hello and welcome to the review of chapter 79 of guyton and hall's medical physiology textbook in this chapter we're going to go over insulin glucagon and diabetes mellitus so going over the pancreatic endocrine organ if you enjoy the video please don't forget to give it a like and subscribe to the channel and otherwise thanks for the great support we've had so far as we're starting to approach the end of the textbook here so i hope it's been helpful but otherwise let's just jump straight into it so we're talking about the pancreas here and it's endocrine function remember it has digestive functions which we've already gone over in the gastrointestinal unit but today we're going over the endocrine function of the pancreas so the two main hormones that the pancreas secretes is insulin and glucagon and this is for the regulation of glucose lipid and protein metabolism trying to stabilize that form of homeostasis it does also secrete other types of hormones so amyloid somatostatin some pancreatic polypeptides but it's kind of a lesser role of the pancreas and we're not going to dive into deeper details in this chapter regarding that this one's all about insulin and glucagon and abnormalities of that which is mainly diabetes mellitus so the pancreas is divided into kind of two groups of tissues we've got the sinai which does the digestive enzymes and then the eyelids of langerhan and within these islets of langerhans we have three types of cells we've got alpha cells beta cells and delta cells now alpha cells secrete our glucagon whereas our beta cells secrete our insulin and also a hormone called amylin and then our delta cells produce somatostatin somatostatin we've talked about in both the gastrointestinal section and it's a role in actually inhibiting or slowing down movements it's a stopper of function but remember somatostatin is also produced from the hypothalamus to inhibit growth hormone which we've gone over in chapter 76 so the main thing here is that beta cells secrete insulin alpha cells secrete glucagon now all of these little hormones that could be produced right next to each other they can have a paracrine effect meaning that they're going to influence each other so insulin inhibits glucagon amyloid inhibits insulin somatostatin inhibits both insulin and glucagon and so forth so they all interact with one another once there is a signal telling one to be really secreted then it inhibits the others so then it's able to have a better effect essentially so if we start off with insulin insulin you can think of it as a hormone that gets produced whenever there is an abundance of energy so whenever there is an abundance of energy meaning that we have a lot of food stuffs so we have a lot of glucose mainly but also amino acids insulin gets secreted to package our energy away to get it out of the bloodstream and get it into our cells to store it for a later use so insulin gets secreted after our meals typically because of high glucose you know glucose is really our main determinant for insulin secretion but as you'll see there are some other factors as well so if there's high glucose insulin is going to tell glucose to go into cells particularly the liver and the muscles to get converted into glycogen it's going to tell the fats to go into adipose tissue hide it away and then it's going to tell proteins to actually go into the cells as well increase amino acid uptake by cells and conversion into proteins as well so it's moving all our energy food stuff into our cells to then actually package them away now the actual chemical composition of insulin is made in those beta cells in the similar fashion as any other protein so ribosomes it will produce pre-pro insulin prepro insulin has cleaved the endoplasmic reticulum into pro-insulin which has these three peptides a b and c then the golgi apparatus comes along chops off the c-peptide to then cause insulin to form insulin so insulin is then packaged within a secretory granule after going through the golgi apparatus as insulin and then also the c-peptide so if you actually have diabetes mellitus and you don't produce much insulin and you're giving your exogenous insulin to maintain your insulin levels then you can actually measure the amount of endogenous insulin produced by the body so how much insulin the patient itself is actually producing instead of injecting in by measuring the c peptide or at least that's a way of doing it now just talking about the normal patient again insulin it gets released it's not protein bounds in the blood so that means that it's going to rapidly get degraded so it only lasts about six minutes and then it's degraded in the liver by insulinase so it just gets rapidly destroyed after doing some of its effects and its effects occur through obviously an insulin receptor which is on the cell membrane and the insulin receptor this time is actually an enzyme the linked receptor and it activates tyrosine kinases tyrosine kinases then actually phosphorylate other intracellular enzymes to then produce multiple effects and those effects include increasing the uptake of glucose into cells particularly muscle cells and adipose cells the brain is not influenced by insulin remember the brain only uses glucose for energy so it's not going to rely on insulin being secreted to be able to use that glucose so the brain is always