63: The Randle Cycle - How Your Body Chooses Between Glucose and Fat with Dr. Ben Bikman

Summary

In this engaging lecture, Professor Ben Bikman delves into the Randle cycle, also known as the glucose-fatty acid cycle, explaining how the body chooses between burning glucose or fat for fuel. He highlights that while some discussions around the topic have been misrepresented, it's a valuable concept for understanding metabolism. Drawing from historic research and his expertise, Bikman explains the biochemical pathways involved and stresses the significant role hormones, especially insulin, play in this metabolic process. The lecture also covers real-world applications, such as their implications on diabetes.

Highlights

• Dr. Ben Bikman introduces the Randle cycle, detailing its history and core concepts. 🧬
• The lecture explains the metabolic pathways that regulate fuel choice at the cellular level. 🔬
• Insulin's role is pivotal in dictating whether the body burns glucose or fats. 🚦
• Real-world examples, especially from diabetes, showcase the cycle's practical applications. 🌍
• Bikman encourages viewing metabolism with a holistic approach for better health decisions. 🌿

Key Takeaways

• The Randle cycle illustrates how cells choose between burning glucose or fats based on their availability. 🔄
• Insulin plays a crucial role in regulating this choice, prioritizing glucose if levels are high. ⚖️
• Diabetes scenarios highlight metabolic flexibility, emphasizing the cycle's role in energy management. 🔍
• Understanding the cycle can lead to better nutritional and lifestyle decisions. 🍏
• Biochemistry may seem daunting, but grasping these fundamentals is vital for health insights. 🧠

Overview

In this lecture, Dr. Ben Bikman explores the fascinating concept of the Randle cycle, or glucose-fatty acid cycle, a principle explaining the body's preference for burning either fats or glucose based on availability. Despite its complexity, Bikman emphasizes its practicality in helping understand metabolic processes and nutritional decisions.

Bikman carefully explains the biochemical processes behind the Randle cycle, illustrating how cells switch between glucose and fat burning. He details how fatty acids can suppress glucose usage and vice versa, highlighting reciprocal inhibition as a key facet of this cycle. The lecture further discusses the critical hormonal role insulin plays in dictating which energy source the body utilizes.

Real-life examples, such as those involving diabetes, demonstrate the cycle's applicability. Type 1 and Type 2 diabetes highlight how insulin impacts fuel selection, revealing the metabolic inflexibility often seen in diabetic conditions. Through rich examples, Bikman underscores the Randle cycle's importance in understanding both energy metabolism and diet effects, encouraging more thoughtful nutritional and lifestyle choices.

Chapters

• 00:00 - 00:30: Introduction to the Metabolic Classroom In the Introduction to the Metabolic Classroom, Professor Ben, a biomedical scientist and professor of Cell Biology, welcomes students to the lecture. He introduces the concept of the Randall cycle, also known as the glucose fatty acid cycle, and explains its significance in metabolic studies. The discussion includes the naming convention of scientific discoveries and the importance of understanding metabolic pathways.
• 00:30 - 01:00: Randall Cycle and its Misrepresentation The chapter discusses the concept of the Randall Cycle, which has been misrepresented on social media. It has value in understanding metabolism and may influence better nutrition habits.
• 01:00 - 01:30: Historical Background of the Randall Cycle This chapter provides a historical background on the Randall Cycle, also known as the glucose-fatty acid cycle. It highlights Philip Randall's crucial role in identifying the cycle with his colleagues at Cambridge in the mid-1960s. The summary mentions seminal papers published by Dr. Randall and colleagues, contributing significantly to our understanding of metabolic functions within the body.
• 01:30 - 02:30: Experimental Model and Fatty Acid Metabolism The chapter delves into understanding fuel utilization in the heart, highlighting that while the heart's metabolism is unique, the experimental model used, which focuses on heart tissue, has its limitations. Despite these limitations, the ideas discussed are considered valuable. The emphasis is on appreciating the experimental model used, specifically hearts, and understanding its implications on fatty acid metabolism.
• 02:30 - 04:00: Understanding the Randall Cycle Concept The chapter 'Understanding the Randall Cycle Concept' explores an experiment involving a rat's heart that is surgically removed but kept alive and nourished. This heart is infused with nutrients, specifically glucose and fatty acids, to study metabolism and substrate usage. The chapter highlights the importance of understanding terms like 'fatty acid' in metabolic processes.
