[Music] today I'll be discussing the normal physiology of two of the body's most critical hormones insulin and glucagon this video can be viewed in two ways either as a standalone physiology lesson or as the lead in to a forthcoming series on diabetes by the end of this video you'll be able to describe the macroscopic and microscopic structure of the pancreas you'll be able to list the major metabolic actions of insulin and glucagon you'll be able to describe the regulation of insulin and glucagon including the role of other hormones for example cortisol epinephrine glp1 and Gip among others and last you'll be able to describe the structure and synthesis of insulin a few things that will not be covered in this video include the structure of the insulin receptor glucose Transporters signal transduction mechanisms and the individual enzymatic steps where insulin and glucagon act while these details may come up on a biochemistry exam in med school their inclusion would add another 20 minutes and these topics are almost never of clinical relevance I'm going to start off by mentioning three very pervasive myths about insulin and glucagon the first myth the only major function of insulin and glucagon is to regulate blood sugar second that insulin and glucagon are the only significant hormones involved in glucose homeostasis specifically the very simple model in which insulin makes the blood sugar go down and glucagon makes the blood sugar go up and last that modern medicine has a complete understanding of the actions and regulation of these hormones despite the fact that I encounter students and doctors alike with these beliefs none of them are true insulin and glucagon do much more than regulate blood sugar there are many other hormones involved in the regulation of glucose there are unequivocally seven other hormones with a clinically relevant role in glucose homeostasis and quite likely more whose role is waiting to be further elucidated and confirmed which brings up the last myth while we understand much about insulin and glucagon modern medicine is gaining new insight into their very complex physiology every year so now where do we begin with what we do understand well a good place to begin is with the pancreas the pancreas is a glandular organ in the upper abdominal cavity located posterior to the stomach it is typically divided into three geographic regions the head which is nestled against the dadm the body and the tail which stretches laterally towards the spleen a network of ducks coales and at the pancreas via the main pancreatic duct while the common bile duct brings bile down from the gallbladder and liver above the pancreatic duct and common bile duct merge just prior to an opening into the deinum called the ampula of v a significant minority of patients have an accessory pancreatic duct which drains proximately to the ampula and is of minimal clinical relevance when viewed microscopically the interesting nature of the pancreas becomes more apparent here are two microscop IC views a histology slide is on the left and an artistic rendering on the right we can see that the organ appears to be composed of two discrete types of tissues Each of which corresponds to one of the pancreases two major physiologic roles the first tissue type is the Asin or asinus when singular the Asin are responsible for the pancreas exocrine function by secreting digestive enzymes into the deinum via the network of pancreatic ducts the second tissue type are the eyelets of langerhans the eyelets are responsible for the pancreas endocrine function instead of secreting enzymes into the gut they secrete hormones into the blood most notably insulin and glucagon they're named after Paul longer Hans a German pathologist and physiologist from the 19th century who first described them when he was a 22-year-old student the eyelets are composed of multiple cell types Each of which secretes a different one or two hormones alpha cells secrete glucagon beta cells which are the most numerous secrete both insulin and another hormone called amalin gamma cells which are frequently referred to as PP cells secrete pancreatic polypeptide the function of which is unclear and which won't be discussed further in this video and last Delta cells which secrete somata Statin a fifth much rarer cell type has recently been discovered and is predictably called Epsilon cells which appear to secrete a hormone called grin as already implied insulin and glucagon play a critical role in maintaining metabolic homeostasis and they act largely in an antagonistic way such that the primary actions of one hormone are the complete opposite of the primary actions of the other when the body is in a well-fed state insulin predominates the primary actions of insulin are glucose utilization known as glycolysis glucose storage as gly logen known as glycogenesis fat synthesis or lipogenesis protein synthesis and general promotion of glucose uptake and tissues which also helps to promote the previous four actions these all make sense when the body is wellfed and Fuel and energy is abundant of course your body should store excess energy when the body is fasting however glucagon predominates its primary actions are glucos synthesis called gluconeogenesis glycogen breakdown or glycogenolysis fat breakdown through a combination of the processes of lipolysis and beta oxidation protein breakdown and last the formation of compounds called Ketone bodies which act as an alternate fuel source when glucose is in short supply this balance between insulin and glucagon and between the wellfed and fasting States is occurring constantly being regulated on a minute-to-minute basis based upon the relative abundance or lack of nutrients in the blood most notably though not exclusively glucose the primary goal of this balance is to provide a constant level of available fuel in the bloodstream irrespective of how recently a person has eaten and in the absence of diabetes extreme physiologic stress or rare hormone secreting tumors the body does a fantastic job maintaining ug glycemia that is a normal serum glucose level I'm going to introduce just a little more detail to that model I've already mentioned that insulin is produced by the beta cells of the pancreas and glucagon by the alpha cells these hormones then enter the bloodstream and travel throughout the body although they act on just about every tissue in every organ there are three particularly important sites first is the liver the liver along with skeletal muscle is responsible for energy storage in the form of glycogen thus insulin effect in the liver is to bring excess glucose from the blood into the liver cells where it will be converted to glycogen fatty acids and triglycerides insulin also acts in the skeletal muscle where it promotes entry of glucose and amino acids amino acids are then used in the synthesis of new proteins while the glucose is used in Glycolysis to produce ATP some glucose may also be converted into muscle glycogen which is energy to be used later finally insulin acts in adapost tissue where it stimulates uptake of fatty acids which get converted into triglycerides which can then be used as