able to uptake glucose constantly giving it a constant supply of glucose so the brain is that one tissue that does not rely on it otherwise there are other tissues once insulin combines we get the activation of the tyrosine kinase which phosphorylates enzymes increase glucose uptake and then we get increased permeability to amino acids potassium ions phosphate ions so basically shuttling as many nutrients into the cell as possible and then over the next 10 to 15 minutes we start to get the metabolic enzymes getting upgraded as well trying to synthesize glycogen you know storing our glucose away and then over a greater period of time we get the production of new proteins so we get transcription of mrnas which gets translated into new proteins for additional metabolic effects so when it comes to muscle cells themselves um muscle will increase its glucose uptake and increase its glycogen storage so then actually shuttling those glucose away into glycogen when insulin is available is going to be available after a meal when we have a lot of food stuffs in our bloodstream when we do not have insulin in the blood that's during the fasting period so in between meals we're not going to have insulin available and muscles actually cannot uptake glucose in the bloodstream at this point and that's important because if they could they would take away the glucose from our brain tissue remember our brain tissue needs that constant glucose supply so during fasting periods the muscle actually converts more into fatty acid metabolism for its energy or uses the actual glycogen that was stored so the muscles can only uptake glucose and use glucose when there is insulin available but it can also do that during heavy exercise so during heavy exercise we do have an ability to increase glucose uptake due to the production of glucose transporter for and that occurs just from muscle contraction itself so the muscle takes in glucose when there's availability stores glycogen uses the glycogen for energy and then fat during the fasting periods so there's enough glucose available for the brain tissue itself when it comes to the liver the liver and the presence of insulin will uptake glucose and convert it into glycogen and it does that by actually inactivating the phosphorylase within the liver which is responsible for breaking down glycogen so it inhibits the breakdown of glycogen enhances the uptake of glucose by increasing glucokinase glucokinase phosphorylates glucose which then traps it within the cell and then it also increases the activities of glycogen synthase which produces the glycogen itself so increases uptake increases glycogen production now in between meals fasting periods just like how the muscle cells could not uptake glucose at that time you know we don't have insulin available when we don't have insulin available and our glucose is all being shuttled out of our blood and hopefully it's dropped if the glucose starts to drop after that low glucose means no insulin is going to be available we will actually produce glucagon but ultimately the liver is a store of glucose for these periods when we do not have glucose in our bloodstream so in order to maintain our glucose levels when we haven't eaten a meal for a period of time the level will then break down its glycogen and also form new glucose via gluconeogenesis to then allow the release of glucose into the bloodstream from the liver so the liver acts as the storage of glucose and helps to maintain glucose in a normal level so when we've eaten and we have a lot of glucose in our bloodstream it gets shuttled into the liver for storage to then be released when we haven't eaten in a certain period of time so then we're able to have enough glucose in the bloodstream to feed the brain essentially so all of those processes that we talked about with insulin inhibiting phosphorylase and activating glycogen synthase are reversed when we do not have insulin present so that's mainly insulin effect on glucose so what is insulin's effect on fat so insulin is able to help promote fat synthesis and storage so since there's so much glucose available it's actually wanting to convert that glucose into fat and it's able to do that by pushing it into the liver once the glycogen stores are full turns the extra glucose into fatty acids and then the fatty acids turn into triglycerides which go in the bloodstream with lipoproteins to go over to our adipose tissue insulin also activates lipoprotein lipase which helps to break down the triglycerides once again into fatty acids to help them be absorbed into the actual adipose cells themselves so it helps to produce fatty acids and store them as well so helping to store the excessive energy that's available it also has an effect right at the adipose cells themselves so at the adipose tissue it actually inhibits hormone sensitive lipase which breaks down the fatty acids within the adipose cell so it prevents the adipose cells from breaking down any fats and then it also promotes glucose uptake into the fat cells themselves so it helps to really store that energy now if you don't have any insulin then you increase the use of fat for energy so no insulin means that we are no longer storing that fat as easily we're no longer producing as much fatty acids consequently we end up releasing a large amount of fatty acids and glycerol into the