DIP Episode 482 - The Floridly HY Insulin Podcast (for Step 1, but helpful for Step 2/3)

All right welcome my name is divine this is episode 482 of the divine intervention podcast into this podcast I'm gonna be talking about insulin so I'm gonna call this the clutch insulin podcast I'm gonna call this the clutch insulin podcast I'm gonna see this right off the bat this podcast is probably one of the highest your podcast I have ever made the stuff's pretty high yield and there's a lot to go through but I'll just say that this is something that you will see tested in some way or some derivative on step one on step two and on step three and I'm gonna try to make lots of integrations and try to break open some things that make confused people as we go along so obviously we know that insulin if they give you a question about like a young child and this child has been having polydipsia and polyureia for the last few days and then the child is some low length is shorter breath has skin tinting has dry mucus membranes and then they give you the child's blood glucose and it's like 700 and the child's by carbase like 10 and the child's pH is like 7.23 or something like that and that child is clearly in DKA and this child is presenting with type one diabetes so how do we treat type one diabetes obviously we're gonna treat that with insulin remember insulin is not usually what you start with in type two diabetes I'm gonna present a type two diabetes you start with many of the other drugs the oral stuff with four men the sulfonyl ureas the phyazolidine diones the sglt 2 inhibitors the endine flows in you know all those drugs but if all that is no longer obtaining good control many times people have type two diabetes terminally they're gonna have to switch to insulin so what's the whole deal with insulin well the thing is again they're just many critical things to know about insulin for the exam first thing is is that it's a hormone right and we all know that insulin is

a peptide hormone it's not a steroid hormone right it's a peptide hormone that's actually very important now where do we make insulin from insulin is made from the beta cells in the eyelets of longer hands it's made from the beta cells in the eyelets of longer hands it's actually pretty high you to understand that these beta cells they are centrally located in the eyelet of longer hands the alpha cells that make glucagon which essentially does like the opposite of what insulin does are located on the periphery in the eyelets of longer hands the thing is insulin has been secreted from the beta cells in the eyelets of longer hands on its way out of that eyelet of longer hands pretty much inhibits the alpha cell so that you do not secret glucagon because you don't want to be secreted in a ton of insulin and then secreted in a ton of glucagon at the same time because they literally do the opposite things you don't want to keep a few tile cycles so that's why the alpha cells that make glucagon they're on the periphery as insulin is leaving the eyelets the eyelets is going to shut down the alpha cells from making a glucagon now do you want to think of insulin as anabolic or as a cannabolic hormone well really what you're seeing will divine is more of an anabolic hormone right insulin is a hormone that builds people up it doesn't tear people down it is not cannabolic it is anabolic right in fact if you see people that have been on long-term insulin therapy many times they can get obese because insulin is almost like a growth factor in fact i'm sure many of you have heard of this insulin like growth factor blah blah blah blah insulin is a growth factor it builds people up right it takes molecules from being small to being large right it takes free fatty acids and mixedoglycerides from those it takes peptides and mixed proteins from those it takes glucose and mixed glycogen f

rom it right and one of the main roles in fact i'll see is probably the primary role of insulin is that insulin helps you get glucose into your muscle cells your dipocytes your lever insulin is necessary for your cells to uptake the glucose that is in the blood right and again insulin helps with many things again i said it's anabolic so it helps with glycogen synthesis so it takes glucose monomers and puts them together from glycogen it helps with lipogenesis right so it takes all your free fatty acids takes your glycerol and it sterilifies them into forming triglycerides right and insulin also inhibits glycogenolizes and glucose in your genesis so if something want if insulin is to help you make glycogen then it doesn't make sense for it to promote the breakdown of that glycogen that is just formed right so insulin inhibits glycogenolizes and glucose in your genesis right and what is one of the primary stimulants of the release of insulin but one of the primary stimulants is going to be high blood glucose every blood glucose is high everybody is like whoa whoa whoa this is not good we need to get some of this glucose into cells into critical cells like your muscle cells your dipocytes your lever so insulin is going to be released heavily in response response to that right it's going to be released heavily in response in response to that and if you look at the hormone that does the opposite job of insulin glycogen well glycogen again as I said come from the alpha cells in the eyelet of longer hands and that glycogen it's release is stimulated by low blood glucose if your blood glucose is low then you don't want you want the lever to supply glucose to the blood stream so your cells can have adequate glucose when your blood glucose is low even increase the release of glucose so just like insulin suppresses blood glucose levels glucose gone increases blood glucose levels

so it shouldn't be a huge surprise to you that if a president has a glucose gone no more they're going to have diabetes why because that glucose gone no more it's going to cause them to have very high glucose levels now as many of us know you know there are two kinds of diabetes right you know there's type one diabetes there's type two diabetes at least on a simplistic level for the USML is which is completely fine and type one diabetes right it's pretty much an autoimmune disease you have autoimmune destruction of your pancreatic beta eyelet cells right and when you have that autoimmune destruction you know with these anti insulin or anti eyelid peptide or anti-gat right anti glutamate decarboxylis antibodies then you're going to be able to make insulin so people that have type one diabetes they have an insulin deficiency now people that have type two diabetes right as many of us know is more of an insulin resistance problem right and many times people that have type two diabetes they are cumulid amyloid within their within their beta eyelet cells and those that amyloid those aggregated beta pleated sheets remember sometimes our friends at the USML is they love to test protein structure especially on step one those aggregated beta pleated sheets you know those amyloids they pretty much distort the proper functioning of those beta eyelet cells that's what at some point people that have type two diabetes are going to require an exogenous insulin exogenous insulin right that amyloid that accumulates in type two diabetes is made of amylin amylin AMYLIN amylin right and you may wonder again where does this amylin come from the thing is amylin is also secretive from the pancreatic beta eyelet cells whenever you secret insulin you also secret amylin as well the problem with people that have type two diabetes is they have a lot of insulin resistance so early in the course o