• 04:00 - 06:00: The Process of Fatty Acid Oxidation This chapter provides an overview of fatty acid oxidation, emphasizing the role of fatty acids as energy substrates. It discusses the mechanisms through which tissues utilize fatty acids, either by directly taking up free fatty acids released from adipose tissue or by extracting fatty acids from triglycerides present in the bloodstream. The presence of triglyceride-rich lipoproteins such as LDL plays a significant role in this energy extraction process.
• 06:00 - 07:30: Glucose Utilization and Its Inhibition of Fat Burning The chapter discusses the role of glucose utilization and its impact on fat metabolism. It explains the relationship between triglycerides and lipoproteins such as LDL and VLDL, highlighting that triglycerides are not free molecules like free fatty acids. The experimental models discussed involve infusing free fatty acids, similar to the methods used in the author's experiments, to study fat metabolism. It concludes that in the body, metabolized fats could originate from free fatty acids released from fat tissue.
• 07:30 - 10:00: The Role of Insulin in Energy Utilization The chapter titled 'The Role of Insulin in Energy Utilization' delves into the complicated processes of fat metabolism, specifically focusing on lipolysis. It discusses how fat cells break down their own fat and the actions of lipase enzymes in this process. The chapter also touches upon how triglyceride molecules in lipoproteins like LDL and VLDL are involved. The narrator warns that the complexity of the topic is a recurring theme in the lecture, hinting at a deeper exploration of biochemical pathways related to insulin's role in energy utilization.
• 10:00 - 13:00: Types and Implication of Diabetes The chapter begins by mentioning the growing general interest in diabetes, particularly in metabolic research and science. The discussion introduces the Randall cycle, a concept related to metabolism, hinting at the chapter's focus on biochemical understanding. Although the transcript is incomplete, it seems to set up a framework for exploring how different biochemical pathways and processes relate to diabetes and its implications. The chapter likely delves into metabolic substrates and the intricate balance involved in conditions related to diabetes.
• 13:00 - 16:30: Insulin Resistance and Metabolic Inflexibility The chapter discusses the concept of fuel competition in cells, focusing on how cells choose between fats and glucose for energy. Although fats and glucose are the primary energy sources, other fuels like ketones also play a role.
• 16:30 - 20:00: Brain Fuel Choices and Hunger In the chapter titled 'Brain Fuel Choices and Hunger,' the primary focus is on the various energy sources available to cells, with an emphasis on fats and glucose as the main providers of energy. The chapter makes a note to mention ketones and lactate as additional energy sources, though lactate is earmarked for a more in-depth discussion at another time. The Randall cycle is introduced as a key concept to elucidate the phenomenon of cellular energy choices.
• 20:00 - 22:00: Conclusion: The Importance of Insulin The section discusses cellular metabolism and how cells utilize different fuel sources. It explains that if a cell has more fats available, it will primarily use fats as its fuel source, but if there is more glucose available, the cell will favor glucose. The chapter emphasizes the importance of insulin in regulating this metabolic shift, underscoring its role in determining whether cells use glucose or fats as their primary energy source.

63: The Randle Cycle - How Your Body Chooses Between Glucose and Fat with Dr. Ben Bikman Transcription

• 00:00 - 00:30 welcome to the metabolic classroom I'm Professor Ben bman biomedical scientist and professor of Cell Biology thanks for joining me in the lecture today we are discussing the concept known as the Randall cycle now anytime you hear a name of something it's named after the person who discovered it or discussed it most thoroughly perhaps is the better word here it's also known as the glucose fatty acid cycle the reason I'm devoting time to talk about this in a metabolic
• 00:30 - 01:00 classroom is because it's something that's been used uh it's been invoked I cons I think somewhat inappropriately or incorrectly in certain social media channels and so but it is a it's an interesting idea it's one that I think has value in helping us understand metabolism a little better and of course hopefully there's some nugget in there that can influence habits to help us to help you all of us make better decisions when it comes to nutrition
• 01:00 - 01:30 and again ultimately just getting a better understanding of how our body works and the metabolic function within it now I'd already mentioned the alternative name the glucose fatty acid cycle named after Philip Randall who first really identified this with his colleagues um this was decades ago in the mid-60s um at Cambridge and Dr Randall and colleagues when they published some of these papers and I'll have a link to some really highlighting some of their seminal work in the show notes um what they wanted to
• 01:30 - 02:00 do was understand fuel utilization in the heart so it's important to note that that was the model for their experiments uh and and there may be limitations to this because heart is a unique tissue uh there aren't a lot of tissues that operate metabolically like the heart does now having said that I don't mean I don't mean to cast shade on the idea on any of the ideas that we're going to discuss I believe they have value but we need to appreciate the model um which again was per used Hearts
