Endocrine 10: Pancreas Flashcards
What are the major cell types of the pancreas and what do they produce?
Collectively called the islet of langerhans
- Beta cells produce insulin
- Alpha cells produce glucagon
- Delta cells produce somatostatin 14
- PP cells produce pancreatic polypeptide
- Epsilon cells produce ghrelin
What are the overall functions of the major pancreatic hormones?
insulin = energy anabolism (storage) glucagon = energy catabolism (breakdown)
Describe the cellular arrangement of the islet of Langerhans.
- core = beta cells
- alpha and delta cells surround it
- highly vascularized
Describe the pancreatic blood supply.
arterioles project into the pancreatic core of beta cells
- they take insulin rich blood and project to the surrounding cells
- hence, insulin can have an effect on alpha (glucagon-producing) cells, but NOT the other way around
Describe the structure of insulin.
signal peptide = B chain = C chain = A chain
- signal peptide cleaved
- chains wrap around themselves
- disulfide bonds formed between A and B chain
- in the vesicle, C chain is cleaved
- vesicle releases both insulin and C-peptide
What is the significance of C-peptide?
- long half life
- good indicator of pancreatic function
Describe the mechanism of action of insulin release from pancreatic beta cells.
- High plasma glucose activates GLUT2 on the B cell membrane => glucose enters the cell
- glucose => glycolysis => ATP production
- High ATP levels close K channel
- K buildup inside cell => depolarization
- depolarization activates voltage-gated Ca2+ channels
- influx of Ca => insulin vesicle release
What is the function of glucokinase in beta cells?
act as glucose sensor
- phosphorylation of glucose to G6P
What is a unique feature of the ATP-sensitive K channels in beta cells?
- contain sulfonylurea (SUR) subunit
- drug target for sulfonylurea drugs
==> keeps K channel closed to force cell to release insulin
(but ONLY if it can still make it
What are other modulatory pathways of insulin release?
- FFAs and AAs will also form ATP => insulin release
- incretins (GLPs) will potentiate intracellular calcium release => insulin release (but ONLY in the presence of glucose)
- catecholamines inhibit alpha-adrenergic receptors and inhibit calcium release => inhibit insulin release
Describe the basis of the biphasic insulin response to a meal.
- first stage results from insulin that is already formed, docked, and ready to go
- second stage results from newly stimulated and formed insulin (takes longer)
What is the insulin receptor?
receptor tyrosine kinase
- alpha subunit is extracellular and binds insulin
- beta subunit is intracellular and autophosphorylates in response to insulin
- beta subunit autophosphorylation recruits intracellular proteins for further downstream signaling cascades
Describe the downstream signaling of insulin in muscle cells.
- RTKs phosphorylation of beta subunit
- recruits IRSs (insulin receptor substrates)
- activates RAS/MAPK to promote growth
- activates PKB/TC10 to translocate GLUT4 (insulin dependent) glucose transporters to the cell surface
Hence, in muscles, there is no glucose uptake without insulin
GLUT1
- expression
- function
Expression
- brain vasculature (major)
- heart, SM (minor)
Function
- insulin independent
- basal uptake
GLUT2
- expression
- function
Expression
- pancreatic beta cells
- liver, kidney, gut
Function
- insulin independent
- low affinity (needs high glucose; postprandial)
GLUT3
- expression
- function
Expression
- neurons
Functions
- insulin independent
GLUT4
- expression
- function
Expression
- muscles
- fat
Function
- insulin DEPENDENT
GLUT5
- expression
- function
Expression
- small intestine
- spermatazoa
Function
- fructose absorption
Describe major physiological effects of insulin target tissues.
Liver
- glycogen synthesis
- lipogenesis
- inhibits gluconeogenesis
Muscle
- glyogen synthesis
- lipogenesis
- promotes protein synthesis
- promotes glucose uptake by transcription of GLUT4
Fat
- lipogenesis
- glycolysis
- inhibits lipolysis
directly inhibits alpha pancreatic cells - no glucagon
Describe glucagon structure.
- preprohormone = SP + GRPP + GLUC + GLP1 + GLP2
- pancreatic hormone = GRPP + GLUC (active)
- intestinal hormone = glicentin (inactive GRPP-GLUC) + GLP1 + GLP2 (active incretins)
When is glucagon released?
- low BG
- counterregulation of insulin
- stimulated by protein
- stimulated by catecholamines
Describe physiological effects of glucagon on target cells.
Liver
- gluconeogenesis
NO EFFECTS ON MUSCLE
Fat
- lipolysis
- glycogenolysis
- ketogenesis
What is required for ketogenesis?
NO INSULIN
Describe the effects and regulation of pancreatic SS14.
- made by delta cells
- stimulated by high fat and CHO
- inhibited by insulin
- clinically, used to inhibit insulin release from insulin producing tumors
Describe the effects and regulation of pancreatic amylin.
- made by beta cells
- promotes insulin activity
- high in obesity and HTN
- formation of amyloid plaques could exacerbate T2DM
Describe the effects and regulation of pancreatic ghrelin.
- typically, peptide is made in stomach to promote hunger and anticipation of food (activates GHRH)
- low in obesity (b/c don’t need to eat)
- made by epsilon cells of pancreas
- inhibits insulin by keeping K channels open (no depolarization = no insulin release)
What are the insulin counter-regulatory hormones?
- primary = glucagon
- delayed = GH and cortisol (defends against starvation)
- catecholamines - inhibits insulin release, stimulates glucagon; increased in exercise/stress, gluconeogenesis, decreased glucose uptake
Describe the relationship between insulin, GH, and IGF1.
- protein stimulates GH => IGF (in presence of insulin)
- IGF stimulates glucose uptake in muscles, proliferation, inhibits proteolysis
- GH opposes insulin lipogenesis
