Endocrinology 10- Pancreas Flashcards
Two major pancreatic hormones
insulin (anabolic) and glucagon (catabolic)
Minor pancreatic hormones
somatostatin, amlin, and pancreatic polypeptide
job of pancreatic polypeptide
regulate satiety
exocrine pancreas
majority of cells, secrete digestive juices
Endocrine pancreas
consists of 4 major cell types clustered in islets of langerhans - highly vascularized fenestrated capillaries go through here and hormones are released into blood directly
beta cells release
insulin
alpha cells release
glucagon
delta cells release
somatostatin
How are clusters of cells in a human islet of langerhans different from a rodent
in a rodent it’s very much beta cells in the middle, surrounded by alpha cells - in umans it’s not quite as straightforward, with a lot of mosaicism which suggests paracrine communication andblood flow is a very important part of this
Arrangement of beta and alpha cells in human tissue
mosaic pattern, but overall beta cells clustered in “core” and other cells are in a “mantle” - alpha cells surround beta cells in sandwich formation, and there is paracrine effect between alpha and beta cells
When blood flow comes into pancreas what are the first cells it reaches
beta cells
Order of events when blood enters pancreas
glucose (in blood) comes in and stimulates beta cells, insulin is released, insulin inhibits cells around it (delta and aalpha cells)
Insulin synthesis -
made as preprohormone, disulfidebonds will connect strands,a nd a “C peptide” is cleaved. Everything is packaged into vesicles, and so when insulin is released you get insulin + c peptide.
C peptide half life vs insulin
C peptide half life is longer so it can be used diagnostically as a tool to see if someone’s pancreas is functioning properly - if somone is releasing c peptide you know they’re releasing insulin
Step 1 of insulin release
glucose outside beta cell - comes in via glUT2 (or GLUT1 depending on if rodents or humans) - have low affinity for glucose, so under basal conditions glucose will not be transported into beta cells, only we insulin is high after a meal will glucose be transported in
step 2 of insulin release
glucose is inside beta cell, glucokinase is goign to trap it into the cell (therefore is known as pancreatic glucose sensor – when enzyme is active, glucose is high)
after glucose has been trapped in pancreatic cell what happens in insulin synthesis and release
Glucose metabolism - G6P –> ATP –> this increased ATP closes K channels, this will lead to passive depolarization of the cell.
Sulfonylurea drug action
closes K channels – to increase MP of these cells to eventually lead to vesicle release.
After K channels close and mP starts to go up what is the next step in insulin release
Increased K causes membrane to depolarize and opens VG ca channels
After Ca channels have been opened what is the next step in insulin release
Vesicle exocytosis - - from Ca influx causes exocytosis of insulin containing vesicles
Insulin release in response to glucose is what, and what is the significance of this
Biphasic - this means you get a first big spike from all insulin contaiing vesicles getting yeeted. It slowly rises again because you need to actually synthesize new insulin. The first phase being lost is going to be one of the first things found in diabetic patients.
What kind of receptor does insulin use
RTK - binds receptor alpha subuni (beta autophosphorylates)
Two types of responses insulin can generate
Mitogenic and metabolic effects
Mitogenic insulin effects
promotes growth of a variety of tissues via RAS/RAF, MAP/ERK
Metabolic effects of insulin (birds eye view)
Akt/PI3K –> primarily going to be getting glucose out of blood and into tissues, and getting that fuel into storage for later useage.
Anabolic effects of insulin (4)
Use glucose – promote glucose uptake into tissues to make FFAs, glycogen, etc
Help with storage of FFAs as TGs
Help with process of making protein from AAs
Help make other macromolecules
Note
The organelle formation and cell proliferation are mitogenic, not metabolic effects
aside from promoting anabolism, what does insulin directly do
impair catabolism and starvation states by protein phospatases that will inhibit gluconeogenesis, glycogenolysis, FFA b-oxidation, ketogenesis (you don’t need ketogenesis with glucose present), lipolysis, inhibiting proteolysis. It will also activate SREBP1 (activates glycolysis) and inhibits FOXO1 which is associated with gluconeogenesis and VLDL export
FOXO1
associated with gluconeogenesis and VLDL export
SREBP-1C
transcription factor that will be pro glycolysis
what is the only glucose transporter dependent on insulin
GLUT4 (primarily found in skeletal muscle and fat)
Because only GLUT4 is dependent on insulin, what does this mean in cases of for instance diabetes when you’re very hyperglycemic
The other insulin transporters are saturated – glucose is high and having no trouble getting into the other tissues but the storage is getting screwed up because it can’t get into muscle and adipose tissue. This means there’s actally a risk for hyperglycemic toxicity in for instance the brain, where GLUT3 (not insulin dependent) is high
What is the primary action of insulin
energy storage
What does insulin tell adipose tissue to do
promotes TG production, release of FFAs from chylomicrons, glycolysis; inhibits lipolysis (uses GLUT4 to bring in glucose)
What does insulin tell muscle to do
Promotes glcogen and TG production, as well as protein synthesis Glucose comes in via GLUT4
What does insulin tell liver to do
promote glcogen and TG production, reduces glucose production and output (inhibit G6-phosphatase, stmulates glucokinase synthase). Glucose enters via GLUT2
How is glucagon made
preoprohormone – proglucagon is once signal peptide is released –> just like other hormones, depending on what tissue it is rocessed in, there are enzymes that will process differentl. In Pancreatic alpha cells, copeptide is cleaved so you get inactive copeptide, and some active glucagon. Inintestinal L cells, you get cleavage to form glicentin inactive - and two peptides that are glucaon like peptides because of how they are processed because they are from the same preprohormone but have opposite actions of glucagon
Glucagon processing in pancreatic alpha cells
copeptide cleaved –> get inactive copeptide, and active glucagon
Glucagon gene processing in intestinal L cells
Cleavage into glicentin (inactive), and two peptides that are glucagon like peptides – this is because they are procesed and because they come from the same preprohormone (same gene) as glucagon, but it has completely opposite actions of glucagon
Glucagon
counterregulatory to insulin, this hormone opposes everything insulin does (Catabolic)
Glucagon like peptides (GLPs)
stimulated in intestinal L cells by high carbohydrates – if you have high carbs you are releasing insulin as well– and GLPs help this process by aiding in insulin release.
