Insulin Secretion and Regulation

00:00 Regulation of Insulin secretion.

00:03 So what regulates insulin secretion.

00:05 Meals are one of the biggest stimulatory events.

00:09 A meal is thought up to be very important because you are going to start getting blood glucose after a meal.

00:17 Therefore, you want insulin levels high to dry that glucose into cells.

00:23 So having high insulin levels after a meal makes a lot of sense.

00:27 There are few agonist that we'll go through one at a time.

00:31 Such as neural ones.

00:33 Other ones from the GI system as well as from the pancreas.

00:36 There are few antagonist that we'll deal with first.

00:40 And that has to do with norepinephrine.

00:42 And norepinephrine is usually released during the sympathetic stimulatory event.

00:47 As well as somatostatin.

00:49 If you remember back that glucagon, you could see somatostatin not only inhibits insulin secretion but also glucagon secretion.

00:57 Now let's look through the meal in a little bit more detail.

01:03 What about a meal stimulates insulin to be secreted? Glucose probably is the biggest stimulant.

01:09 Although amino acids and free fatty acids can also be part of the process.

01:16 Let's talk through glucose.

01:18 Glucose enters a beta cell by a glute II receptor.

01:22 Following the concentration gradient.

01:25 It then undergoes metabolism and ATP is produced.

01:29 That ATP that's produced is going to bind to a potassium channel sensitive to ATP.

01:37 That closes that channel.

01:40 And as that channel closes potassium is no longer allowed to leave the membrane.

01:45 If potassium which is a positively charged ion, is not allowed to leave, positive charges start building up within the cytosol in this beta cell.

01:57 What does that do? It starts to depolarize the cell.

02:01 As that cell depolarizes, it's eventually going to reach a threshold for calcium.

02:08 This L-type calcium channel will open allowing calcium influx into the cytosol of the beta cell.

02:15 It is that calcium that will have vesicles that contain insulin and C-peptide to dock and fuse into the cell membrane of the beta cell.

02:27 It will spill it contents and that will then be picked up by the [? ] with the blood and travel them in the circulation.

02:38 Neural agonists are also involved.

02:40 This is a special acetylcholine.

02:43 But other ones such as vasoactive intestinal peptide also can come into play.

02:48 You notice here that we have norepinephrine here as an agonist.

02:52 And you're going to say, "Why?" You just told me norepinephrine was an antagonist.

02:58 I did, I did.

03:00 But this is now responding to beta adrenergic response.

03:04 That is an agonist as a beta when it binds to an alpha cell it's an antagonist.

03:11 So here with the cholinergic response you bind through acetylcholine receptor.

03:18 These are G protein-coupled receptors and as they are engaged and transduce signal, they will activate an enzyme called phospholipase C.

03:29 Phospholipase C will make IP3.

03:33 IP3 then goes to the endoplasmic renticulum and releases calcium out of the endoplasmic renticulum.

03:42 This calcium further helps the vesicles that had insulin and C-peptides to dock and fuse and release their substance.

03:52 Now besides neural agonists there are few others.

03:56 Such as GI agonists.

03:58 One here cholecystokinin.

04:01 We also have glucagon-like peptide.

04:04 And here we have GIP.

04:06 GIP is also an agonist.

04:11 It works through another receptor that's also G protein-coupled receptor.

04:16 Who simulates and then lays cyclase as the enzyme.

04:20 That increases protein kinase A.

04:24 Protein Kinase A also facilitates this docking and fusing of the vesicles to the beta cell wall which then goes to the interstitial space and picked up by the blood.

04:36 Interestingly, one pancreatic agonist that we haven't talked about is glucagon.

04:43 And we're going to say similar to the norepinephrine.

04:47 A glucagon is supposed to be the opposite, right.

04:51 It is antagonizing most things insulin is doing.

04:54 Yes, that's true.

04:56 I know it's two two.

04:58 But as glucagon is released, eventually it's high enough levels that will stimulate insulin secretion.

05:08 This is probably a negative feedback mechanism so that you can predict when blood glucose levels are going to be high and then you want to drive them in.

05:17 So glucagon is considered a pancreatic agonist.

05:22 This just shows all of our agonists here together with meal constituents, neural agonists, GI agonist and pancreatic agonists.

05:34 Hopefully you can appreciate from looking at all these is there are lot of things that regulate insulin.

05:41 That must mean it's really important.

05:44 You don't get this regulatory factors if they are not important.

05:49 The insulin receptor.

05:53 The insulin receptor is a catalytic receptor.

05:56 This kind of response is going to enact on number of second messengers.

06:01 So not just one, not just two, but a plethora of them.

06:05 They are things like IRA, Ras, mTOR, MAPKinase.

06:10 There are so many things that seem to be involve with the cell signaling for insulin receptors.

06:16 It's almost hard to keep a hold of.

06:19 But just remember that it's going to do a few things and at a couple of different tissues.

06:25 And we're going to go through each one of those responses so that you don't forget it.