabolic effects of glucagon in lipid metabolism?
Increases fatty acid oxidation and formation of ketone bodies from acetyl CoA
What are the metabolic effects of glucagon in protein metabolism?
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
Describe the mechanism of action of glucagon.
- glucagon binds to specific glucagon receptor in cell membrane of liver cells
- Adenylyl cyclase activates and converts ATP to cAMP (leads to an increased concentration of cAMP)
- cAMP activates cAMP-dependent protein kinase
- 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
What is cyclic AMP (cAMP)
a second messenger for glucagon’s metabolic action
What is hypoglycemia?
Low blood glucose
- blood glucose lvl equal to or 70 mg/dl
What are the 2 classes of symptoms associated with hypoglycemia?
Adrenergic
- elevated epinephrine: fight or flight hormone
- Fear, tremors, sweating
Neuroglycopenic
- from decreased brain glucose
- impaired brain function, confusion, seizures, coma, death (lol)
Why is hypoglycemia a medical emergency?
The brain needs continuous supply of glucose or you die
What systems does your body have to prevent and correct hypoglycemia?
glucoregulatory systems?
- Pancreatic alpha-cells release glucagon
- receptors in hypothalamus respond to low glucose
- triggers secretion of catecholamines, cortisol and growth hormone
What are the main counterregulatory hormones? Why are they called this?
Glucagon, catecholamine’s, cortisol, and growth hormones
- they oppose action of insulin
What are the 4 types of hypoglycemia? List from most common to least
- insulin-induced
- postprandial hypoglycemia
- fasting hypoglycemia
- alcohol-related hypoglycemia (not ranked)
What is insulin-induced hypoglycemia?
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
What is postprandial hypoglycemia
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
What is fasting hypoglycemia?
low blood glucose during fasting
- occurs in individuals with damage (hepatic damage, pancreatic cancer)
- severe symptoms: neuroglycopenic symptoms, comas, seizures
- least common type
What is alcohol-related hypoglycemia?
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