Eat a whole box of donuts –> insulin needs help –> glucagon like peptide is this help
When is glucagon released
GLUCAGON glucagon It is suppressed in response to glucose prsence, and will stay down for a while (glucagon like peptide will rise as it is similar to insulin). When insulin is gone, glucagon is no longer inhibited (low blood glucose is why insulin would be down anyway). Amino acids will also stimulate release of glucagon, so all protein diets are meant to stimulate glucagon. Catecholamines also directly stimulate alpha cells to stimulate glucagon release
GLPs
GLP1 cmes from intestinal L cells in response to high carb meal, acts through GPCR at membrane to activate cAMP path to promote excytosis of the insulin vesicles, however it is degraded very quickly via enzyme DPP4. Some new drugs target DPP4 to inhibit it, this maintains more GLP1 and helps ensure a greater insulin release in T2DM patients. Other drugs target the GLP receptor directly.
GLP receptor agonists (trulicity)
meant to aid in insulin release by mimicing GLP1
DPP4 targeting drugs (Januvia)
Target the enzyme that breaks down GLP1 - this keeps more of it around and is meant to make sure the receptor is able to be stimulated –increases GLP1 release
How do amino acids modulate insulin
Can potentially lead to insulin release because amino acids and metablism generate AAs, come in, you get atp –> when you get ATP you close potassium channels, allow Ca to come in (not a big response and remember amino acids are also going to stimulate glucagon, which will inhibit insulin)
How do NE/E affect insulin release
Directly inhibit insulin – sns innervation of adrenal medulla is a stress indicator. This will activate a-adrenergic receptors thorugh cAMP G sub I pathway – this is going to lead to decrease in intracellular calcium and less vesicle release. There will be some b2 adrenergic receptors, but this is very low and contributes to basal low insulin release
Glucagon main action
energy mobilization
Main targets of glucagon
liver and adipose tissue
Are there glucagon receptors in skeletal muscle
no
Growth hormone - is it synergistic or counterregulatory to insulin
counterregulatory
Cortisol - is it synergistic or counterregulatory to insulin
counterregulatory
Somatostatin with regard to its relationship with insulin
produced in delta cells in pancreatic islets (and in hypothalamus) – stimulated by high fat high carb meals in pancreas – inhibits insulin release, used in clinic for management of insulin producing tumors. Only plays modulatory role of islet, but this clinical role is very mportant. you can even shrink sme tumors and prevent high insulin release from them.
Amylin with regard to its relationship with insulin
released in same vesicle as C peptide and insulin (always released WITH insulin) – if produced in high amounts, you get amyloid plaques rom clustering. It acts synergistically with insulin in regulating blood glucose, but what we have here is a problem - by making excess amounts of amylin and making amyloid and having it build up in cells, we get amyloid plaques and you get B cell destruction
what stimulates somatostatin release frm delta cells (metabolites)
high fat, high carb environment
paracrine action of somatostatin
inhibits beta cells and contributes to exocrine pancreas’s ability to digest carbs and fats
Insulin release effect on somatostatin
Can counterblock somatostatin
If you are in rest and digest phase, are delta cells ctively producing somatostatin?
no
MAJOR actions of insulin in skeletal muscle (4)
increase glucose uptake
increase glycogen synthesis
increase amino acid uptake
increase protein synthesis
MAJOR actions of insulin in adipose tissue (4)
Increase glucose uptake, increase glycogen synthesis, increase TG synthesis, decrease lipolysis
MAJOR action of glucagon on adipose tissue
increase lipolysis
MAJOR action of insulin on liver (1)
Glycogen synthesis
MAJOR action of glucagon on liver (4)
increase glycogenolysis
increase gluconeogenesis
increase AA uptake and catabolism
increase FA catabolism
Catecholamine effect on glucagon release
increases it
of the counterregulatory hormones to insulin which is the “primary” one
Glucagon
How does cortisol act counterregulatory to insulin
promotes gluconeogenesis
How does growth hormone act counterregulatory to insulin
prevents glucose uptake by adipose tissues and muscle
Growth hormone effect on muscle vs cortisol effect on muscle
GH protects muscle
Cortisol breaks down muscle
