L76: Pancreas Flashcards
Describe the sequence of ducts with the gall bladder, liver, and pancreas
Cystic duct + common hepatic duct -> common bile duct +pancreatic duct -> greater duodenal papill-> duodenum
What is the the exocrine pancreas?
Makes up majority of cells in the pancreas
Acinar cells: secrete digestive enzymes into pancreatic duct
What is the endocrine pancreas?
3 major cell types making up islets of langerhans (alpha, beta, delta)
What do the ductal cells in the exocrine pancreas do?
secretes mucous and bicarb to the pancreatic enzyme mixture from acinar cells
What which cells of the endocrine pancreas regulate glucose metabolism?
Alpha: glucagon
Beta: inuslin
What do the PP and delta cells do?
produced pancreatic polypeptide and somatostatin
What does pancreatic polypeptide do?
Inhibit acinar cells via paracrine action
What do epsilon cells secrete?
ghrelin
How is the blood flow arranged in the endocrine pancreas?
Blood flow is from arteriole into center of islet outward to the venule
Insulin rich blood flows from the center into the periphery of the islet
How are beta and alpha cells organized in the islets?
Beta cells clustered in core -> alpha cells surround beta cells in a sandwich formation -> allows paracrine effects between them
What does insulin do?
Anabolic hormone: energy storage
What does glucagon do?
Catabolic: energy mobilization
What are the minor hormones in the pancreas?
Somatostatin
Amylin
Pancreatic polypeptide
Ghrelin (hunger hormone)
How i insulin synthesized?
Insulin+ C peptide released together as proinsulin -> cleavage of C peptide exposes end of insulin chain to interact wiht receptor
Insuline and C peptide are packaged together in storage vesicles
Why is the C peptide important for insulin biosynthesis?
C peptide is critical for proper folding and formaiton of disulfide bonds between the alpha and beta chain
How can C peptide be used clinically?
Can indicate pancreatic function status due to long half life (35 mins) compared to insulin (3-8 minutes)
How is insulin released from the pancreatic beta cell?
Glucose outside of the beta cell transported in by GLUT-2 (only when glucose is HIGH) -> glucose phosphorylated by glucokinase (glucose sensor) -> G6P-> increased ATP via glucose metabolism -> closes K+ channels w/ SUR subunits -> cell depolarizes -> open Ca2+ channels -> vesicle exocytosis
What do sulfonylurea drugs do?
Closes K+ channels to cause depolarization of the cell -> and thus cause insulin release
How do FFAs and amino acids modulate insulin release from beta cells?
Increase ATP levels via oxidation and thus close K+ channels
What do incretins (GLP-1) do?
potentiate insulin released
STILL NEEDS GLUCOSE
How do catecholeamines affect insulin release?
Inhibit it
In what behavior is insulin released in response to glucose?
Biphasic:
5% of vesicles available for immediate release at membrane
95% stored or newly synthesized insulin
Initial spike-> followed by gradual increase in 2nd phase
What kind of receptors does insulin bind?
Membrane receptor tyrosine kinases at hte alpha subunit
What does insulin binding to its receptor do?
Binds at alpha subunit on EC space -> autophosphorylation of intracellular beta subunit (tyrosine kinase domains)
What are insulin’s actions on muscle cell?
Glucose cannot enter cell without insulin
Insulin binds- > autophosphorylation of receptors -> recruit IRSs -> activate intracellular signaling cascades -> promote GLUT-4 insertion into membrane -> allows glucose to enter cell
What is IRS(insulin receptor substrate)?
Scaffolding protein that recruits intracellular signaling components like PI3K and MAPK
Which GLUT transporters are insulin dependent?
GLUT-4 (Skeletal muscle, fat)
Which GLUT transporters are insuin INdependent?
GLUT-1(brain, vasculature, erythrocytes, skeletal msucle, fat, heart)
GLUT-2(Pancreatic beta cells, liver, intestine, kidney)
GLUT-3(neurons)
What effects does insulin have on the liver?
promote glycogen and TG produciton
REduce glucose produciton/output
What effect does insulin have on muscle?
promote glycogen and TG production, and protein synthesis
What effect does insulin have on fat?
Promote TG production, release FFAs from chylomicrons, glycolysis, inhibit lipolysis
How is glucagon synthesized and processed?
Preproglucagon (SP-GRPP-GLUC-GLP-1-GLP-2)
Pancreatic Alpha Cells: GRPP cleaved from Glucagon -> secreted as inactive peptide -> GLP-1 and GLP-2 remain linked(inactive) => GRPP(inactive) + GLUC + GLP-1/GLP-2(inative)
Intestinal L Cells: GRPP linked to glucagon (glicentin) -> inactive -> GLP-1 and GLP-2 cleaved -> active INCRETINS
=> Glicentin + GLP-1 + GLP-2
What do incretins do?
Potentiate insulin release from pancreatic beta cells
Stimulated by carbohydrates in intestines
What is the stimulus for glucagon release?
low blood glucose
Amino acidss (protein meal)
Catecholeamines/Exercise
Does glucagon exhibit biphasic release like insulin?
NO
Glucagon levels fall at a constant rate
How do insulin and glucagon work together?
Insulin: dephosphorylate kinase activity enzyme-> phosphorylation activity -> promotes glycolysis
Glucagon: phosphorylates phosphatase activity enzyme-> desphosphorylation activity -> promote gluconeogenesis
What are the main targets of glucagon?
Liver and Adipose: promote energy mobilization
Opposite of insulin
Where are somatostatins produced and what stimulates their release?
Delta Cells
Stimulated by high fat, high carb diets
Inhibited by insulin
What does somatostatin do?
Inhibit insulin released
Can be used clinically to manage insulin producing tumors
What does Amylin do?
Released with insulin from beta cell vesicles and works synergistically with insulin
What causes an increase in amylin?
Obesity, HTN
What does amyloid formation lead to in the pancreas?
beta cell destruction
Where is Ghrelin produced?
Stomach (most)
Epsilon cells in islet
What does Ghreln do/?
Stimulate food intake at hypothalamus
Stimulate GH release
Inhibit insulin release from beta cells by activating K+ channels and decreasing intracellular calcium release
How is ghrelin related to obesity?
Inversely related: obesity -> lower ghrelin
What are counter regulatory hormones to insulin?
Glucagon: primary
GH + Cortisol: promote gluconeogenesis and lipolysis
Catecholeamines: increased with exercise and stress; stimulates glucagon release and inhibit insulin release
How are insulin and GH related?
Absent insulin + GH increased -> cannot stimulate hepatic IGF-1 => direct GH effects on glucose mobilizaiton but no cellular proliferation effects of IGF-1
Also get no neg feedback to GH (NO IGF-1)
