insulin, glucagon Flashcards
insulin synthesis
preproinsulin is synthesized in the RER. the presignal is cleaved to make proinsulin, which is stored in secretory granules. cleavage of proinsulin leads to exocytosis of insulin and C peptide equally. insulin and C peptide are increased in insulinoma, whearas exogenous insulin lacks C peptide.
What does insulin do once it binds a glucose-dependent peripheral cell? What are the insulin-dependent glucose transporters?
- binds insulin receptors –> tyrosine kinase activity:
a) RAS/MAP kinase pathway promotes cell growth and DNA synthesis
b) Phosphoinositide-3 kinase pathway promotes glycogen, lipid, and protein synthesis. it also promotes GLUT4 insertion into the membrane so that the cell can take up glucose.
glucose dependent tissues with GLUT4 receptors: adipose tissue and skeletal muscle
What are the general effects of insulin in the body? does insulin cross the placenta?
incr. glucose transport in skeletal muscle and adipose tissue, incr. glycogen synthesis and storage, incr. TG synthesis, incr. Na retention in the kidney, incr. protein sythesis, incr. cellular uptake of K and amino acids, decr. glucugon.
insulin does not cross the placenta
What are the different glucose transporters?
glut4: insulin-dependent transporters found in skeletal muscle and adipose tissue
the rest are insulin independent:
GLUT1: RBCs, brain, cornea
GLUT2: bidirectional transporters found in beta islet cells, liver, kidney, and small intestine
GLUT5 (fructose): found in spermatocytes, GI tract
What are the sources of energy for the brain and RBCs?
brain usually uses glucose, but it can use ketones during starvation.
RBCs are ONLY able to use glucose- they don’t have mitochondria, which are absolutely necessary for ketone breakdown.
What organs have insulin independent glucose uptake
brain, RBCs, intestine, cornea, kidney, liver
How is insulin release regulated?
glucose is the major regulator go insulin release
glucose enters the beta cell through the GLUT2 receptor. it undergoes glycolysis. high ATP:ADP ratio closes the ATP-sensitive outward K channels. accumulation of K in the cell depolarizes it, which opens the voltage-gated Ca channels. increased intracellular Ca causes exocytosis of insulin granules into the blood.
What non-diabetes drugs affect insulin release?
GH causes insulin resistance and increases insulin release.
Beta2 agonists increase insulin
What regulates glucugon release?
decreased by insulin, hyperglycemia, and somatostatin
biguanides
metformin.
MOA: decrease gluconeogenesis, increase glycolysis, incr. peripheral glucose uptake (insulin sensitivity).
can be used in pts w/o islet function; first line for type 2 DM.
toxicities: LACTIC ACIDOSIS- contraindicated in pts with renal failure. can cause GI upset.
What are the sulfonylureas?
glyburide, glipizide (second gen)
close the K channel in beta membrane, so that the cell depolarizes –> triggers insulin release via incr. Ca influx.
stimulates the release of endogenous insulin in type 2 DM; does not work in type 1 DM.
toxicity: risk of hypoglycemia in renal failure. first gen drugs have disulfram like rxn.
second gen: hypoglycemia.
(first gen drugs: tolbutamide; chlorpropamide)
(other second gen drug: glimepride)
pioglitazole
this is a thiazoladinedione.
it is an insulin sensitizer. it binds PPAR gamma nuclear trnascription regulator.
used as monotherapy in DM2, or can be combined.
toxicity: weight gain, edema, hepatotoxicity, heart failure
(also risglitazone)
acarbose
(also miglitol)
this inhibits intestinal brush-border alpha glucosidases. delayed sugar hydrolysis and glucose absorption decreases post-prandial hyperglycemia.
may cause GI side effects
pramlintide
amylin analog that decreases gastric emptying and decreases glucagon. used for type 1 and type 2 DM.
may cause hypoglycemia, nausea, diarrhea
exanatide. what other drug works this way?
liraglutide.
increases insulin, decreases glucagon release. it is a GLP1 analog.
may cause nausea, vomiting, or PANCREATITIS