f your disease they release very huge huge huge amounts of insulin because the body is kind of resistant to it and I will talk about some potential mechanisms behind that resistance but as they release in all that insulin they also releasing huge amounts of amylin whenever amylin is releasing huge quantity what is like man this thing is like so much it's going to start heaping it up heaping it up heaping it up and you're going to start from in these aggregated beta pleated sheets that ultimately become our common order right and insulin if you look at it from the structural perspective right you pretty much has like an A chain and a B chain right and that A and B chain they are connected by die sulfide bond okay they're connected by die sulfide bond so if you actually want to break up the structure of insulin if you want to degrade insulin you need to break down die sulfide bond you can remember the USML is the love die sulfide bonds do not lose sight of your famous die sulfide bonds right so like for example we know that anacena system can be used in people that have cystic fibrosis to break up the amycus belong to white because it breaks up what die sulfide bond don't lose sight of what die sulfide bonds something you love to test on step one now one weird factoid I think I want to discuss with insulin that you know you may see it show up out of the blown an exam I mean be scratching your head that may have never seen the stuff of never seen the stuff before anywhere is our friends at the USML is every now and then they love to test like weird transcription factors you just wonder like how did they pick this question out of a hat right and usually almost like without fail people just guess on these questions that most people get them wrong right so there's one transcription factor I want you to commit to memory for your USML exams that is very high yield in the synt

hesis of insulin in you transcribing the gene that codes for insulin and that's pdx 1 pdx 1 I promise you need to burn this into your brain for the USML is pdx 1 is a critical transcription factor for the production of insulin it's kind of similar to how the USML is love to test test a Fox p3 you know if you have any kind of USML experience you've probably heard of Fox p3 Fox p3 is a transcription factor that is necessary for the proper functioning of regulatory T cells is necessary for the proper function of regulatory T cells right so again if they can give you like one of these experiment-based questions especially on step one where they tell you that oh which of the following will happen in a state of high blood glucose well guess what you're going to operate the transcription factor pdx 1 in that situation of high blood glucose right because again again again if you operate that transcription factor you'll make more insulin and that more insulin will help you do with that high blood glucose problem that you have right you'll make you do that high blood glucose problem that you have right so the the the thing is we know that blood glucose should be maintained in some kind of homeostasis right you don't want your blood glucose to be high all the time when your blood glucose is high all the time it starts causing many problems in the body right it starts damaging your kidneys damaging your eyes damaging your neurons causing many of the antecedents of diabetes right so you want your blood glucose to be maintained in homeostasis you don't want it to be too high where you have hyperglycemia because causes problems I also don't want you to be too low where you have hypoglycemia that can kill you actually hypoglycemia honestly is more dangerous than hyperglycemia let us say that again hypoglycemia is actually in fact more dangerous than hyper hyperglycemia so because if you

think about it if your blood glucose is high all the time you know you're going to keep operating this transcription factor of PDX1 PDX1 PDX1 but the thing is if you're just making so much of this transcription factor all the time all the time all the time all the time the target of this transcription factor it's it's different targets and I'm going to be a sensitive to PDX1 anymore they're not going to bind PDX1 as well anymore right and if they don't bind PDX1 as well anymore that can begin to cause problems with insulin production and if you don't make enough insulin you're not going to be able to deal with that high blood glucose problem so having high blood glucose is actually not a good thing right and I like to give this analogy think about it let's say you really love you know I'm going to say this as an Nigerian let's say you really love fried rice plantain and chicken mmm fried rice plantain and chicken and then you keep eating fried rice plantain and chicken fried rice plantain chicken you eat breakfast lunch and dinner Monday Tuesday Wednesday Thursday Friday Saturday Sunday at some point as much as you love fried rice plantain and chicken you're going to get tired of it you're going to get sick and fed up of it and you're like no I do not want fried rice plantain and chicken anymore that thing you loved so much your affinity for it goes down precipitously why because you've just had way too much of it so if your blood glucose is high all the time and you're making pdx 1 all the time the target the targets of pdx 1 I'm not going to be very pleased with pdx 1 anymore and if you're not pleased with pdx 1 anymore that's one of the situations where you begin to make less insulin less insulin less insulin less insulin this actually kind of explains why people that have type 2 diabetes over time they will because they usually have just high blood glucose high blood

