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Insulin and Glucose

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<h4>Insulin and Glucose</h4><a target="_blank" rel="noopener noreferrer nofollow" href="https://soloist.ai/stufffdev-test101/insulin-and-glucose">This page gives a somewhat novel perspective on insulin &amp; glucose.</a><h4>Bridge</h4><a target="_blank" rel="noopener noreferrer nofollow" href="https://soloist.ai/stufffdev-test101/bridge">These are my notes on certain aspects of the game.</a>

<ul><li>From a doubleton<ul><li>Top card from doubleton Kx, 8x<ul><li>... except AK when you lead K then A to show doubleton – partner should show suit preference on 2nd card</li></ul></li></ul></li></ul><ul><li>From 3 cards<ul><li>Top of a sequence or near-sequence headed by honour<ul><li>KQJ 1098 QJ9</li></ul></li><li>Top of internal sequence headed by an honour<ul><li>KJ10 K109 QJx</li></ul></li><li>Bottom of 3 to an honour<ul><li>Q53</li></ul></li><li>With Ace and 2 rags<ul><li>In No Trumps – bottom A94</li><li>In Suit Contract – Ace A94</li></ul></li><li>With 3 rags play MUD (Middle Up Down)<ul><li>987 752</li></ul></li></ul></li><li>From 4+ cards<ul><li>Top of touching honour in ‘sequences’<ul><li>KQJx J109x QJ9x Q109x K109x</li></ul></li><li>If interior sequence headed by Ace<ul><li>at No Trumps – lead the interior head</li><li>but in Suit Contract – avoid leading if at all possible but lead Ace if you really have to</li></ul></li><li>With no sequence but honour(s)<ul><li>lead 4th highest</li></ul></li><li>With 4 rags<ul><li>lead 2nd highest then play highest on subsequent round. MUDish</li></ul></li><li>With 5+ rags<ul><li>lead 4th highest</li></ul></li><li>Exceptions<ul><li>AKxx+ lead 4th highest at NT but Ace against Suit Contract</li><li>KQxx+ lead 4th highest at NT but King against Suit Contracts</li><li>Axxx+ lead 4th highest at NT but avoid this suit against a Suit Contract but Ace if you must</li><li>AK bare, lead K the A to show the doubleton</li></ul></li></ul></li></ul>

What Card to Lead ?

<ul><li>Against No Trumps <ul><li>Blind Leads (opponents just bid NT)<ul><li>4th highest from longest and strongest<ul><li>except with 3+ card honour sequence when lead top of sequence</li><li>A 5+ card suit is very attractive, but a 4 card suit headed by a single honour is most unattractive. A second honour makes them more appealing if they don’t have a tenace.</li><li>A 4 card suit with a 3 honour sequence is better than a 5+ card suit of rags or Jxxxx.</li><li>With equal length suits<ul><li>prefer the suit with more honours</li><li>with equal number of honours<ul><li>prefer the suit with the higher honour.</li><li>But with Kxxxx and Axxxx<ul><li>lead from the Kxxxx as the Ace may give you an entry to make the K+ length.</li></ul></li></ul></li></ul></li></ul></li></ul></li><li>Informed leads (if partner has bid)<ul><li>Lead partner's bid suit if its natural, else lead your own long suit.<ul><li>Only diverge from this if you have both a good suit and outside entries. If you don't have both those, lead partner's suit even with a singleton in it.</li></ul></li></ul></li><li>Informed leads (opponents bid suits on way to NTs)<ul><li>If opponents have shown 4+ cards in your long suit don't lead your long suit</li><li>Prefer an unbid major to an unbid minor</li><li>Prefer a 3 card suit to a doubleton</li><li>Prefer the stronger of equal length suits</li><li>But at pairs avoid risky starts with 3 or 4 card suits head by a single honour</li></ul></li><li>When can you lead a suit bid by opponents?<ul><li>When you have 5+ cards headed by a 4 card honour sequence<ul><li>KQJ10x or QJ109x<ul><li>Lead top of sequence</li></ul></li><li>With only a 3 card sequence, and you decide to lead it<ul><li>lead 4th highest (note this is different from leading a suit opponents haven't bid when top of 3 card sequence is best)</li></ul></li></ul></li></ul></li><li>Lead directing doubles<ul><li>A double of a conventional bid asks for the lead of that suit</li><li>A double of 3NT asks of a specific lead in this order:<ul><li>leader's bid suit, else</li><li>doubler's bid suit, else</li><li>if neither of you have bid, dummy's first bid suit, else</li><li>if no suits bid by any of those 3, lead Spades (needs ♤KQJxx + outside Ace to do this)</li></ul></li></ul></li><li>After a pre-empt i.e. 3♧ - 3NT<ul><li>Unless you have a good holding in dummy's suit, lead from a strong short suit. Declarer will chuck his weaknesses on dummy's length if he can, so you need to grab your tricks asap.</li></ul></li><li>Against NT slams<ul><li>Prioritise a 3+ card sequence, otherwise avoid leading suits with honours in them.