• 02:00 - 02:30 from rats so a a heart would be uh surgically removed from the rat and it would be kept alive and beating so nourished properly nourished and then infused with through the blood system with nutrients of course glucose and fatty acids and then analyzing the metabolism of these substrates or what's being used now already I've made I've mentioned a word a couple times you need to understand which is fatty acid we all
• 02:30 - 03:00 know what glucose is fatty acid is what is used for energy however that tissue is pulling it in whether it's pulling it in as a direct free fatty acid which always is coming from fat tissue and that becomes an important point that we're going to highlight in this lecture or whether it's a fatty acid that is pulled off of a triglyceride that is circulating on the blood as it is lumped into a triglyceride Rich lipoprotein like LDL
• 03:00 - 03:30 cholesterol or vldl anytime you get a blood test and it's giving you a triglycerides number the triglycerides are just a part of LDL or vldl they're not free circulating molecules like free fatty acids are so regardless in the experimental model they're infusing free fatty acids which is something I've used in my own experiments um but in the body just appreciate the fact that those fats that are getting metabolized could be coming from either free fatty acids which are coming from the fat tissue the
• 03:30 - 04:00 fat cells breaking down their own fat namely lipolysis or it's coming from the actions of lipase which is pulling off a fatty acid from a passing triglyceride molecule which itself is in a lipoprotein like LDL or vldl boy that's a heck of a start isn't it I'm already getting pretty complicated and that is for better or worse a bit of a theme of today's lecture this is admittedly for a little bit it's focused a little more for kind
• 04:00 - 04:30 of biochem nerds and I wouldn't have discussed this if I didn't think there was a growing general interest in the topic it's very likely by now if you've been swimming in the waters of even kind of social media Metabolic Research or metabolic science you've heard the term Randall cycle all right now all of this has been sort of a history and a teeing up of the topic at this point you might not really even know what it is in general the concept is simply one to explain this substrate
• 04:30 - 05:00 competition in other words how do we understand what which fuel a cell is relying on with the primary fuels at most cells being the cell choosing between using fats for fuel or glucose for fuel now if we were being really really thorough we could include other fuels there are more than just fats and glucose that provide energy to a cell we could talk about ketones I will actually
• 05:00 - 05:30 bring up ketones at the end if I follow my unscripted notes a little bit here um and even lactate which is really a topic for another time lactate is a very viable fuel for many cells so there are a lot of other energy sources that we could highlight I'm focusing on the main ones the ones that provide the vast majority of energy to a cell and most cells namely fats and glucose so again the Randall cycle is this concept to explain this phenomen phon of of energy
• 05:30 - 06:00 use at a cell or bioenergetics where you can't the cell isn't going to use both if the cell has access if there's more fats available to the cell than glucose no surprise it shifts its metabolic function to rely on fats as a primary fuel source if there's more glucose available than fats no surprise the cell will shift its um metabolic processes to rely more heavily on the glucose as the primary fuel now let let's get into this in just a little
• 06:00 - 06:30 more detail that definition would be sufficient for just a lay understanding you now know what the Randall cycle essentially is or the glucose fatty acid cycle it is this competition between substrate or energy sources at the level of a cell this kind of battling between glucose and fats now how does it happen for those who don't want the kind of biochemistry mechanism by all means just sort of skip ahead for the next five minutes or so or speed it up um but it is pretty brief and I'm going to just
• 06:30 - 07:00 touch it at a pretty high level now this is a reciprocal inhibition so if there's more fats it's demanding its own burning and it's generally shutting down the glucose burning if there's more glucose then it's demanding that it gets burned and it's shutting down the fatty acid oxidation or the fat burning so it can go both ways and so without any particular order in mind let's just discuss it first and foremost from the side of the fat getting burned and why
• 07:00 - 07:30 not start with that because that's the fuel that most of us would prefer to be burning for the sake of just maintaining body weight after all good luck controlling your body fat if you're not burning fat okay so first and foremost fatty acid oxidation inhibits glucose utilization so when there are is when there is an increased number of free fatty acids in the bloodstream it will increase the uptake so the the uptake of free fatty acids will be increased no
• 07:30 - 08:00 surprise into the cell and as the fatty acids are coming into the cell the story is not over yet it sort of gets activated and it turns into a fatty acid it get bound to another molecule that kind of locks it in the cell because the fat so readily comes in the fat could readily go out so once it comes in there is some immediate biochemistry that locks the fat within the cell and then it starts to commit to the pathway of what's called beta oxidation now the term
