Audi Quattro with a lawn mower engine

 

 

Spending public money on big research equipment can be ridiculous. Often when regulations on how to spend the tax-payers’ money change, some open ends appear giving opportunity to business piracy. To win the tender and sell at dumped prices these companies are ready to sell something like an Audi Quattro with a lawn mower engine.

Of course it is not possible to use features of such a legendary vehicle with an engine that lacks orders of magnitude on horse power and other parameters of performance, even if one would manage to couple it to the wheels. How we can than rationally expect that our bodies will run well with a key metabolic engine, insulin secreting pancreas that is too small for the size and the needs of the body?

We sent a person back to the natural environment in the first post of this blog. If he/she managed to survive until few months later, his/her body mass index (BMI) is likely around or more likely below 20. This would be a wild type body size, a body volume that could easily run on lawn mower size engine, a body that could easily use a normal size insulin secreting pancreas. It is quite common these days to be 50 – 100 % over this wild type body size. More than three quarters of children at the age of 14 are above the BMI mark 20, often considerably above it. Being significantly above this wild type value changes our bodies into over sized, power-demanding vehicles, rendering insulin secreting pancreas too small to secure adequate insulin levels.

But what about the solutions of this issue? What would an engineer do with a low performance engine? With engines you can tweak control unit to increase its performance. Is it then possible to overhaul insulin secreting pancreas? Our bodies start to secrete another hormone, called glucagon, to increase glucose levels and to give insulin secreting cells a better “fuel/air” mixture to secrete more insulin. SO YES!!! Higher glucose is initially beneficial to make a better use of insulin secreting cells.

It still remains a question, why our therapeutic strategies are so much directed to lowering blood glucose? High blood glucose is the best sign, the best indicator that our metabolic engine, insulin secreting pancreas is lacking power for a long-term operation. If one bothers to change his/her BMI back towards 20, the body will do the rest. It will immediately remove excess glucagon secreting cells and glucose when they are no longer needed.


To be warmed up through your fingertips

For this post let us imagine that we are among the rescuers in circumstances similar to those after the Titanic disaster. We would need to help people that have been exposed to cold water for too long. How would we warm them up? Would it be enough for them to touch something warm with their fingertips to survive? Something really warm or burning hot? Although this may be a matter of myth busting, but it is unlikely that this procedure alone would rewarm their bodies enough to stay alive. It would rather burn their fingertips. Why would we want to use such an ineffective method in the first place? Due to their small cross-section it is simply not possible to move adequate heat through our fingers to warm up the entire body in a reasonable timeframe. The paths for heat to enter deeper in the body are simply too narrow.

In one of my last posts (Pitfalls of insulin delivery) I wrote about the specialized delivery system which is a big avenue that makes sure that insulin level in the liver is high. Delivering insulin from the outside on the other hand is using smaller paths, causing excessive local concentration of insulin, delayed action, poorer control of cell metabolism in the liver, excessive drop in blood glucose or development of insulin tolerance. Again, why would we want to use such an ineffective delivery system? At the moment this route seems to be the only one compatible with the chemical properties of insulin. However, even if we could eat it, use it as a nasal spray, as a suppository, as a skin crème or eye drops, the paths to the liver and other tissues would not get any bigger and would not solve the delivery issue. On the other hand, a skin crème does boost cell vitality if applied locally, for example on non-healing wounds.

It is much easier to rewarm a person that is not too cold. Already holding a cup of warm tea helps a lot. Similarly, less insulin one needs better is the efficiency of the existing but non-ideal insulin treatment. A narrow waist, some visible and hungry muscles are a great start.

Industry and bad genes

One of the central messages I want to communicate with - Why only glucose? - blog is that it is practically impossible to understand how a human body works within the context of a modern civilization. If we are unable to understand the normal function of our body, can we then understand it when it gets sick? Can we make the right diagnosis, design preventive measures or focus industry to develop medication?

Today we eat too much, too often and move too little. Our bodies are therefore rather saturated with food, compared to being depleted when we get lost in the wilderness. Finding food in an untamed nature is an extremely hard job and from our standpoint one needs to be a trained expert to survive. Such individuals can nowadays make money with their survival shows on popular TV channels. In the far past everybody had to be an expert to stay alive. And many did not! In those days meals were far from regular. What adaptations would be beneficial to a human organism in such conditions? For example, everything that could keep the glucose high enough to maintain the brain function would help a lot. In addition, the ability to accumulate as much food in as possible in the cellular stores after a sporadic meal would be highly appreciated. At this point it is again worth mentioning that we do not eat and deliver food to our cells to be immediately converted to energy, but rather to fill the cellular stores for later use. Advantageous adaptations would likely be related to changes in some key proteins in our cells, like enzymes, ion channels, transporters to name a few…It is now popular to say these changes in proteins originate from mutations in some genes. These changes can be later inherited through the generations. It is not my intention to discuss details about the genes in this blog, since biological concepts of how we understand them, are currently changing. My favorite metaphor for them is beautifully described in Denis Noble’s bestseller “The music of life”. But keeping in mind the beneficial adaptations mentioned above, is it then correct to realize that changes in proteins (or genes) that aided blood glucose rise and faster fat accumulation were of an advantage to a Paleolithic human? Would such changed genes be defining survivors, favoring their children? Those of us who carry those genes should know that they were the best genes we could have to survive.