</li></ul></li></ul><ul><li>Returning partner's lead<ul><li>1 card left: return it</li><li>2 cards left: return top card</li><li>3 cards left: return bottom card unless you hold a high sequence (from 98x upwards) that risks blocking partner's long suit when you should return the top of the sequence</li><li>4+ cards left: return original 4th highest or top of touching honours</li></ul></li></ul></li><li>Against a Suit Contract<ul><li>Partner’s suit<ul><li>Reasons not to</li></ul></li><li>Not suits bid by opposition<ul><li>Reasons to lead them</li></ul></li><li>Unbid suits<ul><li>Great Suits to Lead<ul><li>3 card sequence</li><li>headed by AK</li><li>singleton</li></ul></li><li>Abysmal Suits to Lead<ul><li>Ace without the King<ul><li>but if you really really must lead it, lead the Ace, not low</li></ul></li><li>Honour x doubleton</li><li>Singleton Trump</li><li>Suit with only a single Honour<ul><li>But if you have to, lead from suit with highest honour</li></ul></li></ul></li><li>In-Between Suits to Lead<ul><li>Prefer Near Sequence KQ10 over Interior Sequence KJ10</li><li>Prefer Suit with two honours better than a single honour</li><li>Prefer Suit with touching honours than broken honours</li><li>Prefer Suit with no honours to Suit with 1 honour</li><li>A rag doubleton with a weak hand<ul><li>(Partner may have entries to eventually give you a ruff)</li></ul></li><li>From 3 or 4 rags of an unbid suit</li><li>From 2 or 3 rag trumps</li></ul></li></ul></li><li>When Leading Trumps might be OK</li><li>Opening Leads against Suit Slams<ul><li>vs Grand Slams<ul><li>A solid sequence</li><li>A trump, but still not from a singleton</li><li>Other wise play safe with a long rag suit or a short rag suit</li></ul></li><li>vs Small Slams<ul><li>Sequence or AK if available</li><li>Singleton if partner might hold that Ace or the Ace of Trumps</li><li>Avoid a Trump lead unless your other suits have broken honours</li><li>Prefer an unbid suit headed by KQ or QJ</li><li>With a likely winner in Trumps or an outside long suit bid by opposition, try to set up 2nd trick by leading from K-high or Q-high or an Ace</li></ul></li></ul></li><li>Lead Directing Doubles<ul><li>Double of an artificial bid ask for that suit to be led</li><li>Double of a sacrificial slam is for penalties<ul><li>Make a normal lead</li></ul></li><li>Lightner Double of a non-sacrificial slam – make an unusual lead, so:<ul><li>Not a suit bid by your side</li><li>Not an unbid suit</li><li>Not a Trump</li><li>Do lead a suit they’ve bid, especially dummy’s first bid suit<ul><li>You’re aiming to find doubler’s void for a ruff</li></ul></li></ul></li></ul></li></ul></li></ul>

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Which suit to lead?

<h4>And what does this mean for what’s considered ’normal’ in human nutrition?</h4>Glucose is frequently described as the main fuel for the body1 and the primary fuel for the brain2.Insulin is commonly portrayed as the hormone essential for the body to use glucose for energy, working like a key in a lock opening the door and allowing glucose to enter the cell3, and in type 1 diabetics, its absence and subsequent failure to open those doors is characterized as the primary reason for uncontrolled blood glucose levels.These perceptions are true but only in certain circumstances, yet they have contributed to putting glucose (or the starches it comes from) front and centre of human metabolism and hence nutrition, while the real work of insulin is obscured. This article will argue that a re-appraisal of their role in human metabolism might offer insights into how best to treat and prevent diseases of metabolism.<h4>Glucose isn’t the main fuel for the body</h4>First, let’s address glucose and the assumption that it is the main fuel for the body.Most energy production in cells creates ATP, a high energy molecule that can later be used to power movement, enzymatic reactions and other numerous activities that are essential for keeping cells alive and functioning well.Most cells generate most of the ATP they need inside their mitochondria, specialised organelles that, through the ‘citric acid cycle’, allow short 2 Carbon-atom molecules with any attached Hydrogen atoms to be combined with Oxygen from the blood to become Carbon Dioxide (CO2) and water (H2O). This is done in a controlled way so as to produce ATP. The carbon &amp; hydrogen atoms ‘burnt’ in this way can come from fats, carbohydrates, proteins or ketone bodies.In most circumstances a mixture of all 4 of these are being used to produce ATP, but evidence points to the majority of energy coming from fat in healthy fasted people4 (e.g. not just eaten a meal).This evidence comes from measurements of the Respiratory Quotient (RQ), the ratio of the amount of CO2 produced divided by the amount of O2 consumed. Carbohydrates consume less O2 to produce the same amount of CO2 because they already contain one atom of Oxygen for every atom of Carbon as part of their molecular structure, whereas fats contain very little Oxygen.It has been calculated that when the body is getting energy purely from carbohydrates the RQ is close to 1. When purely fats are being used for energy the RQ is close to 0.7. If an equal balance of fats &amp; carbohydrates are being used, an expected RQ would be in the middle of these two figures, e.g. 0.85A study5 looking at development of a portable respiratory gas analyser used 40 healthy young adults to compare the results from the new device with an existing lab-based device. Their results gave an