• 08:00 - 08:30 oxidation itself is really loaded and sometimes used inappropriately when I'm referring to oxidation I mean that the fat is getting burned for energy sometimes people refer to oxidation as a fat turning into a harmful molecule to be a little more precise that accurate the word should be peroxidation when we refer to fats becoming these uh molecules of oxidative damage that should technically be called
• 08:30 - 09:00 peroxidation any just as an aside so when I'm saying oxidation for the purpose of this lecture I'm talking about the molecule getting broken down for the sake of producing energy or ATP now again back to the fat with if the fatty acid is getting burned it's going through beta oxidation as a result of this it's producing two important molecules acetal COA and nadh both of these molecules acetyl COA and nadh will inhibit a very critical
• 09:00 - 09:30 enzyme in glucose burning so at the end of normal glycolysis this is really deep stuff so hopefully I'm discussing it in a way that you can understand and if my goals are met even share it with someone else it's always my my hopeful outcome um so at the end of glycolysis at the end of glucose burning right when the glucose wants to go into the mitochondria it uses this complex enzyme called pyrovate dehydrogenase pdh
• 09:30 - 10:00 pyrovate dehydrogenase so normal glycolysis or glucose burning gets down to pyate and then if the glucose burning is going to continue and go into the mitochondria it has to go through this iovate dehydrogenase complex again when you're burning a lot of fat you're creating a lot of acetal COA and a lot of nadh and the nadh is particularly important for the electron transport chain or system I call it um which we're
• 10:00 - 10:30 not going to talk about that's entirely too complicated and not overly relevant to this lecture again you're burning a lot of fat you're producing a lot of acetyl COA and a lot of nadh and those start to both together inhibit pyate dehydrogenase pdh when pyate dehydrogenase is inhibited now fats uh now glucose can't be fully kind of broken down even still that's the last step of normal glycolysis before the
• 10:30 - 11:00 glucose burning goes into the mitochondria also when you have a lot of fat burning you start to create a lot of what's called citrate a molecule called citrate within the mitochondria citrate then can come out of the mitochondria and inhibit an enzyme further up on glycolysis on that glucose burning pathway so we now have two points of attack where when you're burning a lot of fat you are inhibiting one of the steps at towards the end of glycolysis and then another step in the
• 11:00 - 11:30 middle of glycolysis so it's some of these products so when you're burning a lot of fat you're making various metabolites or metabolic byproducts then these byproducts not while being part of an essential part of fat burning and ultimately getting energy from fat they also end up having this influence to tell the cell hey you're burning me right now stop burning glucose now you know where that's happening it's happening at PD and the other enzyme that was a little further up kind of at the midpoint of glycolysis
• 11:30 - 12:00 in fact it's a critical regulating enzyme which is what just it's a long name it's pfk1 pfk1 gets inhibited as well so that's how you could discuss it if you want to sort of talk about this in um in in various circles because you're really bored and you want to impress someone with your knowledge of metabolism that's how you could discuss it uh this part of it at least remember we've only covered one part of this kind of reciprocal inhibition namely how fats inhibit
• 12:00 - 12:30 glucose burning and when you have a lot of acetyl COA and nadh and citrate which you do all three of those will start to accumulate as you are burning a lot of fat for some extended time they will start to inhibit pretty quickly actually despite what I said I said for some period of time I it's pretty quick if as those molecules start going up they will inhibit the cell's ability to use glucose now as I said it's reciprocal meaning this is this thing can go two ways it's not just fats that are kind of
• 12:30 - 13:00 beating down glucose with a club now glucose can too sometimes glucose holds the club and and it's the one in charge so now let's sort of flip this coin and talk about how glucose utilization can inhibit fatty acid oxidation so when we have high levels of glucose it will increase glycolysis and increase pyrovate when we continue with this increased glycolysis will end up resulting in the increase of another COA
• 13:00 - 13:30 molecule this time not acetal COA but a molecule called malinal COA now there's still the COA that they have in common but they're different molecules in fact malinal COA is made from acetal COA so when you continue to burn a lot of glucose you start getting more and more malinal COA and then malinal COA actually goes right to the mitochondria and shuts down the enzymes an enzyme complex called cpt1 which is necessary for the mitochondria to pull
• 13:30 - 14:00 fats in so fats need to be burned in the mitochondria whereas glucose have both an external mitochondrial burning and an internal mitochondrial burning and pdh is the kind of intermediate that pyv dehydrogenase complex that I mentioned earlier that's how the glucose progresses from burning outside the mitochondria and finishes all of its burning in Mal uh cpt1 is how the fats get burned at all there's no if you can't get a fat into the MIT Andria it's not burning and so when when you have a