glucose high blood glucose over time pdx 1 will not be as sensitive as it should be and this people are going to start making less insulin at that point they're going to start needing exogenous insulin and actually one other thing that people many people taking the USML is are completely unaware of is that glucose actually can lead to the formation of free radicals going to say that again glucose in a time dependent fashion can induce oxidative stress it can lead to the formation of free radicals especially in pancreatic beta cells because pancreatic beta cells they bring in huge amounts of glucose right and if you have those free radicals popping up that can actually lead to the destruction of these pancreatic beta cells and it can actually lead to the subsequent hipoptosis and this can cause problems they can this can cause problems so again having high blood glucose over time is not a good thing I promise you it's not a good thing that's why when a physician is saying oh watch your diet keep the carbs low exercise so you don't get in trouble they're not saying you're for fun they're actually saying it for good good reason so we've kind of talked about the genetic thing with insulin talking about pdx 1 again you're like man the vine it's been way too much time on pdx 1 I wish you all the best when you see an example question you're like she they're spending so much time on pdx 1 again I'm not talking about it because I love to hear myself talk now so now I've talked about the genetic level how is insulin made well insulin you know when you make the mRNA you're gonna translate that mRNA and you're gonna form pre-pro insulin right you're gonna form pre-pro insulin that pre-pro insulin has to go into the endoplasmic reticulum the thing is really making this insulin podcast the one of the reason I chose insulin as a topic is that there are so many integrations you can make

with insulin literally there are tons and tons and tons of integrations that you can make with insulin they are just many ways you can according to cell biology according to genetics according to biochemistry according to pharmacology according to metabolism many different things so think of this as almost like a podcast that will help you deal with a section like multi-systems processes and disorders when you're a simileexams right so insulin is made as pre-pro insulin and then that pre-pro insulin has to be taken into the rough endoplasmic reticulum right remember the rough endoplasmic reticulum right has this thing called signal peptidase right a peptidase is means it cuts out a peptide right so it cuts out the signal peptide because the signal peptide is the thing that gets insulin from the cytosol into the rough endoplasmic reticulum so that signal peptidase is gonna cut away the signal peptide once you cut away that signal peptide that pre-pro insulin becomes pro insulin and that pro insulin starts folding indian to plasma reticulum and then it continues on its way to the goji apparatus after going through the goji apparatus right remember the goji apparatus has the cis goji network and the trans goji network it's gonna be packaged into secretory vesicles right and when it's packaged into secretory vesicles is then pretty much waiting to be released when the right signals come along right when the right signals come along and the thing is when you're about to release insulin typically you're gonna actually like cut out the middle part of the insulin molecule which is the CPEP Tide right many of us are familiar with CPEP Tide so how do you think our friends at the USMLE will love to test CPEP Tide well let me explain the thing is if insulin before insulin is released like I said from those vesicles the CPEP Tide part which is like the middle portion is cut off so whe

never insulin is released CPEP Tide is gonna be released as well so think about it for person has an insulinoma and insulinoma you have a tumor right usually you're gonna find this in a person that has MEN1 because remember we would have MEN1 they have thyroid problems pancreatic problems you know pancreatic neuroendocrine tumors and pitotary adenomas these people are gonna release they can have insulin omens is one of these pancreatic neuroendocrine tumors that can make a tumor insulin that insulin can cause problems right so you notice this person keeps having weeple stride you know they have hypo glycemia they have signs of hypo glycemia and in the asymptoms magically improve with the administration of glucose you know like fruit juice or whatever right so the reason they have that hypo glycemia is this tumor is pumping out tons and tons and tons of insulin right so one of the ways you can see that man this person has an insulinoma is that you're gonna notice that the insulin levels are very high but their CP Tide levels are also high as well now let me ask you this how about a person that's taking a sulfonyl urea well sulfonyl urea they work with the the meq secret more insulin we're gonna talk about how insulin secreted but it makes you secret more insulin so guess what because sulfonyl urea is meq secret more insulin from your endogenous so that means from within your pancreatic beta cells stores right it's also gonna raise your insulin and your CP Tide levels so how do you differentiate between a person that is taking a sulfonyl urea and a person that has an insulinoma well the way you're gonna differentiate is that both will be out socializing with the increased insulin both will be out socializing with increased CP Tide but they something known as a secreted gog screen a secreted gog screen as a secreted gog screen is like a block test for a sulfonyl urea the sec

reted gog screen is gonna be positive when you're taking a sulfonyl urea it was gonna be negative in a person that has an insulinoma that's very important and then the third kind of thing you may want to keep in mind with CP Tide is what if a person is exogenously so that means like taking something on the outside not something that everybody's producing the exogenously taking insulin maybe to create hypo glycemic symptoms maybe they have like monchalcent or something weird like that then in that circumstance those people's insulin will be high you'll have signs and symptoms of hypo glycemia but the CP Tide levels will be almost nonexistent why is that well the thing is if you're taking a ton of exogenous insulin first things first exogenous insulin does not contain CP Tide at all the insulin you can buy at a drug store you know not buy at least not in the US I gotta get a prescription for those insulin you can get from a drug store does not contain CP Tide exogenous insulin does not contain CP Tide so as you're taking that insulin right your insulin levels are gonna be high but your CP Tide is gonna be like nonexistent because that insulin you're taking in your body is gonna induce a hypo glycemia that hypo glycemia is going to suppress insulin production so your endogenous stores of insulin your pancreatic beta cells are gonna see the hypo glycemia and say whoa we better not make any insulin at all so even your own pancreas your beta eyelet cells are not gonna be making insulin and if they're not making insulin they're not gonna be making CP Tide as well right that's actually pretty important to understand so when you're exogenously taking insulin your insulin will be high and your CP Tide will be low right because again that exogenous insulin you're taking first there are two reasons why you don't have a high CP Tide that exogenous insulin you're taking first does not conta