actual circulating blood the liver notices all this extra fatty acids and actually converts them into phospholipids and cholesterol so it increases the presence of lipoproteins remember we've talked about the dangers of increased lipoproteins during the lipid metabolism chapter but that helps to promote the development of atherosclerosis which is just the development of cholesterol plaques within your actual blood vessels and then that can lead on to other cardiovascular side effects so with insulin deficiency we end up with more fatty acids in the bloodstream which gets converted by the liver into cholesterol and phospholipids which increases our complications secondary to arthrosclerosis now that increased fatty acids also gets converted into acetoacetic acids so the liver has to do something with all this extra fatty acid all this extra energy so it's going to actually convert it into ketones essentially so the increased production of ketones which we've once again talked about in the lipid metabolism chapter so if you need a refresher on this go back to the video the increased ketones within the body results in acidosis because these are acids within the body and then that can lead to coma and death as well now the ketones also goes to the saliva and you can actually have a sweeter breath because of these ketones and that's one method of diagnosis of an insulin deficiency state insulin deficiency is a type of diabetes as we'll get to so getting back to the normal points on insulin we're going to talk about insulin's effect on protein now once again it's going to want to store the protein as much as possible energy excess get the amino acids into the cells and store them so it does that by transporting them into cells as we've mentioned which is similar to our growth hormone function except for it seems like insulin actually causes the uptake of different amino acids to growth hormone so both are needed for effective amino acid uptake and production of proteins and growth that's shown in this figure 796 here where they actually prevented the production of endogenous insulin and growth hormone in a rat and as it grew they gave just growth hormone and there was a little bit of growth spurt just insulin a little bit of a growth spurt but with both the synergistic effect because you're getting all the amino acids all of the substrates really to make proteins available and there's a sudden increase in growth but not only that insulin also increases the translation of messenger rnas to produce more proteins eventually increases transcription of certain genetic sequences inhibits the catabolism of proteins so then you reduce the amount of proteins it is getting destroyed and then also depresses gluconeogenesis in the liver remember gluconeogenesis is turning amino acids into glucose so we're ultimately helping to increase the amount of amino acids available within the cell and turning that amino acids into proteins so as you would expect without having insulin you end up with the catabolism of proteins increased amino acids within the bloodstream and then increased amino acids conversion into glucose or gluconeogenesis in the liver and also increased urea excretion in the urine as we have too much amino acids they have to get destroyed and removed so with the destruction of proteins we end up with extreme weakness and derangement of organs as well so next up is actually talking about insulin secretion now insulin secretion is mainly determined by glucose concentration so increased glucose meaning that there's increased energy availability and we need to store that and get rid of it the increased glucose goes into the beta cell via glutes too and just that has free access into the cell so as glucose increases in the bloodstream it increases in the beta cell that goes through a series of reactions get turned into glucose 6-phosphate and oxidized to produce atp the increased atp actually closes a potassium channel on the cell which was trying to remove potassium so since potassium increases within the cell it actually depolarizes the beta cell with a depolarization of the beta cell we open a calcium channel so then we're able to allow calcium to enter the cell the increased intracellular calcium promotes exocytosis of insulin so we end up with insulin increase within the bloodstream whenever glucose increases now this kind of is a biphasic response where first there is a release of all the insulin that's already made so there's an instant increase in insulin then there is a drop as the insulin that's been made is now released and now there's essentially not as much left but then now the intracellular machinery is going to turn on and we're going to produce more insulin within that cell so then there's a steady increased secretion of insulin that gets higher than that initial spike and insulin secretion will constantly increase with increasing glucose concentration and then eventually plateau and while glucose is high you will have constant insulin secretion to try to reduce that glucose so you have to have a relatively high amount of insulin within the bloodstream while your glucose is high as soon as glucose reduces because it's having all those positive effects with increasing uptake of glucose increasing glycogen formation preventing gluconeogenesis etc that we've talked about as soon as glucose