average RQ across the group of around 0.78, ranging from 0.7 to 0.85. This suggests that for this group of people, they were getting, on average, more than 2/3rds of their energy from fat rather than glucose and that none of them was getting the majority of their energy from glucose. This in turn suggests that, in non-exercise situations, fat rather than glucose is the main fuel for the body.Another study6 comparing whole body RQ from respiratory gases with that of local forearm RQ from O2 &amp; CO2 in arterial and venous blood during an oral glucose tolerance test (OGTT - consuming 75g of glucose as a single drink) reported a baseline whole body RQ of 0.8, in line with the previous study. During the OGTT the whole body RQ increased to a maximum of 0.91 before declining back to baseline levels after 4 hours.These results suggest that, in non-exercising subjects, while glucose can displace fat as the majority energy source when the body is challenged with a significant rise in blood glucose levels, under ‘normal’ non-exercise conditions measurements show fat to be the main fuel for the body,.<h4>Glucose isn’t the primary fuel for the brain</h4>Next, let’s look at the claim that glucose is the primary fuel for the brain7,8.Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are commonly viewed as a backup fuel for the brain9 that only really gets called upon during extended periods of food unavailability, e.g. starvation. This may be partly due to the fact that the liver only really starts to produce ketone bodies from fat when insulin levels have been consistently low for an extended period (18+ hours) and modern diets of 3+ carbohydrate-heavy meals a day will keep insulin peaking across 16 hours a day, precluding any chance of the liver producing appreciable levels of ketone bodies. Until recently, it has only been during the study of complete starvation that ketone body production has been highlighted as an alternative fuel for the brain10.Yet actual measurements of ketone body usage by the brain indicate that ketone bodies are used in preference to glucose11. When both glucose and ketone bodies are available, the brain will increase its ketone body use in proportion to the concentration of ketone bodies available, while reducing its use of glucose. This suggests that ketone bodies are the preferred fuel of the brain and the brain only uses glucose as a replacement for ketone bodies when ketone body availability is limited – the opposite to how it is usually presented in the scientific literature and more widely12.Almost all tissues in the body can use ketone bodies for fuel, not just the brain. The only major exceptions are red blood cell, which don’t possess mitochondria, and the liver, which doesn’t express the enzyme needed to convert ketone bodies back into Acetyl-CoA which can then be fed into the citric acid cycle in the mitochondria. This is why the liver is the main source of ketone bodies for the rest of the body, producing them from fat that has come from adipose tissue.Adipose tissue stores fat as triglycerides but releases them into the blood stream as free-fatty acids where they bind with the protein albumin and are carried around the body for tissues to use them. The rate of ketone body production by the liver is heavily influenced by the availability of free-fatty acids in the blood. The main influence on the rate of release of fatty acids from adipose tissue is the concentration of insulin in the blood. When insulin levels are low, free fatty acid release from adipocytes is uninhibited. In most normal circumstances this will result in blood ketone body levels rising to somewhere between 0.5 to 5mmol/L, a condition referred to as nutritional ketosis.Nutritional ketosis has its own negative feedback mechanism whereby as blood ketone levels increase, insulin secretion increases. When insulin levels rise slowly, free fatty acid release is gradually inhibited by a reduction the activity of the main enzyme in adipocytes responsible for splitting off the fatty acid moieties from the glycerol backbone of stored triglyceride molecules (aka adipocyte lipolysis) and thereby releasing free fatty acids. This downgrades the supply of free fatty acids in the blood and this then gently reduces ketone production decreasing the substrates for it in the liver.When a high carb meal is eaten, the resultant insulin release is much, much larger, and this has a sudden &amp; drastic impact on adipocyte free fatty-acid release, resulting in blood levels of ketones typically falling back below 0.1mmol/L. Typically, people stop producing ketones to any great extent when they consume over 50g of carbohydrates a day.Altogether, this information suggests that for most people following a normal diet consuming 200-300g of carbohydrate over 3 meals per day plus snacks, their ketone body production will be very limited, so the brain will have to depend on glucose for most of its energy. This is a diet induced situation, not necessarily the body’s preferred way of operating.

Are the common perceptions of glucose and insulin wrong?