in CP Tide at all well that exogenous insulin is also gonna suppress your blood glucose when you suppress your blood glucose that is a very powerful suppressant of insulin production because think about if your hypo glycemic you don't want to make more insulin because if you make more insulin you're gonna so lower your blood glucose even more and die your body does not want that right so your body your body if you're taking so much exogenous insulin your endogenous insulin production will be suppressed right that's also gonna suppress CP Tide production okay so now that you've made insulin packaged it in these vesicles how in the world do you secret that insulin well you're gonna secret insulin in two phases insulin secreted in two phases there's an initial rapid phase usually within the first like 10 minutes and then there's like a sustained slow release that happens over the subsequent two to three hours right so let's maybe break this down again at the biochemical level how do you release insulin how do you secret out insulin from your beta cells in the eyelets or longer hands or the first thing that happens is that glucose is gonna enter the pancreatic beta eyelets cell through what glue two transporters glue two transporters remember glue two transporters they are bi-directional they can let glucose go in either direction literally it just works by concentration gradients okay they are bi-directional remember the two for bi bi-directional right so you find these glue two transporters you're gonna find them in the pancreatic beta eyelets cells you gonna find them in the liver as well right so when glucose enters the pancreatic beta eyelets cells through the glue two transporters glucose kinase is gonna cover that glucose to glucose six phosphate to glucose six phosphate right so the more glucose you have entering the cell the more glucose six phosphate you also have

as well right and many of us know that the glue two transporters has a high KM and a high V max right so it doesn't have a high affinity for glucose but it has a very high capacity it has a very very high high V max okay remember the higher your KM the lower your affinity the lower your KM the higher your affinity just thought I should throwing that mechanism in an integration here right so the more glucose enters this beta eyelets cells the more glucose six phosphate you have right and remember that glucose six phosphate does not inhibit glucose kinase like it does hexokinase hexokinase is inhibited by its product glucose six phosphate glucose kinase is not inhibited by its product glucose six phosphate that's another weird but high you'll think to know like many of these things you see me seeing the spot like wow divine these are meaningless details I promise you for step one many of these things are very important and some of these things not all of them but some of these things are absolutely important for step two and step three the absolute important for step two and step three some not all some not all this detailed cell bio stuff probably more for step one but there are some things you're gonna hear me seeing this podcast that are coming down the line I've said already that I certainly for step two and step three right so this glucose six phosphate right obviously it's gonna go down glycolysis and do all the glycolysis TCA cycle electron transport chain I gonna create ATP right and as ATP is created what's gonna happen to the ATP to ADP ratio within the cell well it's obviously gonna arise your ATP to ADP ratio within the cell is gonna rise and those high levels of ATP are gonna close potassium channels right and when you close this potassium channels is gonna prevent these is book on a prevent potassium from leaking out of the cell by facilitated diffusion i

f potassium does not leak out of the cell anymore then it's gonna start accumulating and pulsating potassium is a positive charge so as it accumulates it's gonna cause the cell to depolarize and when the cell depolarizes there are some channels that will open voltage gated channels remember a voltage gated channel is a channel that opens in response to a change in voltage this is different from a ligand gated channel that opens in response to the binding of a ligand right so because the cell depolarizes the voltage gated calcium channels right one of the voltage gated channels that opens is a voltage gated calcium channel it's gonna open and calcium is gonna rush into the cell by facilitated diffusion right as calcium rushes into the cell this is gonna trigger the release of insulin from secretory vesicles okay it's gonna trigger the release of insulin from secretory vesicles and these potassium channels that I said that are blocked by ATP those actually the targets of sulfonyl ureas sulfonyl ureas actually blocked those potassium channels as well which will again prevent potassium leaking out of the pancreatic beta-ilett cell by facilitated diffusion that's gonna cause the cell to depolarize and then you're gonna again open up these voltage gated calcium channels calcium is gonna rush into the cell and then insulin is gonna be released from secretory vesicles okay insulin is gonna be released from secretory vesicles again very very very important to know right because again remember the if you block a potassium channel potassium normalize an intracellular ion right because if you think about it potassium your sodium potassium ATP is bomb sticks three sodiums out of the cell and puts two potassiums into the cell right remember the sodium potassium ATP is bomb consumes like 70% of the energy of any cell so it constantly puts potassium into cells so potassium builds up