• 14:00 - 14:30 lot of glycolysis you start producing a lot of malinal COA and then malal COA shuts down that entrance enzyme so now the fats can't get into the mitochondria to be burned and that's it that's the one point really of Regulation so it's a little more simple um than the reciprocal regulation that I outlined earlier where with fatty acid oxidation it's regulating glucose burning at a couple different points glucose burning is now inhibiting fat burning at only
• 14:30 - 15:00 that one point it's inhibiting cpt1 and it works because fats have that one singular kind of entrance there's it's not as complicated nothing happens really until it can get into the mitochondria okay now as outlined in Randall's experiments and the only thing people ever talk about is what I've just talked about I'll i'llbe it perhaps with a little less detail but the principle is still there and it's accurate the way I've heard it described in general social media circles
• 15:00 - 15:30 more fats results in less glucose burning more glucose results in less fat burning even at that superficial level it's helpful it's important even then you can start to see why I don't like the old adage of you are what you eat I prefer this more accurate adage of you burn what you eat if you're eating more glucose no surprise you're burning more glucose if you're eating more fat in the absence of glucose of course I mean then you're burning more fat and the Randle cycle kind of makes some sense of that
• 15:30 - 16:00 however it's not that simple and even Randall himself and his colleagues colleagues never suggested it was that simple so we people stop there they have done aervice um a disservice not only to anyone who's listening to them but even to Dr rall and his colleagues because they went a little further and looked at the role of hormones now before I get into that imagine a situation where both substrates are high both calorie sources are elevated imagine the situation where
• 16:00 - 16:30 the person has both high glucose levels and High free fatty acids how does the cell know what to do does it look at both and just sort of give up and say I'm helpless I can't choose between the two of you lovely substrates I don't know who to give the rose to in to burn how does it decide what happens then if both are elevated the answer is in endocrinology there is a little known hormone that
• 16:30 - 17:00 ends up telling the cell if we look at the whole body level and Dr Randall included this in his work we need to remember that if we go beyond the experimental model which in this case was isolated profused hearts and look at the whole organism or the whole body the cells aren't acting in isolation how does one cell know what's going on with the rest of the body how is a signal conveyed to it from the rest of the body it's hormones that allow different parts of the body to talk with other parts of the body can you guess which hormone
• 17:00 - 17:30 influences the use of the energy sources can you yes yes you're right of course if you're thinking that it's insulin because you know me too well you're absolutely correct even the Randall cycle in the original experiments in the mid-60s looked at insulin and found that insulin had a tremendous role on dictating which energy source was used it plays a critical role it's not the only one but it is extraordin important and I would say it's the most important so here are
• 17:30 - 18:00 some of the key parts of that and then we're going to look at some full physiological examples to really highlight the importance of this so with insulin we have the promotion of glucose utilization insulin does not want to burn fat to to put it in a in a bit of a silly way as if insulin has some desire insulin its actions um coordinate to prevent the body from burning fat it wants the body to to use glucose as a fuel it does so when it docks to its
• 18:00 - 18:30 insulin receptor on a cell all of its biochemistry at that cell is going to be well there's so much that happens insulin does so much much of it the metabolically focused aspect of insulin the nutrient focused aspect of insulin is going to promote the use of glucose now if it is tissues that need insulin for glucose uptake it will ultimately open those glucose Transporters called glute four if a tissue has glute four the glucose
• 18:30 - 19:00 transporter number four then it needs insulin generally in order to act that's tissues like muscle and fat and that matters a lot because most of what we're made of is muscle and fat for the average individual for almost everyone it's muscle except for the profoundly obese and in that case of course it's fat but even in the average individual now it's still generally muscle and fat Mass constitutes the majority of their mass and they're insulin dependent for glucose um so they need insulin in order
• 19:00 - 19:30 to open those GL those glucose transport doors the glute four doors so insulin does that directly but even in tissues that don't have glute four like the liver the liver doesn't need insulin to tell it to take in glucose but it still needs insulin to tell it what to do with the energy every single cell of the body will follow that pattern even if insulin isn't directly controlling the the direct movement of the nutrient in like