<h4>Insulin’s key/lock/door action isn’t a major player in glucose homeostasis</h4>Having described evidence that suggests that glucose isn’t the main fuel for the body or even the brain, let’s look at the common perception of insulin as acting as a key in a lock on the cell surface that opens doors to let glucose into cells and compare that to what insulin really does. Glucose cannot simply diffuse across cell membranes. Cell membranes are made of bi-layers of phospholipids and other fats that act as a barrier to molecules with even a slight electrical charge and to those of any significant size. This leaves only O2, CO2 and H2O as the only molecules that can freely cross such a barrier. Everything else needs the assistance of some sort of protein transporter traversing the lipid bi-layer, and glucose is no exception. To transport glucose into/out of cells there are two types of proteins.The first is a small ‘family’ of very similar proteins that are referred to as Glucose Transporters (GLUTs). These all work without the need for any energy input from ATP, so glucose flows through these GLUTs following a concentration gradient – generally, the larger the difference in glucose concentration on either side of the membrane, the faster the net glucose flow through the transporter from the high concentration side to the low concentration side.The second type of transporter are ‘active’ transporters that use a concentration gradient of Sodium ions across the cell membrane to transport glucose across the membrane even if that goes against the glucose concentration. These proteins are known a Sodium Glucose Linked Transporters (SGLT) and there are 2 versions of this type of protein active in different parts of the body. Each member of the GLUT family is given its own suffix, hence GLUT1, GLUT2, GLUT4 etc… up to GLUT7 &amp; possibly more. Different GLUTs are expressed in different cells/tissues but all of them work in much the same way: once the glucose concentrations on either side of the membrane are the same, then there is no net transport of glucose across the membrane. The differences between the individual members of the GLUT family are mainly down to how fast they can work, that is, how quickly their transport capacity gets saturated by rising glucose concentrations. For instance GLUT1s get 50% saturated very quickly at a level of about 1 to 3mmol/L, lower than the normal blood glucose concentrations, while GLUT2s don’t get 50% saturated until concentrations reach 14mmol/L, so seldom get saturated under normal conditions. Most tissues express predominantly one member of the GLUT family in their cell membranes, so the liver expresses GLUT2s, allowing its intake of glucose to vary significantly in line with blood glucose levels coming from the intestines. Conversely, the brain is protected by the blood-brain barrier that excludes most blood-born molecules from freely crossing into the brain. This expresses GLUT1 receptors, which get maxed out very easily with normal blood glucose levels, meaning that the brain almost always has a constant steady supply of glucose, irrespective of blood glucose fluctuations. While this ensures a steady supply, it also protects the brain from being exposed to high glucose peaks straight after a meal. The possible significance of this will be discussed later. The rate of glucose transported into cells depends on the concentration of glucose, the saturation level of the individual transporters and the number of transporters present in the cell membrane. Obviously, the more GLUTs there are in a cell’s membrane, the quicker more glucose can pass into the cell. All the GLUTs, except for GLUT4, are permanently present in the cell membrane and operate independently of any action from insulin. GLUT4 is different, but it is only present in skeletal &amp; cardiac muscle cells and adipocytes. Firstly, unlike most other GLUTs, GLUT4 isn’t normally present in cell membranes to any large extent. Instead, it is mostly sequestered inside cells in special vesicles, and as such, in normal circumstances, it plays a very modest role in transporting glucose into the cells that express it. Secondly, the number of GLUT4 s in the cell membrane is insulin-sensitive. As peripheral insulin levels rise after a ‘normal’ meal with, say, 100g of carbs, the insulin binds to its receptor in the cell membrane triggering a series of actions that result in the GLUT4 vesicles migrating to the periphery of the cell and fusing with the cell membrane. Suddenly, those cells can take in glucose at a higher rate than prior to the insulin spike, and not just due to the increased extra-cellular glucose concentration – in which case the key/lock/door metaphor is fully justified. However, once in the cell membrane, GLUT4s operate like the other GLUTs, facilitating glucose’s movement down the concentration gradient but with a 50% saturation point of about 5mmol/L. Historically, a lot of the early research into insulin, glucose transporters and glucose homeostasis was conducted on easily isolated tissue samples, and these were mostly skeletal muscle. As such, the early ground-breaking research emphasised this key/lock/door metaphor and that early understanding has been extrapolated to make it central to the commonest perception of blood glucose homeostasis13. However, even with these extra GLUTs translocated into the cell membrane through the influence of insulin, the total contribution that skeletal muscle makes to glucose removal after a meal is about 13% of the total glucose ingested14, and adipose tissue takes less than 2%. These sorts of figures argue against the key/lock/door metaphor being the major player in glucose homeostasis, let alone an essential role of insulin throughout the body. It is a fact that modern carbohydrate-heavy