to a higher level within cells okay so normally the natural place that potassium wants to flow to is flow out of the cell right on its own on its own right because there is much higher concentrations in the cell than outside right but if you block those channels potassium will not leak out the cell will depolarize it's gonna open up voltage gated channels like the voltage gated calcium channel calcium is gonna rush in and in those secretory vesicles are gonna release a insulin okay they're gonna release insulin so if you think about this anything if you understand the insulin is released it should then make logical sense to you that anything that increases the amount of intracellular calcium should also increase the release of insulin right in fact if you think about it if you've learned about your G protein coupled receptors you probably know that there are three major types of G protein coupled receptors tested on the USM Ls there's the G-OXS you know the stimulatory G protein coupled receptors like you know like your beta one beta two there's your GI there you're in inhibitory G protein coupled receptors you know like your alpha-tore receptors and then there's your GQ G protein coupled receptor so the one we're gonna focus on today is the GQ G protein coupled receptor how does this work basically the way this works is that forceful IPC is gonna clip something on us PIP2 I think it's called like forceful inocitor 4, 5 this force feet it's gonna clip PIP2 into IP3 that's inocitor try force feet and that that means that is so glycerol right IP3 is gonna go to the endoplasmic reticulum it's gonna cause the release of calcium into the cytosol right and obviously think about it if you release calcium into the cytosol basically there's more calcium in the cytosol that's gonna trigger insulin release so if you understand this then it should pretty much help you understand h

ow the parasympathetic system causes insulin release the parasympathetic system actually in that rest and digest phase actually causes a release of insulin well if you think about it there are two key most chrysanctors I mean they're many but if you think of the M1 and the M3 most chrysanctors those are GQ G protein coupled receptors so because they are GQ G protein coupled receptors they do this PIP2 IP3 release more calcium from the endoplasmic reticulum business right so because they cause more intracellular calcium to accumulate it actually makes sense that they're gonna increase your release of insulin gonna increase your release of insulin and then honestly if you want to throw in another integration here you know many people memorize that oh phyazides cause hyperglycemia phyazides cause hyperglycemia hyperglycine with phyazides many people have memorized that stuff well how do you think phyazides caused many of those problems remember this potassium channel I just mentioned the thing is phyazides love to open potassium channels gonna say that again phyazides love to open potassium channels so think about it if you're a potassium channel opener hmm what potassium channel have we talked about already today G we've talked about the potassium channels in the in the beta cells of the eyelets of longer hands right if you open up those potassium channels more potassium will leak off from the intracellular environment of the pancreatic beta cells if more potassium leaks out then those cells are not gonna depolarize if those cells don't depolarize voltage-gated calcium channels will not open if calcium does not enter then you will not release insulin so phyazides since the open potassium channels they actually lower your release of insulin they actually lower your release of insulin if you lower your release of insulin are you gonna be able to deal with your blood gluco

se problem no you're gonna have hyperglycemia if you lower your release of insulin are you gonna be able to store fat within a depo site no so those fats will literally stay in your bloodstream will literally stay in your bloodstream you're gonna get hyper lipidemia that's the reason that's one pathophase behind why phyazides diuretics cause hyperglycemia and cause hyper lipidemia okay now one other thing i want to say about the release of insulin or the secretion of insulin is that insulin is not released at a continuous high level it is not it is not released at a continuous high level it's actually released in an oscillatory fashion so you release high amounts then low amounts and then back to high and then back to low why is this important to understand the thing is if you released insulin at a continuously high level that will actually cause a down regulation of the insulin receptor again remember i've mentioned this concept already that oh the more you get exposed to something you love the more heat you begin to build up for that thing you love right so if insulin is released at a continuously high level that's actually gonna cause a down regulation of the insulin receptor and by the way the insulin receptor is a tyrosine kinase receptor i'll talk about that later right but the thing is if insulin receptors are down regulated that will reduce your response to insulin if you don't have insulin receptors around to respond to insulin they're gonna start having some kind of insulin resistance so think about it can you see how insulin resistance can develop in a type 2 diabetic because think about it people that have type 2 diabetes they have you know the their bodies are almost like they always have high blood glucose high blood glucose high blood glucose so guess what over time the pancreatic bittersomes are gonna just be releasing high amounts of insulin high amou

nts of insulin high amounts of insulin but those high amounts of insulin that are being released all the time it's gonna cause a down regulation of insulin receptors if you have a down regulation of insulin receptors then you're not gonna be getting that insulin effect so you're gonna have a worsening and a worsening of your hyperglycemia and the more hyperglycemia you have the more glucose enters through those blue two transporters into the pancreatic beta-ilate cells and the more insulin you make and then the more insulin you make the more down regulation of those insulin receptors you'll have so it's almost like you have this self-fulfilling prophecy that keeps making the condition worse and worse and worse and worse and worse right in fact let me tell you this there's a reason why insulin dosing in diabetics is done in interval four you don't see a diabetic taking insulin all the day long no if they did that their insulin receptors in their bodies will be down regulated and it's gonna be a huge huge huge problem for them so insulin dosing in diabetics is actually doing an interval you'll basically get like you know you have this insulin take with meals and then you have this long-gatin insulin that gives you like a basal low level all throughout the day right so it's actually pretty so the the thing is again many things in life or many things in medicine who just memorized but many times there's actually a reason behind the stuff that is that is done okay so now that we've talked about you know insulin release let's talk about the things that stimulate the release of insulin right so again as I've said already if you have high blood glucose that's gonna cause you to release more insulin if obviously right make sense to help your lower your blood glucose levels better too if you stimulate better to receptors that's actually gonna cause you to release more insulin a