• 19:30 - 20:00 glucose it's still directly controlling what the cell does with the energy including the Randle cycle so not only is insulin stimulating the either direct uptake or the keeping of the glucose and activating other enzymes further down like pfk1 i' mentioned earlier hexokinase which is the first step of glucose locking it into the cell whether it's going to get burned or turned into glycogen in activates that too so it generally is promoting glucose
• 20:00 - 20:30 glycolysis at the same time it's inhibiting the breakdown of fat now there's two parts here of fat to talk about lipolysis which is the breakdown of fat from the fat cells to be shared and then there's the oxidation or the burning of that fat they're not the same when people say fat burning they sometimes only are actually referring to the breakdown of the fat which is more technically to be called lipolysis um so there's two steps here it's the lipolysis or the releasing of
• 20:30 - 21:00 the fat and then there's the burning of the fat which is the oxidation part that's when burning should be used most appropriately insulin inhibits both of those it inhibits lipolysis and it directly inhibits fatty acid oxidation so it doesn't want the fat to leave the fat cell and even if there is some that's left the fat cell it doesn't want the tissues like the muscle to burn the fat so insulin is absolutely critical for understanding which fuel is going to be used if insulin is high it will both
• 21:00 - 21:30 aggressively activate all of the glucose burning Pathways and aggressively inhibit any of the fat breakdown and burning Pathways in contrast if insulin is low there is a much diminished signal to burn glucose and there's nothing to stop fat breakdown and burning so now fat breakdown and burning is just going non-stop it's going uncheck there's nothing really to inhibit lipolysis other people want to
• 21:30 - 22:00 invoke other little hormones here and there and other can M others do have an influence but nothing matters if insulin is low or not there at all and we're going to get into that in just a moment we're almost there and so again just to really put a fine point on it if insulin is high the body is burning glucose and if insulin is low the body is burning fat and glucose burning is shut off this is this happens even if both are elevated insulin dictates which one
• 22:00 - 22:30 is used now with that point in mind I can I wanted to be able to give you a real physiological example of this point and diabetes is the perfect example both type one diabetes and type two of course the difference with them and there's far more different between type 1 and type two diabetes than there is similar I will state this again as I've stated it before I think it's a tragedy that they're even put in the same family the only only thing they have in common is the high the high
• 22:30 - 23:00 blood glucose everything else is profoundly different between them they shouldn't be even lumped together they're diseases of opposites they're not diseases of similarities with type 1 diabetes there's twoo little insulin with type two diabetes there's too much all right now let's talk about type one diabetes first because it provides the most extreme example here and it's a perfect scenario where both glucose is high the person is profoundly
• 23:00 - 23:30 hypoglycemic and guess what free fatty acids are also through the roof they have both they have extremely high levels of both substrates so it's the perfect sort of case study here that I um alluded to earlier how do we reconcile this and when there's no insulin which one is the body using so this diabetic body again tons of glucose tons of fatty acids the cell can't choose which one and so who helps it decide it's insulin and if insulin is
• 23:30 - 24:00 present then the cell would know okay I'm burning glucose if insulin is absent as it is in this case even though both are available both substrates glucose and fats insulin if it's absent like it is in the untreated type 1 diabetic can't stop burning fats it can't stop it's just burning fats like Gang Busters in fact it starts to burn fats so much that it can't so if you take a tissue like the liver where the liver doesn't need insulin for say glucose uptake but
• 24:00 - 24:30 again it needs insulin to tell it what to do with the energy it's burning so much fat that it starts to get to a threshold if you will and I'm describing this a bit imprecisely but I think it's helpful nonetheless normally a cell is only burning as much energy as it needs ATP the main Mo molecule of energy that the cell actually that is actually kind of energetic for the cell to use to get work done whatever the cell wants to do it's ATP that allows the cell to do it so normally this the burning of energy
• 24:30 - 25:00 is demand driven the Cell saying hey I need this much ATP and so the cell will say okay no problem I'm going to burn this much fats or glucose to give you that much ATP but if insulin is absent firstly the liver is primarily burning fat but then it can't stop burning there's nothing to really turn it off and so even so the cell again this is a little imprecise it's met all of its energetic needs where the liver is saying hey I'm I'm full I'm getting all the energy I need um so now the cell
• 25:00 - 25:30 which still can't stop burning fat starts to turn it into ketones so ketones are kind of this release valve where the liver cell is saying one I don't need any more energy but two I can't stop burning fats for energy and so three I'm going to start changing this energy into something else that other parts of the body can use ketones particularly the the the brain of course but every tissue every cell with mitochondria will gladly use ketones for fuel and of course in the case of the