diets produces a GLUT4 inducing insulin response at least 3 times a day, so one can also understand how this has been perceived to be a perfectly ‘normal’ part of physiology. But let’s look at blood glucose homeostasis in a bit more detail to try to get a better feel for what the body might consider ‘normal’. Homeostasis is generally seen as the principle behind the maintenance of an organism’s internal environment (such as body temperature, or the concentration of many different ions or molecules in the blood or interstitial fluid) in the face of changeable environmental conditions. For instance, if body temperature starts to get too high, the person might start sweating to increase heat loss and return the body temperature back to normal. If body temperature starts to get too low, the person may start shivering to generate more heat, again returning the body temperature back to normal. In this way when a particular factor moves outside of its ‘normal’ range, the body reacts so as to bring that factor back into the ‘normal’ range. To achieve this the body must have ways of sensing the level of many different factors that are under homeostatic control, and ways of manipulating them. Homeostasis is important because if parts of the internal environment start to get outside of their normal range, this can lead to seriously bad consequences. Getting too hot leads to heatstroke &amp; death. Getting too cold leads to hypothermia &amp; death. If your Potassium levels get too high it can lead to irregular heart beats and death, while too little Potassium can lead to cramps, fatigue, paralysis and death. It is a similar picture for all the other internal environmental factors that the body keeps under tight control – if they slip outside the ‘normal’ range that the body’s homeostatic mechanisms strive to maintain, then bad things start to happen, and the further the excursion from ‘normal’, the worse things get. This applies to blood glucose too but in a slightly different pattern. If blood glucose drops too low, then problems can suddenly occur, such as falling into a coma and death. However, when blood sugar levels get above the ‘normal’ range the problems that causes are more drawn out and take longer to have a severe impact on the body’s functioning. The blood glucose normal fasting range is generally viewed as between 4 and 5.4mmol/L, and the body works to keep it in that range. The body uses glucose all the time so the supply in the blood has to be continuously replenished, but how much is needed and where does it come from? A 65kg adult has about 5L of blood, and a concentration of 5mmol/L equates to about 5g of glucose dissolved in the entire blood stream. If the body uses 2000kCal per day, that is 83kCal per hour. If, from above, only 33% of energy typically comes from glucose, that means glucose is providing 28kCal per hour. Since glucose provides 4kCal per gram, that equates to 7g of glucose per hour meaning that the supply of glucose in the blood must be continuously topped up at 7g/hour when a person is in the fasted state. This supply role is almost wholly played by the liver. The liver can supply glucose from two sources, gluconeogenesis and glycogen, and typically both contribute. Gluconeogenesis is the process whereby the liver (and, to a much lesser extent, the kidneys) reforms glucose from various intermediates. These intermediates include lactate, some amino acids and glycerol.In the rested state, lactate comes mostly from red blood cells which lack mitochondria and can only produce ATP by splitting glucose in two, producing lactate. Glycerol comes from the catabolism of triglycerides mostly occurring in adipocytes (when they release free fatty acids, they also release the glycerol backbone to which the fatty acids were esterified). The amino acids alanine and glutamine used for gluconeogenesis come from dietary amino acids or muscle catabolism.Gluconeogenesis tends to continue at a fairly constant rate with high insulin only reducing it by 20%15. Glycogen is a storage form of glucose where individual glucose molecules are joined together into long polymeric chains. Glycogen can be broken back down into glucose which can then be released into the blood stream, but this mostly only happens in the liver, and to a lesser extent the kidney, which express the requisite enzymes. The balance between the rate of polymerisation and the rate breakdown dictates whether the liver is releasing glucose or storing it (glucose produced by gluconeogenesis can end up being stored as glycogen). Many hormones can impact on the relative balance between the production and breakdown of glycogen, but the primary controllers are glucagon and insulin which are both secreted by the pancreas. Insulin is secreted by the beta-cells in the Islets of Langerhans in the pancreas, and its rate of secretion is mainly driven by the prevailing blood glucose levels. As blood glucose goes up, insulin secretion increases. As blood glucose drops, insulin secretion diminishes. The perceived whole body actions of insulin mostly stem from the symptoms of type 1 diabetics who’s beta-cells have been destroyed by an auto-immune reaction. These people produce no insulin and are most commonly diagnosed when they present at hospital with raging thirst yet copious urination, tiredness and loss of weight. Sometimes they will also have symptoms of diabetic ketoacidosis (blood pH dropping outside of the homeostatic range), detected by blood tests. Their blood glucose levels will be really high, but their ketone levels will be high too, into the 15+mmol/L range. The blood glucose levels are so high the kidneys can’t resorb it all and so glucose is leaking out into the urine. This creates an osmotic pressure that sucks water into the urine too, hence the copious