nd then certain amino acids like leucine and arginine actually cause you to release more insulin and then there are things known as in creatins right so like GLP1 and GIP right you know glucose like you know GLP1 is one and then GIP like glucose I think derived insulin or tropic peptide or or something like that but just remember GLP1 GIP gain creatins they actually things released in the GI tract that actually help you make more insulin right so if you've heard of the GLP1 agonists those are diabetics drugs right so things like exenatide or lyraglutide those things actually cause you to release more endogenous insulin right so if you're taking exenatide or lyraglutide it should make sense that your insulin levels and your CP peptide levels should be elevated why am I saying all of this I'm saying all of this because many people just say uh the only drugs that can raise my insulin and CP peptide are the sulfonial ureas no the other drugs that do that like your GLP1 agonists also do that and then there these drugs known as the meglit mines so drugs like repaglinite or not taglinite they pretty much work like sulfonial ureas they are just shorter acting right all those things are going to raise your levels of insulin and CP peptide those those things are going to raise your levels of insulin and CP peptide right again you have to be living under a rock it's not a fred of ozempic right it's a GLP1 agonist right you know many people using these days for a week loss actually I think it's been approved by the FDA before for a week loss but again just something you want to keep at that in the back of the line now what are some things that inhibit insulin release well if your blood glucose is low that's going to inhibit insulin release we've talked about that if you actually stimulate the alpha two receptor so if you take an alpha two agonist like clonidine for example that's

actually going to lower your production of all of uh insulin okay now let's talk about the insulin receptor in a little more detail again this is one of those things that you may see there's an off-handed question on step three or you may show up as a pretty detailed question on step one right so the insulin receptor is a tyrosine kinase receptor right basically when insulin binds to this receptor the the tyrosine kinase portion of it is going to auto-phosphorylate and as it auto-phosphorylates is then be going to begin to phosphorylate things in the cell known as insulin receptor substrates right it's a tyrosine kinase kinases at phosphates to things okay it's going to begin to phosphorylate things in the cell known as insulin receptor substrates right and as you phosphorylate easily receptor substrates we're going to start seeing effects of insulin okay but I want to make something abundantly clear in your mind please like this thing I'm about to say burn this into your brain for as long as you humanly can so insulin it's initial actions involve phosphorylation right through this tyrosine kinase receptor right it's it's a little receptor that activity tyrosine kinases right it's going to up for sphinct to things but the true downstream effect of insulin is de-phosphorylation gonna say this again the true downstream like final final effects of insulin is de-phosphorylation right the tyrosine kinase receptor does all its auto-phosphorylation and everything but the true down down down down downstream effects of insulin is de-phosphorylation I promise you if you understand this fact a lot of the regulation in biochemistry and metabolic pathways that people memorize you absolutely don't need to do any of those memorizations please burn this into your brain and it will make your life profoundly simple insulin is a de-phosphoryliter insulin activates things by de-phosphor

ylid in them gonna say that again insulin insulin activates things by de-phosphorylate then you're gonna see me make a few integrations with this as we slowly begin to come to the end of this of the spot cast right now one other offhanded factoid I want to throw in there with the insulin receptor is that you know insulin has many tasks right what two tasks have like a particular signaling cascade that you need to know for your USM Ls and that's glycogean synthesis and glute 4 insertion into the membranes of like your your adipo sites are your skeletal muscle that's actually done by the PI3 kinase pathway by the PI3 kinase pathway when insulin you know activates this PI3 kinase pathway it's gonna cause you to put more glute 4 transporters on the surfaces of adipo sites and skeletal muscle cells and also again it's gonna cause you to activate glycogean synthesis right so let's maybe go ahead and summarize this what are the critical functions of insulin well insulin induces glucocainase in the in the lever right glucocainase is gonna convert glucose to glucose 6 phosphate in the lever right and also in the pancreatic beta cells but that glucose 6 phosphate can then go down many pathways in glycogean synthesis right insulin activates PFK2 PFK2 is something that makes and a product known as fructose 26bis phosphate fructose 26bis phosphate is a very powerful activator of PFK1 PFK1 is the rate limiting enzyme of glycolysis I'm gonna say that again PFK1 is the rate limiting enzyme of glycolysis okay is the rate limiting enzyme of glycolysis PFK1 is the rate limiting enzyme of glycolysis PFK1 can be activated by fructose 26bis phosphate fructose 26bis phosphate is made by PFK2 insulin activates PFK2 so let me ask you this PFK2 the active form will it be an enzyme that is phosphorylated one enzyme that is defaults for related well I would hope you're telling me that oh divine the

active form of PFK2 is the defaults for related form again insulin wants you glycolysis to run insulin is a glycolysis activator okay insulin is a glycolysis activator so insulin activates PFK2 I said that insulin is a defaults for a leader that's his downstream effect so that means the defaults for related form of PFK2 has to be the active form and if PFK2 is active you'll make more fructose 26bis phosphate if you make more fructose 26bis phosphate you're gonna activate PFK1 if you activate PFK1 you're gonna make more you're gonna upregulate glycolysis right so again if defaults for related and activate PFK2 right which we use to make fructose 26bis phosphate which is a stimulator of PFK1 which is the real limiting enzyme of glycolysis right and then insulin also defaults for related and activates pyrovid dehydrogenase right remember the pyrovid dehydrogenase complex deals with the pyrovid that comes from glycolysis and then insulin also activates acetylquic carboxylis inactivites acetylquic carboxylis and that's actually the real limiting enzyme of fatty acid synthesis and then insulin induces the genetic expression of fatty acid synthase or fatty acid synthase which again is helpful in the synthesis of fatty acids and triglycerides right and then again as I've said many times insulin opereglides blew forth targeting to the membranes of your depo sites and skeletal muscle cells so those kinds of cells can take up a blood glucose right and then insulin also activates glycojin synthase it defaults for related glycojin synthase right and when you defaults for related glycojin synthase it's going to make glycojin synthase active so you can make glycojin I promise you like many people they spend hours and hours and hours and hours and hours memorizing a lot of regulation in biochemistry but you won't have to do any of those things if they just remember two simple rules