• 25:30 - 26:00 diabetic this is generally trying to make up for what is perceived to be a lack of glucose even though glucose is through the roof in the absence of insulin the cell can't really use it it doesn't know what to do with it so in the untreated type 1 diabetic both glucose levels are high and fats are high there's nothing to turn off the use of fats so fats win at the same time there's nothing really to tell the cells to use the glucose because almost like the cells can't see it it needs insulin
• 26:00 - 26:30 to tell it what to do with that glucose so the cell just sort of sees the glucose and says yeah sorry I just don't know what to do with you so don't come in I'm not going to store you you just keep circulating in the blood insulin hasn't come and told me what to do because there is no insulin so this is it should be generally proof positive of the importance and indeed critical aspect of insulin when it comes to understanding the Randle cycle if people are trying to discuss the cycle in the absence of
• 26:30 - 27:00 insulin uh it doesn't work um there's really true no there's no true understanding of the Randle cycle or this competition between substrates fats and glucose okay now um there is also that there's I've been talking about it from the level of burning but if we go one step back up of course there's what's happening at the fat cell which is that in the absence of insulin we can't stop breaking down fat um so that no surprise in the case of the diabetic the person's losing an extraordinary amount of weight
• 27:00 - 27:30 and this is something I've alluded to before in various Outlets namely the the the phenomenon of diabelia which is when a type 1 diabetic uh before they're diagnosed they've become quite used to being able to eat whatever they want and be really really skinny now they feel miserable they're dying in this state where their ketones are getting into the realm of acidosis and their hypoglycemia is destroying blood vessels and nerves but they get used to being thin and now when
• 27:30 - 28:00 they start taking their insulin injections they aren't they start gaining fat very very quickly they learn this and unfortunately in some instances it leads to them abusing that fact and continuing to eat whatever they want and simply deliberately underdosing the insulin to stay thin this is because if insulin is low they can't stop burning fat thus they're as thin as they want albeit um pathologically so unfortunately all right now let's shift
• 28:00 - 28:30 the topic then and talk look at what happens in type 2 diabetes interestingly in type 2 diabetes as I said before that's when we have too much insulin so this should be resulting in the cell shifting only over to glucose burning and there is still some glucose burning but because of the insulin resistance it's created a unique a unique very odd scenario which is a little more nuan than is it than it is in the case of type 1 diabetes because
• 28:30 - 29:00 there's more tissues involved in different ways so insulin is high but as the body has become insulin resistant the fat cells are altered in their responsiveness to insulin in fact the fat cell I argue is one of the first if not the first tissue to become insulin resistant normally insulin would be telling the fat salt to hold on to its fat insulin is saying to the fat cell hey I'm not going to let other tissue I'm not going to let the muscle use you for fuel so just keep it in the
• 29:00 - 29:30 fat cell you just store that fat because I'm telling the muscle right now and the fat cell to use glucose for fuel that can still happen to some degree there is still some glucose utilization happening especially because remember there are some tissues that don't really need the insulin for glucose uptake and some degree of insulin functioning is sufficient to allow some glucose burning but the high fat the high insulin is having this weird effect because remember insulin resistance is
• 29:30 - 30:00 two things it's both insulin not working well like we have at the muscle at the fat cell where it's not inhibiting lipolysis anymore so the fat cell is breaking down fat so free fatty acids are higher but the insulin may still be sufficiently working at the muscle to tell it not to use the fat so once again we come to this scenario where in the type two diabetic we can have high glucose and High free fatty acids in general the type 2 diabetic is
• 30:00 - 30:30 primarily using glucose and can't shift out of glucose burning this is something I've alluded to before called metabolic inflexibility metabolic inflexibility is nothing more than the high insulin altering the Randle cycle the glucose fatty acid cycle in a healthy individual you eat a mixed macronutrient meal with fats carbohydrates and and proteins because there's an insulin increase you go to glucose burning once you've gone
• 30:30 - 31:00 through that glucose glucose and Insulin comes down and you get into the fasted State now you're fat burning what had been noticed decades ago now is that in a type two diabetic or someone with insulin resistance they they are sort of stuck in that glucose burning mode that even though they haven't eaten for some period of time and in a healthy insulin sensitive person they would have transitioned into the fat burning state of fasting they don't they stay stuck in glucose burning and that's because of