urination. The attendant water loss leads to the raging thirst. The total absence of insulin has released any brakes on the release of free fatty-acids from adipose tissue and so ketogenesis proceeds at full pelt in the liver. With the body awash with fatty acids, glucose and ketones all at the same time, the availability of this smorgasbord of energy substrates means that ketone levels build up and create the acidosis condition that can prove fatal. Administering insulin in such a situation is often life-saving. Ketone production abruptly stops, free fatty acid release drops and blood glucose levels drop too. Blood pH returns to normal. From this the assumption has been that insulin is responsible for getting rid of the excess blood glucose by reducing glucose release from the liver by stopping glycogen break down and down-regulating gluconeogenesis, pushing blood glucose into muscle &amp; fat cells through GLUT4s or into the liver where it is turned into glycogen or fat, as well as turning off ketones &amp; free fatty-acid supply so pushing the whole body towards use of glucose for energy. However, the situation is more complicated than that and the main complicating factor is insulin’s shadow sister, glucagon. Glucagon appears to do pretty much the reverse of insulin: it promotes the break down of liver glycogen and stimulates gluconeogenesis so increasing hepatic glucose release, along with promoting free fatty-acid release from adipocytes. In untreated type 1 diabetes producing no insulin, very high levels of glucagon are seen in the blood along with high levels of glucose. So while glucagon and insulin are antagonistic in a healthy person and blood levels of these hormones fluctuate in opposite directions as blood glucose levels change, evidence suggests that insulin secretion is the main inhibitor of glucagon release, not high blood glucose levels16. This makes sense from an anatomical perspective as both are secreted from within the Islets of Langerhans in the pancreas so are at their most concentrated there. So maybe damping down glucagon release is the primary function of insulin? It is certainly its first action. <h4>What does Hypoglycaemia reveal?</h4>Insulin injections have revolutionised the treatment and life expectancy of Type 1 Diabetics but their lives are far from normal. They have to constantly try to match the amount of insulin they inject with how much carbohydrate they eat and what their blood sugar levels are doing as a result of their activity levels and emotional state. This is almost impossible to do with consistent accuracy and they live with the ever-present fear of overdosing with insulin and falling into a hypoglycaemic event (‘hypo’) where the brain doesn’t get enough energy and starts to malfunction. Part of the ‘treatment’ of Type 1 Diabetics involves being taught how to recognise the symptoms of an on-coming hypoglycaemic episode (by both reductions in mental capability and the side effects the brain’s neural &amp; hormonal responses to low energy) and how to avert it. However, since some of the symptoms of hypos are confusion and a lack of concentration, a T1D falling into a hypo isn’t best placed to self-diagnose what’s happening to them and hypos resulting in hospitalisation are all too common. The 4mmol/L bottom limit of the blood glucose homeostatic range is accepted in the Diabetic community as a hard and fast limit. Any drop below that is considered a ‘hypo’ in need of urgent treatment. The advent of continuous blood sugar monitors (CGMs) has made avoidance of hypos &amp; hospitalisations much more reliable, but this hard &amp; fast lower limit for blood glucose appears, again, to be a diet induced situation. There is evidence from the 1970/1980s that blood glucose levels can be dropped down to the 1mmol/L range, normally considered as lethal, without hypoglycaemic symptoms if the brain has an alternative source of fuel17.Admittedly, these were only short term experiments lasting a few hours, so the longer term effects of such extreme low blood sugar levels are unknown, but its demonstrates again that the idea of glucose being the primary fuel for the brain is misguided. Given that blood glucose homeostasis keeps the lower limit around the 4mmo/L suggests that’s the lowest optimal level for whole body functioning. Another problem that T1Ds have to deal with is that they inject insulin subcutaneously, from where is gets absorbed into the blood stream. So the highest concentration is at the injection site and everywhere else in the body gets a lower concentration. This is different to non-T1Ds who produce insulin in the pancreas, where insulin concentration is at its highest. From there it flows into the hepatic portal vein so the liver gets the next highest concentration. The liver also binds as much as 2/3rds of the insulin passing through it so the eventual insulin concentration that flows out to the periphery is much lower than that impacting the glucagon secreting alpha-cells in the pancreas. To avoid inducing hypos, not too much insulin can be injected subcutaneously, so there is no way T1Ds can expose their alpha cells or the liver to the levels of insulin enjoyed by nonT1Ds. This leads to chronic raised glucagon levels, driving release of glucose from the liver regardless of any glucose supply from the intestines. So while injected insulin can have peripheral effects on muscle and adipose tissue to help dispose of raised blood glucose, concentration restrictions mean it has a greatly reduced ability to reign in liver glucose production either directly or via glucagon suppression. This matches the range of importance often ascribed to insulin’s glucoregulatory actions, but it is the opposite of normal insulin action when released from beta-cells, especially in the fasted state.