What about those genes today? What do they mean to a modern human enjoying the benefits of a modern civilization? Sure enough we do not call them the best genes any longer. We rather call them bad or even the worse genes. We tend to dig them out within the studies on large and progressively larger populations. Then we correlate polymorphisms with statistical risks and attract investors and industry with putative drug targets. We certainly want to knock them out in the near future. It is too easy to blame genes for being obese, diabetic… I believe that better understanding of how our bodies work offers much less sophisticated solutions for most metabolic diseases.

Healthy vs. normal

The size of the body is related to how much insulin we need. Being leaner will definitely make your pancreatic insulin reserve to last longer, maybe even for a lifetime. However, it may be useful to know that there are ways to make sure this reserve will serve you at least that long. Most of us eat too much and move too little. Our cells are overloaded with nutrients and have to find ways how to pack more food into stores within cells that are already full. Since in the past, humans have been mostly exposed to lack of food, their bodies developed very efficient ways how to fill the cellular stores. And the key hormone helping here is again insulin. More insulin will move more food into cells and lock it there. After a meal, a normal person will have very high insulin levels in blood that will efficiently fill the cells with food. We can measure this in clinics in a diagnostic test to show that our pancreas insulin release works well. We interpret this information that our insulin release from pancreas is normal. A diabetic person cannot reach those high insulin levels after a meal, so among other nutrients, blood glucose levels will be high. Those two scenarios represent a normal and sick condition, respectively. What about healthy condition?

We know for decades that a similar meal as above in well trained athlete will not produce a normal level of insulin release. In fact, in such a person the insulin level shall be closer to that in a person with diabetes. So, what is the message here? Why are well trained athletes not normal? Can we call them healthy instead of normal? The main reason for lower insulin level after a meal in well trained people is that during training they burn a lot of food and that their cells, particularly muscle cells, are constantly hungry. As soon as some food arrives to the muscle it is consumed. There is no need for insulin to push the food into the cells. The whole body seems to be more sensitive to insulin. It is not difficult to calculate that if we use about 20 times less insulin per meal, we can use our pancreas for much longer. To be close to healthy it is fine to keep our bodies lean. It is even better if we are lean and well trained. And do not forget, being lean and well trained is also an example of good life practice for people with diabetes since less insulin shall be used for treatment. Less insulin equals less side effects.

Pitfalls of insulin delivery

The vast majority of cells in our body needs insulin to support constant supply of foods to build cells and support their well being. When a body mass increases, so increases also the need for insulin. On the other hand, the major part of insulin released from pancreas ends up in the liver. The whole blood delivery system around liver is specially designed for that. It is like grand avenues leading to the center of a major city, to deliver goods that stay there due to large demand. Further away from the center, on the periphery, roads get smaller, and the concentration of goods, like insulin, is lower. Insulin is a rather short-lived hormone and lasts only for some minutes before it is removed from the blood. To achieve an adequate supply of foods into cells, which is essential for anabolic metabolism, a new dose of the hormone has to be released from pancreas about every five minutes. Such intermittent release of insulin never overloads the cells with the information this hormone carries. Cells in our body are permanently eager to get more.

Keeping those few facts in our minds, let us think about the current use of insulin by millions of people around the world “to control their blood glucose” (see Glucose vs. insulin). Below is a list of few issues that we have to seriously take into the account. First, insulin injections cannot utilize the specialized, central delivery system to the liver. Small streets, instead of the grand avenues of the big city, are challenged to deliver insulin to satiate the large demand. Second, insulin is delivered to the periphery, where cells are not at all used to high loads of insulin. Not anymore the cells are eager to get more insulin, they rather defend themselves against constant information overload. Third, for the same effect, more and more hormone is needed, the body is developing a tolerance, which can lead to complete insensitivity to insulin. Fourth, since cells are exposed to an excess of insulin, they load up too much nutrinents that can eventually end up in fat, increasing body mass and requiring even more insulin for the basic needs (see also How much insulin?). And fifth, once we start adding the hormone to the body, it will limit or stop producing its own, making those people critically dependent on the health and financial system stability. Causal relationships related to hormonal control in our body are complex. Injecting a hormone may remove the signs and symptoms of diabetes mellitus, but will in addition do much more, mostly damaging. I shall cover different aspects of that in my future posts.

Boot camp style lesson on blood sugar

It was a cold, rainy and foggy day in June 2007, almost 9 AM and I was facing an exhaustive exercise. Those days I had a project to explore the limits and variations of sugar in my blood using one of the continuous glucose measuring devices. I got a pretty good idea about what happens with sugar levels after a regular meal, small snack, during sleep, during giving a lecture or a moderate exercise. Apart from sleeping at night, most other activities raised my blood sugar level. The plan behind the physical activity on that particular June day was to explore how low my blood sugar can fall during simulation of boot camp training. After an hour and a half of self-inflicted suffering I barely managed to connect the glucose sensor back to my laptop to realize in disappointment that the plan failed. My blood sugar did not drop at all, it rose! Almost like I would be taking my favorite chocolate bar!