produces insulin secretion equally reduces so as soon as glucose is normal insulin suggestion goes right back to barely any secretion at all now there are some other factors which will also stimulate this secretion of insulin but this should be thought of as more supplementary so just these factors by themselves do not cause that much increase in insulin but these factors with a high glucose concentration causes an even exaggerated secretion of insulin so one of these factors is amino acid concentration so increasing amino acids means that there's increased energy this with glucose will result in a large increase in insulin even more than just glucose itself gastrointestinal hormones also do this so gastrin secreting cholecystokinin etc etc is this preemptive anticipatory increase in blood insulin because it you know that these gastrointestinal hormones are only released while we're eating so it's predicting that we're going to have a high glucose and once high glucose occurs we get an increase in spike in insulin and then we have other hormones as well so glucagon actually increases insulin secretion which seems a little ironic i know that seems a little bit difficult to understand because glucagon does the complete opposite effects of insulin but it does so just so we don't get an exaggerated effect in a roller coaster of our glucose then we also have growth hormone that does a cortisol that does it but remember cortisol antagonizes insulins effect which we talked about in the previous chapter and then progesterone and estrogen as well mainly also through increased antagonism so prolonged secretion of any of these guys will also exhaust our beta cells and then end up with an insulin deficient state increasing the risk of diabetes remember diabetes mellitus literally just means low insulin or ineffective insulin resulting in high glucose diabetes mellitus the actual name diabetes mellitus means sweet urine because of sugar being in the urine because there is high blood sugar glucose being sugar now getting back to insulin the secretion of insulin can also be increased due to parasympathetic nervous supply because parasympathetic nervous supply is the rest and digest and we're wanting to shuttle our energy stores whereas the sympathetic nervous system wants to do the opposite it wants glucose available for work to occur our flight or fight response so then it will actually decrease insulin secretion so insulin has this role in promoting the increased utilization of carbohydrates for energy and reduce utilization of fat and remember shuttling fats away converting it into more of a storage so there's a switch in metabolism between carbohydrates and lipids now some other hormones also do that we've talked about in the past so growth hormone cortisol they actually do the opposite effect of inhibiting our utilization of glucose and promoting fat utilization and then we also have epinephrine that has a role with glucose lipid metabolism of actually increasing the utilization of both because we just want energy during states of sympathetic stimulation so moving on to glucagon now glucagon like it mentions that does the complete opposite of insulin it's secreted by alpha cells and secreted as glucose falls you only need a smaller amount of glucagon to actually have influence so glucagon has this very very strong effect of increasing blood glucose through a secondary messenger system so remember the adenocyclase system that we talked about in a lot of different chapters here as glucagon is released it goes to the liver mainly it activates adenyl cyclase which then produces camp which activates protein kinases protein kinases ultimately phosphorylate various enzymes the but the main one is the activation of phosphorylase a which then promotes the degradation of glycogen so now we actually releasing glucose allowing it to go into the bloodstream so since glucose was low glucagon gets secreted to then break down the glycogen within the liver it also helps to promote gluconeogenesis in the liver to help produce more glucose and increase our blood glucose levels mainly helping to make sure our brain gets enough glucose because we do not want to be hypoglycemic or else our neurological system suffers it also activates adipose cell lipase to increase fatty acids that's available in the bloodstream so then the other cells are able to use fatty acids instead of glucose since glucose is low we want the other cells to switch their metabolism over to energy utilization through fats and save the glucose for our brain it also has these other lesser important effects of enhancing the strength of the heart increasing blood flow to tissues and then enhancing bile secretion inhibiting gastric acid secretion as well and glucagon is mainly just influenced by blood glucose level it can also be stimulated by amino acids but similar to insulin you know glucose is our main influence here beta adrenic stimulation will also increase glucagon you know that's our sympathetic nervous system wanting glucagon to be released so then we increase glucose and increase energy available for the cells now there is a little little portion here about delta cells and somatostatin remember cementostatin is released from delta sales in the islets of langerhan and these are stoppers so metastatins are stoppers so they are released whenever food