insulin is a defaults for related blocagon is a false for related I'm going to say that again insulin is a defaults for related blocagon is a false for related I'm going to say that again insulin is a defaults for related blocagon is a false for related so that means that if you're dealing with a process that involves insulin and they are enzymes in that process that need to be active for that process to work and insulin regulates those enzymes you automatically can know that the defaults for related forms of those enzymes are the active forms but if a process like like policies for example or gluconeogenesis for example we know that those processes activated by glucagon and we know that glucagon is a false for a leader so since glucagon is a false for a leader that tells you that oh the active form of those enzymes that are involved in those pathways that glucagon promotes have to be the false for related forms of those enzymes okay now what are a few more higher things that insulin does well insulin does things like activating cholesterol synthesis right it shots down like policies right insulin wants you to make triglycerides not break them down right insulin also shots down glycogen or lysis right because again you don't want to be breaking down the glycogen you've just made right and insulin also inhibits auto-phaging auto-phaging auto-phaging is actually a process that helps you remove and degrade poorly functioning cells basically like garbage in your body can be degraded and safely got rid of by auto-phaging right insulin inhibits auto-phaging right so this can actually kind of tell you why fasting can be very beneficial fast and suppresses insulin production because think about it if you're a fast and you're in a low blood glucose state if you're in a low blood glucose state then you're not gonna be making insulin if you're not making insulin then auto-phagin

g will not be suppressed that's why you see some people the fast and then they kind of start getting healed from like weird stuff because auto-phaging is being operated but that's a deeper discussion I don't that's not appropriate for this for this podcast and then another thing that insulin does is that it activates the sodium potassium ATP spot it activates the sodium potassium ATP spot right so you can actually use insulin to acutely lower persons blood potassium levels right so if a person has like hyperkalemia and they're very symptomatic right remember many times you're gonna see like topic t waves you're gonna see a yqrs first thing you're gonna do is give calcium gluconectus stabilize the myocardial right but after doing that one thing you can actually give that's helpful is insulin in giving insulin because insulin is gonna operate a person's the activity of the sodium potassium ATP spot and as I've said already in this podcast that pump brings three sodium out of the cell and puts two potassium into the cell as you put those potassium into the cell you're basically redistributing potassium so the person's blood potassium levels will go will go down although many times when you're giving that insulin you're gonna give glucose as well because that insulin you're giving the person is tanking their glucose you know what I mean to go into a hypoglycemic crisis and dying addition to the hyperkalemia okay um so what are the organs that help us get rid of insulin well insulin um can be degraded and cleared by the liver and by the and by the kidneys right and the high old factoid to know about insulin is that insulin um when insulin is very high it actually uh message of surfactant synthesis actually message of surfactant synthesis um so if you're an infant of a diabetic mom you can see why infants of diabetic moms are prone to respiratory distress syndrome because t

hink about if you're an infant of a diabetic mom your mom has a ton of diabetes right well or has diabetes right your mom has high blood glucose levels well through the placenta the phytosis also gonna be seen those high blood glucose levels so the phytobita eyelights cells we're gonna make a ton of insulin to deal with that high blood glucose right that ton of insulin that we see in these in the phytoblot stream it's gonna suppress surfactant synthesis in that phytosis right so when that phytosis is born that phytosis may not have enough surfactant right that's why being an infant of a diabetic mom has a stronger cessation on respiratory distress syndrome okay has a stronger serum respiratory distress syndrome and they remember that you know insulin resistance is not just in type 2 diabetes it's something you also find a lot in in PC OS and then the final thing I'm gonna say about insulin promise that I'm done uh make sure you know the types of insulin or there are many types of insulin there's the rapid active insulin like a lispro um aspart and gluelysin lispro aspart and gluelysin right these are the ones you take with meals and then there's the intermediate insulin you know MPH I think MPH means like neutral predominant hargadon or something like that but basically it's the one that you have to dose twice a day it's just a cheaper form of insulin the thing is ideally you want to be using these rapid active insulin I just mentioned and the long active insulin you take once a day right like glargene I think glargene is the one that's called lanthos if I'm not mistaken but you know glargene uh demer and degludec those are the long active insulin right so in general a diabetics regimen you want a long active insulin you take once a day and these rapid ins active insulin you take with meals so you want to be taking like glargene demer or degludec like once a day and t