long-term energy storage as you can see each of these processes are reversible and wherever insulin stimulates a process it generally inhibits its opposite for example in atap POS insulin stimulates lipogenesis and inhibits lipolysis for Simplicity I've only discussed insulin's actions here glucagon's actions on each pathway are essentially the opposite while insulin and glucagon are unquestionably the two most key hormones involved in the momentto moment regulation of metabolism there are many other contributors which I'll go through now there are two other hormones to discuss that are produced in the pancreas as mentioned earlier amalin is produced by the beta cells and is co-secreted with insulin and somatostatin produced by the Delta cells I'll spend a moment focusing on just how these four interact with one another first the secretion of insulin amalin and somatostatin are all stimulated by high serum glucose while glucagon secretion is inhibited by it while insulin suppresses glucagon secretion somewhat counter intuitively glucagon stimulates insulin secretion to the best of my knowledge this is the only interaction between glucagon and Insulin that is not antagonistic amalin helps with insulin suppression of glucagon while somatostatin actually inhibits both in addition to the regulatory role within the pancreas emalin and somatostatin have other interesting actions for example both slow down gastric emptying and slow down gut motility in general this helps to blunt postprandial hypoglycemia in addition amalin promotes the sensation of satiety in the brain moving beyond the pancreas there are two important hormones secreted by the gut the first is called Gip which originally stood for gastric inhibitory polypeptide because it's been since learned that it has minimal gastric inhibitory properties it has since been renamed glucose dependent insulinotropic polypeptide a great example of a backronym in which the full name of some is created after the fact in order to conform with a pre-existing acronym Gip is secreted by K cells located mostly in the dadm and upper junim and its major role is to promote insulin secretion in addition there is the more important glp1 which stands for glucagonlike peptide which also stimulates insulin release and inhibits glucagon release as well as slowing gastric emptying promoting satiety and increasing insulin sensitivity in atap POS and skeletal muscle glp1 is secreted by the L cells of the ilium and colon Gip and glp1 are known collectively as incron hormones or incretins for short incretins are hormones produced by the intestines which influence blood glucose without affecting the pancreases exocrine function their existence was discovered after it was observed that study sub objects secreted more insulin in response to orally delivered nutrients than in response to an equivalent amount of intravenously delivered nutrients thus the stimulus for their release is dietary fats and carbohydrates one last clinically relevant detail is that Gip and glp1 are both rapidly inactivated by an enzyme called dpp4 which stands for Di peptidal peptidase this is relevant because dpp4 makes for an interesting drug Target which will be discussed in a future video on diabetic medications so far all of these ancillary hormones have largely been either supporting the general effects of insulin or in the case of somatostatin playing more of a neutral role however there are three hormones that directly and indirectly antagonize insulin's actions they are the so-called stress hormones of cortisol epinephrine and growth hormone while each of these have more important primary actions their General Collective effect on metabolism is to decrease insulin secretion increase gluconeogenesis increase lipolysis and to decrease insulin mediated glucose uptake with a net consequence of hyperglycemia you should not try to commit this diagram to memory because it could be summarized without too much loss of information hormones whose net effect is to decrease serum glucose are are insulin amalin Gip and glp1 and hormones whose net effect is to increase serum glucose are glucagon cortisol epinephrine and growth hormone an additional topic to discuss is the structure and synthesis of insulin insulin is a small protein composed of two amino acid chains linked by disulfide Bridges it's synthesized in four distinct steps first a single amino acid chain is formed from routine protein translation this is known as preproinsulin the signal peptide is then cleaved off in the endoplasmic reticulum forming proinsulin the proinsulin protein has three sections to it designated the B chain the C chain and the a chain disulfide Bridges form between the A and B chains the C chain is then removed which results in the final active hormone because the C chain serves to connect the A and B chains it is more often referred to as the connecting peptide or C peptide for short equimolar amounts of insulin and C peptide are stored in secretory granules and eventually released together therefore C peptide can serve as an important surrogate for insulin secretion this is particularly true in situations in which one must distinguish between a patient who has excessive endogenous insulin presence as with an insulin producing tumor in which case levels of C peptide will also be High versus excessive exogenous insulin as seen in fictitious hypoglycemia in which case C peptide levels will be very low the final topic to discuss is the temporal relationship of glucose sources that is where does the glucose come from that it's utilized by the tissues in the hours and days following ingestion of food in the first several hours after a meal when the patient is is in the well-fed state the effects of insulin predominates and almost all peripheral glucose utilization draws from dietary glucose however after approximately 4 to 6 hours that dietary glucose has been removed from the bloodstream and the body's metabolism enters the fasting State insulin levels are diminished and glucagon increases this results in glycogenolysis which provides the body glucose for the next half day or so at this point glycogen stores are gone and Metabolism enters starvation mode this is the point at which gluconeogenesis becomes the primary and eventually the sole source of glucose to remind you the process of gluconeogenesis synthesizes glucose from combination of amino acids liberated during proteolysis glycerol from lipolysis and lactate from Anor robic respiration while in Starvation mode the body also directly utilizes fatty acids and Ketone bodies for fuel Ketone bodies specifically are discussed in more detail in the video covering diabetic keto [Music] acidosis so that concludes this video on the normal physiology of insulin and glucagon if you found it helpful please remember to like and share it if you are viewing this as part of a desire to learn endocrine physiology I suggest also checking out my videos on thyroid hormones and calcium phosphate regulation if on the other hand you are viewing this as an introduction to diabetes the next video in the diabetes series will cover the pathogenesis and classification of that [Music] disease