has been taken and it's really just a dampening effect of all of these other systems so since there's increased glucose amino acids fatty acids gastrointestinal hormones they all increase the metastatin release symmetry inhibits the secretion of insulin and glucagon and it's not that it just completely stops it it's just trying to prolong the secretion it decreases motility of the stomach decreases the secretion absorption from the gastrointestinal system it's basically trying to extend the period over which the food nutrients are assimilated into the bloodstream so trying to smooth out our processes rather than having a big roller coaster of up and down and up and down so metastatin is trying to really help everything be prolonged it is also the inhibitor of growth hormone release when it's released from the hypothalamus so we have a little summary here where we have of the blood glucose system so the liver acts as a buffering system so it increases its storage when we have high blood glucose and then it releases glucose when we have low blood glucose insulin and glucagon have important feedback control mechanisms to actually control the blood glucose level mainly through the liver and then also through the utilization of fatty acid metabolism and also uptake or release of glucose or production of glucose if we have a severe hypoglycemic state and let's say that our other systems aren't working well or we have too much insulin or we've been exercising something along those lines the sympathetic nervous system will release epinephrine to help increase our glucose so help these mechanisms they do have other hormonal systems that are going to help to increase glucose if need be and if we have severe prolonged hypoglycemia then we will actually release growth hormone and cortisol to really help increase glucose and convert over the fat utilization to make sure our brain gets enough glucose now glucose regulation is super important because if we have low blood glucose our brain rarely suffers if we have high blood glucose it has this high osmotic effect so it sucks water away from our cells we end up with cellular dehydration it sucks water into the kidneys so we end up actually peeing a lot as well so you get even further dehydration so you get both intracellular and extracellular dehydration and then you start to convert all of your glucose into fatty acids you end up in a ketolic state or a metabolic acidotic state you then also produce more cholesterol as you're trying to convert all those fatty acids into other forms and you end up with atherosclerosis and you end up with a really high risk of heart attacks strokes end-stage renal disease which then results in hypertension which has a myriad of other effects and you can end up with blindness as well so high blood glucose is definitely bad low blood glucose is definitely bad so we want to maintain it nice and normal using these mechanisms now diabetes mellitus will go briefly through this diabetes like i said is sweet urine and not that i recommend this but a diabetic patient will have sweet tasting urine we have two types type one just is insulin dependent meaning that there is a total lack of insulin so for some reason those beta cells are not producing insulin and that may occur due to an autoimmune disorder that destroys the beta cells or a viral infection something along those lines but there also seems to be a hereditary effect as well and because of that this is usually more of a younger disease juvenile diabetes the median age of around 14 years in the u.s and that results in all the problems you would expect with low insulin so increase blood glucose increase utilization of fats for energy increase cholesterol in the body increase ketones and acids in the body so metabolic acidosis and then the depletion of bodies proteins so you end up actually starving your muscles or proteins and you can waste away and you can get a reduction in body weight so that's type 1 diabetes is insulin dependent whereas type 2 diabetes is actually non-insulin dependent meaning that the problem is actually insulin resistance so this is typically high insulin in the bloodstream but that insulin is not being recognized by the cells and the effects aren't occurring so it's an effective absence of insulin but it's because the cells are not responding to it so insulin is still getting highly produced by the beta cells and that high production over time can actually exhaust them so eventually they actually stop producing insulin so the end stage of type 2 diabetes is actually low insulin but it actually starts off with high insulin in the bloodstream because of insulin resistance at the target organs now that results in a very similar presentation you know we end up with high glucose we end up with ketones in the body cholesterol we get atherosclerosis all of those risks but the main difference is that we actually have high insulin so we have to take into account what factors can result in insulin resistance so the causes of this one are usually unfortunately obesity so that's the most common cause in the u.s and that seems to be causing this disease in younger and younger populations as obesity becomes more of a problem in young populations but this is usually an adult onset diabetic state because insulin resistance occurs over time now there are other causes