Physiology: Endocrine #3: Pancreatic Hormones

Front 1

endocrine pancreas - how many islets are there and what kinds of cells are present?

Back 1

more than one million islets.

there are alpha cells (make glucagon( and are 20-25%

beta cells - 60-70% and make insulin.

delta cells - make somatostatin and gastrin.

PP cells = pancreatic polypeptide.

Front 2

describe the transcription of insulin and the initial product made up into its packaging.

if you're going to test for insulin function, what test do you run?

Back 2

Insulin is first transcribed, as all peptide hormones, as a pre-pro insulin. here, there's an A chain and a B chain, with a C chain in between. By the time it gets to the ER, the signal locating sequence on the N' has been cleaved off.

While in the golgi, the C is removed and the A/B chains are connected with 2 disulfide bonds.

Note that the C gets packaged into the granules along with the A and B "insulin".

Insulin is readily degraded in the blood, but C sticks around - so if you want to do a test for insulin function, you simply look for the amount of protein C in the blood.

Front 3

how does insulin exist in the blood? How are stabilities compared?

Back 3

can be monomer, dimer, hexamer. The monomer is the least stable. Drug companies try to make hexamers in their drugs so people don't have intense insulin spikes.

Front 4

we know insulin secretion goes up when blood glucose increases. between what blood glucoses do we see insulin go up?

Back 4

starts to increase linearly between 50 and 100, and has a big response up until 300.

then there's a serious plateau above 300.

Front 5

in addition to high blood glucose, what else can stimulate the release of insulin?

Back 5

high free fatty acids, keto acids, amino acids, and high [K+]

Arginine is the main AA that ups insulin. lysine can also do it.

Front 6

how fast can insulin respond?

Back 6

can reach peak insulin secretion within a couple minutes.

note that secretion is SIGMOIDAL - no secretion below 50 mg/dL.

Front 7

describe the response of insulin to a constant glucose challenge.

also, when does insulin secretion peak after eating?

Back 7

insulin response to constant glucose challenge is biphasic. it spikes immediately within a minute or two, then crashes back down.

it slowly begins to rise around 10 minutes and eventually gets as high as the original peak after 40 minutes.

note that in typical eating, insulin secretion is highest after 30-40 minutes and secretion happens for a few hours.

Front 8

briefly describe how insulin is released by glucose:

Back 8

glucose is let into pancreatic beta cells via Glut 2 transporters.

Glucose gets oxidized and forms lots of ATP and NAD(p)H, which close some K+ channels (hyperpolarizing the cell). This opens come Ca++ channels.

Extra Ca++ floating around signals for the binding and release of insulin-carrying vessicles. This is voltage dependent.

Also, PKA can also release it in a voltage-independent manner.

Front 9

describe the insulin receptor and briefly how it works.

Back 9

insulin receptor is a dimer, each unit with ALPHA and BETA subunits. The 2 betas hang into the cell through the membrane, the alphas stay on the surface. alphas bound to each other with disulfide bonds - ditto for the betas.

The beta subunits have TYROSINE KINASE on them, and when the alphas get bound by insulin, they become active as an RTK.

This phosphorylates the IRS (insulin receptor substrates), which activate PI-3 kinase, which ups AKT and PKC to translocate Glut4 vessicles to the surface. Also ups transcription of more Glut4.

Front 10

what tissues does insulin act on? what enzymes/pathways does it affect? what is its really interesting effect on ketones?

Back 10

liver, muscle, and fat cells.

in the liver, insulin activates glycogen synthase and turns off glycogen phosphorylase (stop glycogenoloysis).

also turns off glucose-6-phosphotase to stop gluconeogenesis.

note that in ADIPOSE TISSUE, it inactivates hormone-sensitive lipases. This makes it ANTI-KETOTIC and is probably the only anti-ketotic hormone we know.

Front 11

does it take a lot of insulin or a little insulin to get body effects?

Back 11

only a little insulin, normally. see figure 5 in the handout.

with very little insulin release, stop glucose release, then lower glycerol/FFA.

AA's take awhile longer to drop (branched guys like valine, leucine, and isoleucine) drop first, followed by other AA's.

Front 12

how does sensitivity affect insulin release?

Back 12

if you're sensitive, don't release a whole lot of insulin. generally, the body tries to release just enough insulin to get the job done. if you become resistant, up insulin secretion.

Front 13

what affect do insulin and glucose have on glucagon?

Back 13

both suppress glucagon transcription

Front 14

glucagon secretion - what makes it happen? what AA's on glucagon are interesting?

Back 14

all the handout says is that it's secreted by alpha cells in response to low preceived blood glucose.

also from stress, burns, surgery.

Residues 1 thorugh 6 on the N terminus are required for activity.

Front 15

glucagon's affects - what kind of receptor does it act on and what gets activated/inactivated?

how do ketones get produced?

Back 15

works on a typical g-protein coupled 7 pass receptor with a Gs, so it works through cAMP and causes catabolism.

ups gluconeogenesis, glycogenolysis. stops GLYCOLYSIS. all act to increase glucose secretion from the liver.

glucagon activates hormone-activated lipolysis, which uses up a lot of NAD. without NAD, can't shuttle acetyl CoA into the CAC, Builds up and inhibits glycolysis and instead, it's converted to KETONE BODIES.

Front 16

talk about typical insulin to glucagon ratios after normal meals and during fasting.

compare all carb meal to an all protein meal in terms of insulin/glucagon secretion

Back 16

a few hours after a meal, insulin to glucagon ratio is typically around 2.0.

during fasting, may drop to 0.5.

big carb meal = insulin/glucagon ratio up to as high as 10.

only protein meal = up insulin and glucagon. insulin helps get the AA's into muscles and stop proteolysis, while glucagon helps release sugars from the liver and keep hypoglycemia from happening.

also, and now i'm just guessing, a lot of AA transporters require glucose to be around - maybe you need the glucagon to make gluconeognesis so you can get AA's into tissues?

Front 17

somatostatin secretion - what encourages it and what stops it?

Back 17

it comes from islets (D cells), also from d cells in the GI tract.

think that somatostatin is what you make when you have too much stuff in you. glucose, AA, FAA, glucagon increase somatostatin secretion.

insulin suppresses somatostatin.

Front 18

what's somatostatin's effect?

Back 18

shut down everything. glucagon, insulin, shuts down both. also stops uptake of nutrients through the GI tract. stops a lot of other hormones, too.

NOTE - it's down regulated by insulin

turned on by the same things that turn on insulin, with the addition of glucagon. so everything turns it on, it turns off everything.

Front 19

what turns off glucagon?

Back 19

glucose and insulin

Front 20

review:

Back 20

insulin INACTIVATES somatostatin. Glucagon TURNS IT ON.

Insulin turns off somatostatin and glucagon.
glucagon turns on insulin and somatostatin.

other mechanisms of insulin secretion: CCK and ACH go through PLC/IP3/DAG to up Ca++.
Glucagon, which turns on insulin, works through cAMP. Ketoacids and amino acids work just like glucose (upped ATP).

insulin receptor action: dimerize, autophosphorylate RTK, IRS, PI3, PKC/PKB.

things that turn on insulin include vitamin D, CCK, glucagon, tyrosine/lysine, ACH