hen lispro aspart of gluelysin with your meals but you know these glargene demer degludec they're very expensive so sometimes some people that good middle ground is you know what I'll be taking these rapid active insulin with meals but I'll be taking MPH this intermediate active insulin twice a day okay so I'm gonna stop here again I know this is one of probably the longest podcasts I've made um but I promise you this probably one of the highest your podcasts I've made um there's definitely some key nuggets here for puttikin step two and step three but for people taking step one pretty much everything I've said in this podcast you need to know I'm gonna say that again if you're taking step one pretty much everything I've said in this podcast you need to know um so I'm gonna go ahead and stop here again I'll for one one to learn for step one to step three and I have a bunch of review classes coming up so I have a test taking strategies class actually this evening um all these classes over zoom the testing in strategies classes for the usml exams is for step one all the winners step three it's two and a half hours long and then I have a bio stats class tomorrow also for step one to step three uh that one is a four hour class uh the usml is these these the test bio stats but most of the bio stats uh uh topics um many times these days they don't make you do any math on you exams it's more reasoning right so if you want to get that reasoning down because maybe we just memorize the formulas and then you notice that man I'm still struggling bio stats questions well you know the formulas but you don't have understanding if you want to truly deeply understand bio stats the four hour class is exactly what you need and then on Saturday uh it's a five hour class also for step one to step three I have a class that covers ethics quality improvement social sciences health care syste

ms communications professionalism and things things like that basically these things make up about 10 to 15 percent of all the usml exams these days so um if you want to attend those uh reach out to me and these classes are not lectures if you expect to lectures please don't come uh these classes are pretty much almost entirely all scenarios because those are things that are more attuned to how the usml presents itself and then next week from Monday to Saturday have a 25 hour step one class and then the week after that I have a 20 hour step two and step three class so if you're interested in any of these classes they are all gonna take place over zoom shipping and email and I'll give you some more information and also help with the ERAS process you know rec letters personal statements ERAS apps supplemental apps mock interviews and then I have these podcasts on the major apps Apple Google and Spotify have a You Tube channel divine intervention you have some media podcasts and videos and that's where I post the videos that I make and then finally I have uh another website called divine intervention life lessons.com um actually you know many people said man divine I love the life lessons you put at the end of your of your podcasts um and so I'd say to make another website divine intervention life lessons.com there's actually an Apple podcast associated with it called the divine intervention life lessons podcast and every week I post like two podcasts that address a life lesson from a biblical perspective actually have more than 200 podcasts on them actually I want to share a quick life lesson today and I just want to share the importance of running your race in life without distractions um I just want to think of it like this if you're a distracted driver your risk of getting to an accident is extremely high right if you are a distracted driver your risk of getting to an

accident is extremely high is very very very high right if you're like texting or doing whatever as you're driving you're probably going to end your journey prematurely right so that's the thing like many people go through life being very distracted they don't focus on the road ahead of them they don't focus on the core things they're supposed to do with your lives they're just distracted by all these things that don't really matter for their long-term destinies and then they wonder why they're not making any headway or they wonder they seem to keep falling into a failure of the other right so I'm just encouraging you to think this is actually a huge huge huge problem amongst many people in medicine very very distracted you see sometimes patients stay in the hospital for much longer than they need to because the physicians and the medical students taking care of them the residents taking care of them are very distracted right so the thing is when you come to work you're there to work you're not there to chat chat chat chat and watch watch watch watch watch stuff on social media right you can do those things there's nothing wrong with that but do it after the job has been done right just have a target have a focus you see many people I kind of noticed this quite a bit at least during my pre- my pre-linear you see a lot of people their shift ends at three and you're leaving at five because they're just soaked by work so by where they're like man I have so much work on my plate but check those people's lives and they were just while in a way time the whole day literally they were while in a way time the whole day right so just be a person that works with focus you'll think yourself for it that you end up having more time to do the things you truly love okay so I'll see you in episode 483 have a wonderful rest of your day God bless you bye for now thank you

It is a peptide hormone.

Insulin is made by beta cells (central) and glucagon is made by alpha cells (periphery) within the Islets of Langerhans.

It promotes the uptake of glucose into muscle, adipocytes, and liver cells, facilitating storage (anabolic).

Phosphofructokinase 1 ($\text{PFK}1$).

Closure of the $\text{K}_{\text{ATP}}$ channels (potassium leak).

Sulfonylureas or GLP-1 agonists (e.g., exenatide, liraglutide).

Exogenous insulin does not contain C-peptide; therefore, high levels of insulin from an external source will result in low/undetectable C-peptide.

PDX1 (Pancreatic and Duodenal Homeobox 1).

The disulfide bond.

C-peptide (Connecting Peptide).

PI3 K pathway (leading to GLUT4 translocation) and Glycogen synthesis.

Tyrosine Kinase Receptor; it auto-phosphorylates upon binding.

It inhibits glycogenolysis (breakdown of stored glycogen) and gluconeogenesis.

Infant of Diabetic Mother; leads to suppressed surfactant synthesis due to high fetal insulin levels.

PDX1 (Pancreatic and Duodenal Homeobox 1).

The disulfide bond.

C-peptide (Connecting Peptide).

PI3 K pathway (leading to GLUT4 translocation) and Glycogen synthesis.

Tyrosine Kinase Receptor; it auto-phosphorylates upon binding.

It inhibits glycogenolysis (breakdown of stored glycogen) and gluconeogenesis.

Infant of Diabetic Mother; leads to suppressed surfactant synthesis due to high fetal insulin levels.