but obesity is definitely one of the main ones and obesity increases insulin resistance and you can think about this is because obesity you know you're going to be eating a lot have a high energy state in your body for a long period of time so insulin is constantly being secreted so whenever you have a high energy state in your body insulin is constantly there and over time the body just stops responding to it that's an easy way to think about it we can have other causes of insulin resistance however so remember those hormones that antagonize insulin so excessive glucocorticoids so such as cushing's syndrome or steroid therapy that can antagonize insulin and stop its work so we can end up in a diabetic state as we talked about acromegaly pregnancy which results in gestational diabetes due to the hormones produced in pregnancy that's similar to polycystic ovaries disease which releases a lot of androgens which antagonize our insulin and then so on and so forth so we do have some other hereditary causes for insulin resistance but ultimately that is the main difference here so the the main differences are outlined in this table 79.3 where type 1 diabetes is usually younger body mass is low and we have low insulin type 2 typically older we have obesity and we actually have high insulin now that really changes our treatment for these two groups because type 1 diabetes is just a lack of insulin you're not producing it so the therapy is giving insulin type 2 diabetes is a lack of response to insulin typically due to obesity but we have a reason for insulin resistance so you want to get rid of that cause of insulin resistance so weight loss really can help this disease in the early phases weight loss exercise proper diet they can really help to treat type 2 diabetes without the need for insulin you can also try some drugs other than insulin so maybe a drug that increases insulin sensitivity or suppresses liver glucose production such as metformin or actually increase the release of insulin from the pancreas you're trying to increase it even further to really help maintain normal glucose levels you can try those drugs in the early phase and then eventually ultimately if there are severe clinical signs associated with it which can actually just take some time for that to occur you know you can live in an obesity state with diabetes or pre-clinical diabetes where you have high insulin and your glucose is high but the high insulin is able to keep it at a certain level we are not too clinical for it but eventually you may actually end up requiring extra insulin because your glucose has gone over that critical point all your beta cells are now exhausted so they're no longer producing insulin so then you need insulin at those stages of type 2 diabetes so that's the main differences between the two types in order to diagnose diabetes it's relatively simple in terms of just testing for glucose so you're going to have glucose in your urine as it is over that threshold that renal threshold and then you're also going to have fasting high blood glucose levels if you're type 2 diabetic you're going to have high insulin during those periods as well you can do a glucose tolerance test we're giving a little bit of glucose you start off already hypoglycemic before you get the glucose and then suddenly you have this massive response in prolonged hypoglycemia versus a normal patient acetone breath from the ketoacids these are all relatively simple ways to diagnose diabetes now in order to treat it once again we kind of talked about this insulin is the main thing weight reduction exercise and there may be some drugs with type 2 diabetes and we do have this risk for atherosclerosis or and atherosclerosis due to high levels of cholesterol from all those fatty acids getting produced into cholesterol and phospholipids so we do have this high risk of atherosclerosis and also high risk for hypertension as the kidneys start to get impacted so you may also consider lipid lowering drugs so that is diabetes mellitus but there is also a condition where you have too much insulin so remember diabetes is not enough insulin too much insulin typically occurs from an insulin over so natural cancer of the beta cells causing an increase insulin production so then you dramatically reduce your blood glucose levels so there's such high levels of insulin when there is no insulin resistance resulting in hypoglycemia and that results in neurological side effects as you would expect with the central nervous system needing glucose for its energy production that can eventually lead to a loss of consciousness coma and even death the treatment is just as you would expect give some glucose in the short term you can also give some glucagon and then consider removal of that mass and then that is the end of the chapter for today if you'd like some questions here are some to give it a go so what cell secretes insulin and what cell secretes glucagon number two is what type of receptor is the insulin receptor and then number three lists three causes of insulin resistance and what type of diabetes mellitus is this if you'd like to support the channel you can do so through the patreon link where you can get access to downloadable audio files of these chapters otherwise i hope you enjoyed this chapter feel free to drop a comment and we'll see in the next video