• 31:00 - 31:30 this High insulin that is reflective of insulin resistance and of course that's very much reflective of type two diabetes so type one and type two diabetes both reflect the relevance of insulin in understanding the Randall cycle now one I debated on whether or not to share this and I generally like these to be about 30 minutes so I'll be very brief here because I think it's important and that's something I'm going to touch on in a future lecture so be
• 31:30 - 32:00 sure to stay tuned for that which is the relevance of insulin and the Randle cycle in altering hunger this is particularly relevant in the type two diabetic so it's I'm deliberately placing it here as we wrap up after talking about insulin resistance in the type 2 diabetic the brain is unique it doesn't quite fit into our understanding of the Randle cycle because it doesn't use fats for fuel in general even though it has access to fats it's I think more
• 32:00 - 32:30 correct to say that the brain uses fats for structure it uses it to build stuff rather than using fats to burn for energy so the brain's fuel choices are between glucose which is a ubiquitous fuel source and ketones um that's the brain's availability and once again the Randle cycle would be relevant here a brain cell like every cell of the body just can't infinitely use all energy sources available to it it doesn't need an infinite or an unlimited access to
• 32:30 - 33:00 energy it's going to choose one or the other and and I wanted to mention this in in the context of hunger because if you have insulin resistance the brain can become insulin resistant there are regions of the hypothalamus that can become insulin resistant where particularly we have our hunger and satiety centers as that part of the brain becomes insulin resistant it can't pull in glucose as well even though there's plenty of gluc glucose in the blood the brain isn't getting it in very
• 33:00 - 33:30 well because the glucose isn't working well so the glucose doors aren't opening very well glute 4 isn't working particularly well now imagine in that same situation because of the high insulin reflective of their insulin resistance what has happened to the ability of the liver to make ketones which is a favored fuel by the brain or of the brain of course it's compromised and so it's this particularly metabolic tragedy a particular metabolic tragedy where the
• 33:30 - 34:00 brain which has so much glucose surrounding it isn't able to use it very well because of the insulin resistance and the one fuel that it's crying out for namely ketones in the midst of this compromised glucose use is a fuel that it doesn't have access to it's not available um to be a little more precise because of the high insulin inhibiting the liver's ability to burn fat because insulin is stopping the liver's fat burning there is a compromised production of ketones resulting in the
• 34:00 - 34:30 brain going a little hungry and if the brain is going hungry not only can that contribute to Chronic neurological pathologies like depression and migraines and Alzheimer's disease and Parkinson's all of those have this aspect of glucose hypometabolism to it in other words a compromised ability to use glucose but to compound the problem we're not giving it access to the alternate fuel source namely ketones so so I like to sort of jokingly invoke the rhyme of the Ancient Mariner here which
• 34:30 - 35:00 may sound a little familiar um the the Sailor who's on the sea tossed um and and dying of dehydration bemon the fact that he's surrounded by water water water everywhere nor any drop to drink he can't drink it even though he's surrounded by water that's sort of analogous to the brain being surrounded by glucose but it can't get it and the one thing it's crying out for the the the the freshh water that we could provide this stranded sailor would be the ketones in the case of the brain to
• 35:00 - 35:30 bring the analogy back full circle so there's a relevance there not only to the brain going hungry and contributing to pathologies but if the brain is hungry it thinks the body is hungry and then it stimulates hunger that's this idea of the fuel partitioning theory of obesity that I'm going to talk about in a future lecture so stay tuned and of course insulin being extraordinarily relevant okay as usual I talk quite quickly as I'm generally freely thinking
• 35:30 - 36:00 through these ideas I hope that some of this sticks um even though the biochemistry might have seemed a little daunting at first if listen to this again and slow it down pause it take a note you know be true students with this lecture it'll stick um but now I'm confident you know the most relevant information regarding the Randle cycle the glucose fatty acid cycle the reciprocal nature of the inhibition of these two caloric energy sources wanting to be used each sort of demanding
• 36:00 - 36:30 priority boarding onto this metabolic bus if you will um but remember that there's a conductor there's someone who's dictating ultimately which one gets to go on and be burned and that is the humble hormone insulin if insulin's up the body is burning glucose or blood sugar the body's sugar burning if insulin's down the body's burning fat it's fat burning one of those is ultimately better when it comes to maintaining insulin sensitivity and body fat I hope all of this has been helpful
• 36:30 - 37:00 thanks again as always for tuning in remember until next time more knowledge Better Health