Lecture 9: Pancreas Flashcards
The exocrine cells of the pancreas are
acinar and duct
beta cells make and secrete __________
insulin
glucagon is made by ________
alpha cells
Somatostatin is made by _________
delta cells
What do PP cells make?
pancreatic polypeptide (inhibit acinar cells)
What are the 2 major pancreatic hormones?
1) Insulin (anabolic)
2) Glucagon (catabolic)
What are the 4 minor pancreatic hormones?
1) somatostatin
2) amylin
3) pancreatic polypeptide
4) ghrelin
How many islets does the human pancreas have?
1 million
What kind of capillaries populate the pancreas?
fenestrated
Beta cells are clustered in the _______ while other cells are in the _________
core (surrounded by alpha cells); mantle (near vasculature)
True or false: glucagon has a direct effect on the beta cell to influence insulin
FALSE (paracrine effects only)
How does blood flow to the islet?
arteriole projects into center of islet, insulin rich blood flows from center to periphery of islet
What is the half life of insulin?
3-8 mins (VERY short)
What is the half life of C-peptide?
35 mins (used as indicator of pancreatic function)
Why is the cleavage of C peptide so critical?
exposes end of insulin chain that interacts with receptor
What peptides make up insulin?
A and B chains
What is the first step in insulin release?
1) glucose outside the beta cell stimulates insulin production
GLUT-2 receptor senses high glucose (has low affinity for glucose so only detects high conc. allowing glucose into the cell)
Once glucose enters the beta cell, what happens?
glucokinase phosphorylates glucose which traps it into the cell
What is the pancreatic glucose sensor?
glucokinase (not activated unless glucose is high)
What is the second step in insulin release?
2) glucose inside beta cell (glucose is phosphorylated by glucokinase —— G6P generates ATP)
What is the third step of insulin release?
3) glucose metabolism
increased ATP closes K+ channels (as do sulfonylurea drugs since K+ channels have a SUR subunit)
How do sulfonylurea drugs work and what are they used for?
close the potassium channels (used as the earliest antidiabetic drugs) and bypass glucose step
What is the benefit to the K+ channels closing?
holds more K+ inside the cell causing it to depolarize (influx of sodium into the cell)
What is the 4th step in insulin release?
cell depolarization
closing K+ channels depolarize cell which opens the Ca++ channels
What happens after Ca++ channels open/the cell is depolarized?
5) vesicle exocytosis
Ca++ influx causes exocytosis of insulin-containing vesicles
Go over the steps of insulin release once more
1) high glucose outside beta cell (GLUT-2)
2) Glucose inside beta cell (G6P via glucokinase)
3) Glucose metabolism (makes lots of ATP)
4) Cell depolarization (activates Ca++ channels)
5) Vesicle exocytosis (insulin)
What are 3 modulatory pathways to promote insulin release?
1) FFAs, Amino Acids (both increase ATP)
2) Incretins (GLP-1) potentiate insulin release but still needs glucose
3) catecholamines (inhibit release via alpha-adrenergic receptors)
Why is insulin release biphasic in response to glucose?
5% of vesicles are available for immediate release (docked at membrane)
95% are “stored” or reflect newly synthesized insulin
Diabetic patients usually lack which phase of insulin release?
first phase (fewer vesicles docked at membrane)
second phase is a flat line
What kind of receptors are insulin receptors?
RTKs (insulin binds alpha subunit and then beta subunit is autophosphorylated)
Where are the 2 sites of greatest insulin stimulated glucose uptake?
muscle and fat
Once insulin binds to RTKs and they are autophosphorylated, what happens inside the muscle cell?
phosphorylated receptor recruits IRSs (insulin receptor substrates) which activate intracellular signaling cascades
What is the end result of insulin binding on a muscle cell?
insertion of GLUT-4 so that glucose can enter the cell
What are the 2 downstream pathways for insulin substrate?
1) MAPK (recruits docking proteins which activate MAPK effecting growth and mitogenic effects)
2) PKB (causes GLUT4 to be inserted into the membrane)
Metabolic effects of insulin are mediated through __________ which mitogenic effects are mediated through __________
Metabolic: PKB (get GLUT4 on the membrane)
Mitogenic: MAPK
What is the ONLY insulin dependent transporter?
GLUT4 (skeletal muscle, fat; stored inside cell under basal conditions)
What is the glucose transporter used in the brain?
GLUT3
Where is GLUT2 expressed?
pancreatic beta cells, liver, intestine, kidney
What is the glucose transporter for brain vasculature?
GLUT-1
What are the effects of insulin on the liver?
promote glycogen and TG production — can get too much TG synthesis/fatty liver (stimulates glucokinase)
reduces glucose production/output (inhibits G6 phosphatase)
What are the effects of insulin in the muscle?
promotes glycogen and TG production, protein synthesis
What are the effects of insulin on fat?
promotes TG production, release FFAs from chylomicrons, glycolysis
inhibits lipolysis
Overall, net effect of insulin is __________
anabolic! builds things to store energy, not breaks them down
What are incretins?
GLP-1 and GLP-2
GLP-1 responds to carbs and travels to pancreas to potentiate release of insulin
What do incretins do?
target beta cells to stimulate more hormone production
how are incretins related to glucagon?
synthesized from the same prohormone
have tissue specific enzymatic activity
Name 2 things that stimulate glucagon release
1) Amino acids (protein meals)
2) catecholamines (exercise)
BOTH WANT TO MOBILIZE ENERGY
What are the main targets of glucagon?
liver and adipose
True or false: there are no glucagon receptors in skeletal muscle
TRUE
How does insulin affect ketogenesis?
INHIBITS IT (which is why diabetics have ketoacidosis - no insulin to stop producing ketones)
Why dont type 2 diabetics experience ketoacidosis?
insulin is still present
True or false: insulin and glucagon target the same enzymes but have different functions
TRUE
insulin: dephosphorylate to turn enzyme into kinase pushing metabolic pathway towards glycolysis
glucagon: phosphatase activity
What does somatostatin do?
suppresses insulin release (and is inhibited by insulin) stimulated by high fat, high carbs like insulin
What does amylin do?
contributes to beta cell destruction? released with insulin in vesicles from beta cells
What can be used to treat insulin producing tumors?
somatostatin (blocks insulin release)
What does ghrelin do?
inhibits insulin release (G activation of K+ channels)
decreases intracellular Ca++ to decrease insulin release
Where is Ghrelin made? and when?
stomach (responds to lack of food/stretch to stimulate eating)
What are insulin counter regulatory hormones?
1) Glucagon
2) Growth hormone/cortisol
3) Catecholamines (epi) – raises plasma glucose levels during exercise
When insulin is present, what happens to GH levels?
increase! AA from protein stimulates GH which stimulates IGF-1
GH opposes insulin lipogenesis
True or false: insulin directly affects glucagon but not the other way around
TRUE (due to blood flow)