<h4>What does Hyperglycaemia reveal?</h4>Hyperglycaemia (blood glucose rising above 6mmol/L) only occurs in non-T1Ds following a meal containing significant quantities of sugars or starch. In such people the blood glucose rise is accompanied by a large surge of insulin secretion. This surge is the result, firstly, of a neurological response to eating, known as the cephalic phase of insulin release, that triggers insulin release through direct nervous stimulation of the pancreas based on visual and olfactory cues even before any nutrients have been absorbed into the blood stream. Secondly, it results from an amplification of the beta-cell response to blood glucose levels by other hormones (incretins, primarily GIP and GLP1) released by cells in the small intestine in response to the presence of nutirents. This postprandial insulin surge does the following:<ul><li>it suppresses glucagon secretion, thereby preventing glucagon from stimulating the liver to release glucose</li><li>it switches the liver from glucose release to glucose storage by increasing or decreasing various enzyme activities</li><li>it suppresses a key enzyme needed to burn fat in the mitochondria in all cells</li><li>it turns on the production of saturated fat from glucose in the liver, which can’t get burnt for energy so gets stored for later release in VLDLs</li><li>it triggers GLUT4 translocation in muscle cells, flooding them with glucose for energy or for storage as glycogen</li><li>it triggers GLUT4 translocation in fat cells, flooding them with glucose for energy or for storage as fat</li><li>it suppresses fatty-acid release from fat cells thereby reducing the availability of fat to all the other cells in the body</li><li>it turns off ketone production in the liver by both the reduced fatty acid availability and by suppressing key enzymes involved in ketone production</li><li>it stimulates use of glucose in all cells by stimulating the key enzymes in the glycolytic pathway leading to the oxidation of glucose for ATP, making them ‘suck’ glucose in through the GLUTs at an increased rate by reducing the concentration of free glucose inside the cell.</li></ul> All these actions together shunt the body away from burning anything apart from glucose for energy, instead, forcing it to prioritise burning or storing glucose, presumably to get the blood glucose levels back down below 6mmol/L as soon as possible. Why does the body put so much effort into doing this? What is the problem with high blood glucose? As mentioned earlier, high blood glucose levels are rarely an acutely critical problem. Instead, repeated or prolonged high blood glucose accelerates the development of chronic issues. But how? Higher blood glucose concentrations are associated with increased blood viscosity, meaning the blood doesn’t flow as freely as viscosity increases. This doesn’t just occur in diabetics with very high blood glucose levels, but also in prediabetics and in those with blood sugar ranges below the prediabetic range18. One of the key factors affecting blood viscosity is the deformability of red blood cells, i.e. how easily they can change shape to squeeze through small capillaries. Red blood cells generally have a diameter of around 8µm but capillary diameters can get down to 4µm, requiring red blood cells to adopt an elongated shape in order to squeeze through. As erythrocytes become unable to do this easily they will start to clog the flow of blood through the peripheral tissues, reducing oxygen &amp; nutrient delivery.19Glucose also has a tendency to react, non-enzymatically, with proteins and other molecules found in the body. This reaction is known as the Maillard reaction.20 A complicated series of reactions can occur resulting in Advanced Glycation End-products (AGEs) which attach to proteins, lipids and nucleic acids throughout the body. They are thought to contribute to the general aging process by binding to proteins and altering their function, so impacting enzymatic efficiency, and cross-linking long-lived structural proteins like collagen, reducing their mobility &amp; flexibility. Since these AGE forming reactions happen without enzymes, they tend to happen fairly slowly but in a concentration dependant manner – the higher the glucose concentration the higher the rate of AGE formation. Indeed, a greater formation of AGEs is seen in diabetics and is considered to be one of the primary origins of the many complications associated with T2D: kidney disease, peripheral nerve damage, damage to the eyes, poor circulation to the peripheral tissues leading to tissue death requiring amputation of toes &amp; feet20. These problems that worsen with blood glucose levels above the normal homeostatic range give a good explanation for why the body works hard to keep it within that range. As as such, this can cast a different perspective on insulin. <h4>Glucose &amp; Insulin: a new perspective</h4>Collectively, this understanding allows one to paint a picture of insulin operating in two different modes depending on its level of secretion. In the fasted state with no glucose coming from the intestines and no appreciable levels of incretin hormones, insulin’s action is mainly to keep glucagon in check, preventing it from overstimulating the liver to release glucose, as seen in type 1 diabetics when insulin is absent. This level of insulin has no real impact beyond the pancreas and the liver, and no inhibitory effect on free fatty acid release from adipocytes. If a low insulin state is allowed to continue long enough, it allows ketones to be released by the liver to fuel most tissues in the body and especially the brain. However, when a carbohydrate rich meal is consumed, the glucose load that enters the