Pancreas B&B Flashcards
where are beta, alpha, and delta cells anatomically located in the pancreas?
beta cells (insulin) centrally located, most abundant
alpha (glucagon) and delta (somatostatin) cells found in outer islets surrounding beta cells
describe the process of insulin secretion from beta cells of the pancreas (3 steps)
- synthesized as preproinsulin in RER
- cleaved to proinsulin and transported to Golgi
- packaged into secretory granules and cleaved to insulin + C-peptide
describe the structure of insulin
alpha chain + beta chain, connected via disulfide bridges
C-peptide (“connecting”) initially connects alpha/beta chains but is cleaved from proinsulin… has a long half life and can be measured as indication of insulin production
describe the mechanism of insulin release from pancreatic beta cells (3 steps)
- glucose enters via GLUT-2, leading to ATP production
- increased ATP causes K+ channels to close (K+ is trapped within cell), triggering depolarization
- depolarization causes voltage-gated Ca2+ channels to open, triggering exocytosis of stored insulin
what is the effect of epinephrine on beta cells of the pancreas?
acts on beta-2 receptors to increase insulin release
acts on alpha-2 receptors to decrease insulin release - this is the dominant effect
net: increase plasma glucose during fight/flight response (overall decrease insulin release)
which glucose transporter is bidirectional?
GLUT-2: bidirectional
found in liver, kidney, pancreatic beta cells - allows for regulation of blood glucose levels
what are the steps of insulin receptor activation, and the 2 possible outcomes?
- insulin binds, triggering autophosphorylation of tyrosine kinase domains
- IRS (insulin receptor substrates) mediate downstream effects
3a. PIK3 pathway forms PIP3 —> increase GLUT-4 expression
3b. RAS/MAPK activation (G protein) —> modify cell growth/ gene expression
how does insulin lead to the increase in GLUT-4 expression?
insulin binds tyrosine kinase receptor, which downstream forms PIP3 —> this catalyzes increase in GLUT-4 expression on cell surfaces
GLUT-4 stored in vesicles, esp. important for glucose uptake in muscle and fat … it makes sense that you want this to be really responsive to insulin levels !
describe why muscle and fat are referred to as insulin-dependent organs, while brain and RBC are insulin-independent
muscle/fat use GLUT-4 for glucose uptake - surface expression depends on insulin receptor activation and downstream formation of PIP3
brain/RBC use GLUT-1 for glucose uptake, which takes up glucose whenever it is available (RBC has no mitochondria, brain has not fatty acid metabolism - these tissues rely on glucose/glycolysis)
liver/kidney/intestines are also insulin dependent, via GLUT-2 (bidirectional)
which enzymes does insulin activate or inhibit to have the following metabolic effects?
a. increase glycogen synthesis
b. inhibit gluconeogenesis
c. increase fatty acid synthesis
a. increase glycogen synthesis - activates glycogen synthase, inhibits glycogen phosphorylase
b. inhibit gluconeogenesis - inhibits fructose-1,6-bisphosphatase 1 (F-1,6-B1)
c. increase fatty acid synthesis - activates acetyl-CoA carboxylase, inhibits hormone sensitive lipase
explain why glucose + insulin is used for the treatment of hyperkalemia
insulin lowers serum K+ by enhancing Na/K/ATPase pumps in skeletal muscle (recall insulin causes K+ channels to close)
must give with glucose to prevent hypoglycemia with insulin administration
on what tissues does glucagon exert its effects? what are its effects (4)?
works on liver mostly (NO receptors in muscle)
- glycogen breakdown
- increases gluconeogenesis
- amino acid uptake (more carbon skeletons for glucose via gluconeogenesis)
- activates lipolysis via hormone sensitive lipase
what signaling pathway is activated by glucagon receptors?
glucagon (protein hormone, single polypeptide chain) binds glucagon receptor (GPCR) —> adenylyl cyclase —> cAMP —> PKA
what are the 2 clinical uses of glucagon administration?
- hypoglycemia in unconscious patient
- beta blocker overdose - raises intracellular cAMP like beta-adrenergic receptors do, but via binding glucagon receptors (getting around the fact that the beta receptors are blocked)
what are the top 2 treatments of choice for hypoglycemia in an unconscious patient? (can’t feed them cookies)
- IV dextrose
- intramuscular glucagon - useful when IV cannot be established