bloodstream quickly pushes blood glucose levels over the top end of the homeostatic range and the body reacts urgently, indeed, pre-emptively, to correct this by releasing a large surge of insulin. This switches almost every tissue in the body from burning fats &amp; ketones to buring glucose for energy or, in those tissue that can, to store the glucose in some way. Indeed, this view is in accord with Dr Eric Westman’s recent attempts to explain what’s happening to his weight-loss patients21. He describes the body as being able to use carbohydrates or fat for fuel, but to lose weight you need to burn your body fat. He continues that when you eat carbohydrates, your body has to burn through all those carbohydrates before it can get back to burning your body fat.He likens weight loss to a car journey: as you cruise along with the accelerator pressed you are burning fat. When you eat carbs, that is like stepping on the brake – suddenly the journey stops. This perspective encourages one to reconsider whether high carbohydrate meals are an essential part of human existence. Indeed, no carbohydrates are essential in the human diet22. Instead, each time a high carbohydrate meal is consumed the body has to react in a drastic manner to correct an acute problem caused by a dietary choice. Together with the facts that glucose is not the preferred fuel for the body or the brain, this casts blood glucose as a necessary evil to be tolerated for the sake of red blood cells. Worse still, dietary carbohydrates have the capacity to force a powerful glucose-lowering response from the body that can put the brain in danger from a lack of energy if hypoglycaemia results, requiring an equally powerful counter-response to boost blood glucose levels. This see-saw of hormonal responses to dietary carbohydrates allows the body to exploit them for energy, which has obvious benefits in a foraging/subsistence lifestyle, but it has long term costs in terms of wear &amp; tear on the body. It looks more like an emergency response rather than a smooth, calm, well established and evolutionarily honed adaptation to the environment. It works OK mostly, until it doesn’t, and then type 2 diabetes results. But that’s another story of common perceptions concealing what’s really going on. <h4>References</h4>1. Hantzidiamantis, P. J., Awosika, A. O. &amp; Lappin, S. L. Physiology, Glucose. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).2. Ritter, S. Monitoring and Maintenance of Brain Glucose Supply: Importance of Hindbrain Catecholamine Neurons in This Multifaceted Task. in Appetite and Food Intake: Central Control (ed. Harris, R. B. S.) (CRC Press/Taylor &amp; Francis, Boca Raton (FL), 2017).3. What Is Insulin? Cleveland Clinic <a target="_blank" rel="noopener noreferrer nofollow" href="https://my.clevelandclinic.org/health/body/22601-insulin">https://my.clevelandclinic.org/health/body/22601-insulin</a>.4. Zierler, K. Whole body glucose metabolism. Am. J. Physiol.-Endocrinol. Metab. 276, E409–E426 (1999).5. Seo, H.-C., Shin, D., Leem, C. H. &amp; Joo, S. Development of a Portable Respiratory Gas Analyzer for Measuring Indirect Resting Energy Expenditure (REE). J. Healthc. Eng. 2021, 8870749 (2021).6. Simonsen, L., Bülow, J., Madsen, J., Hermansen, F. &amp; Astrup, A. Local forearm and whole-body respiratory quotient in humans after an oral glucose load: methodological problems. Acta Physiol. Scand. 147, 69–75 (1993).7. Sprague, J. E. &amp; Arbeláez, A. M. Glucose Counterregulatory Responses to Hypoglycemia. Pediatr. Endocrinol. Rev. PER 9, 463–475 (2011).8. Mergenthaler, P., Lindauer, U., Dienel, G. A. &amp; Meisel, A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 36, 587–597 (2013).9. García-Rodríguez, D. &amp; Giménez-Cassina, A. Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling. Front. Mol. Neurosci. 14, 732120 (2021).10. Owen, O. E. et al. Brain Metabolism during Fasting. J. Clin. Invest. 46, 1589–1595 (1967).11. Jensen, N. J., Wodschow, H. Z., Nilsson, M. &amp; Rungby, J. Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. Int. J. Mol. Sci. 21, 8767 (2020).12. What Are Ketones? Cleveland Clinic <a target="_blank" rel="noopener noreferrer nofollow" href="https://my.clevelandclinic.org/health/body/25177-ketones">https://my.clevelandclinic.org/health/body/25177-ketones</a>.13. Sylow, L., Tokarz, V. L., Richter, E. A. &amp; Klip, A. The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia. Cell Metab. 33, 758–780 (2021).14. Dimitriadis, G. D., Maratou, E., Kountouri, A., Board, M. &amp; Lambadiari, V. Regulation of Postabsorptive and Postprandial Glucose Metabolism by Insulin-Dependent and Insulin-Independent Mechanisms: An Integrative Approach. Nutrients 13, 159 (2021).15. Hatting, M., Tavares, C. D. J., Sharabi, K., Rines, A. K. &amp; Puigserver, P. Insulin regulation of gluconeogenesis. Ann. N. Y. Acad. Sci. 1411, 21–35 (2018).16. Unger, R. H. &amp; Cherrington, A. D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012).17. Dom D’Agostino - Achieving Therapeutic Ketosis. (2024).18. Irace, C. et al. Blood Viscosity in Subjects With Normoglycemia and Prediabetes. Diabetes Care 37, 488–492 (2014).19. Cho, Y. I., Mooney, M. P. &amp; Cho, D. J. Hemorheological Disorders in Diabetes Mellitus. J. Diabetes Sci. Technol. Online 2, 1130–1138 (2008).20. Peng, H. et al. Effects of Maillard reaction and its product AGEs on aging and age-related diseases. Food Sci. Hum. Wellness 13, 1118–1134 (2024).21. ‘But Keto Goes Against Everything I’ve Been Taught!’ - Dr. Eric Westman. (2025).22. DiNicolantonio, J. J. &amp; Berger, A. Added sugars drive nutrient and energy deficit in obesity: a new paradigm. Open Heart 3, e000469 (2016).

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