It soon appeared to me why I failed. I was well trained at the time, which means I could easily mobilize other nutrients apart from glucose to be burnt for the muscle activity. Insulin level in trained people drops faster and more compared to non-trained people. The insulin drop makes it possible for an organism to become catabolic and use energy from its fat stores and proteins. The same as during starvation… The second reason was that I have not been suffering long enough. I estimate that an additional hour would drain my sugar stores and made me hit the wall. But before that, several hormones in my body pushed the blood sugar up and kept my brain and muscles active. For my failure I pay special tribute to glucagon, adrenaline, noradrenalin, cortisol, and growth hormone. And the last reason was my ignorance. If I would prevent insulin to fall during my physical activity, my boot camp session would likely be even shorter and successful. This is in fact very easy to achieve. All what I would need to do on that cold June morning would be to have some heavy breakfast at 8:30 AM.

How much insulin do we need?

Insulin in an anabolic hormone. Actually it is the key anabolic hormone. Without it we do not grow, regenerate, heal, gain weight, we are ageing faster… Our cells simply do not work well. This hormone holds a key for food (or nutrients) to enter the cells. And the real question is how much of insulin we need? The more the better? As little as possible?

As we have seen in my previous post, lack on insulin in the body will cause mobilization of nutrients from the cells. Glucose, and other carbohydrates in addition to fats and proteins, will be released from cells and specialized tissue stores following a principle of intercellular solidarity to keep the main body functions running. In case of complete starvation this can be enough to survive for some tens of days in case there is sufficient water supply. However, intercellular solidarity has its price. Fats and proteins can only be burnt with sufficient oxygen supply (aerobic conditions). If the oxygen supply is not high enough and without moderate activity, undesired molecules, like ketones and cholesterol, abundantly form to acidify our body fluids or plug our arteries. Starvation must therefore be controlled and associated with aerobic activity and lack of insulin will not exactly foster the vitality of our cells on the long run.

What about the more the better? This condition is the most likely scenario in people treated with insulin. Overload of insulin can cause two major issues. First, cells will get overloaded with all kinds of nutrients. We can only store or integrate a limited amount of carbohydrates or proteins in a typical cell. All excess will typically transform and deposit as fat. And we do not generally need fat deposits outside the fat storage tissue. Our heart surely does not work better with this additional load. And the second, if we bombard our cells with active substances, they will start hiding the receptors on the cell surfaces and develop a tolerance. More and more insulin will be needed until it will simply stop being effective.

So, how much insulin do we need then? Our bodies need enough insulin to keep us mostly anabolic during daytime. At night, when we want to sleep for eight hours or more, drop of insulin should allow some limited intercellular solidarity and together with other hormonal systems prevent us waking up as hungry and aggressive as wolfs. It is now easy to understand that if we let our body waist circumference to increase, the insulin demand will grow too. It is also likely that pancreas can follow such an increased demand until a certain limit. And after crossing this limit the glucose will start to rise to boost insulin release to help keeping the body mass. Should one then go to the doctor and get treated or simply just try to stop the process and get leaner? To try to bring the body dimensions back to the range where internal insulin supply can handle it on its own. I believe this is the simplest thing to do.

About the name

Diabetes is a generally used name for a group of diseases where patients have high blood glucose. This short name, or even its full name, diabetes mellitus, does not really tell us much about the disease. It tells us only that our kidneys can only prevent a certain quantity of glucose from being washed out into the urine and then lost from our body. When kidneys get overloaded with glucose, because there is much more glucose in the blood than normally, excess glucose will stay in urine. A dramatic side effect of glucose in the urine is that an organism can no longer economize water. A volume of produced urine is large and a person urinates frequently. To keep the water balance, a person needs to drink significantly more. This is how much diabetes tells us.

So why are the name diabetes or in many languages sugar disease so widely used? Likely because features like large volume of urine, its honey-like smell and its attraction to insects have been the only diagnostic handles for thousands of years. But these names are misleading. Diabetic patients do have high blood glucose, but glucose is not at all the only blood nutrient that is raised. I told you before that inability to produce insulin results in emptying cell storages of proteins and fats. These get degraded to smaller molecules like fatty acids and amino acids their levels also significantly increase in blood. But they are much harder to measure compared to glucose and we can do such measurements sufficiently well only in the last decades. A much more appropriate naming of the disease would nowadays be wasting disease or catabolic disease.

What is then the story around sugar, around glucose? I made an argument that a raise in blood glucose is a defense line to prevent or delay protein and fat wasting. Obviously, it is cheaper for a body to risk loss of glucose and water through kidneys after blood glucose overload needed to kick enough insulin from pancreas. And enough insulin stops catabolism of more important proteins and fats. But what would be enough insulin for an organism? We will talk about that next time…

Glucose vs. insulin

It is a common belief that insulin is of major importance in controlling blood glucose, since it is the only hormone that is able to lower the concentration of glucose in blood. This is why we have major industry to produce insulin and why we mostly use insulin for. It is true, that if we inject enough insulin into a healthy person, this person will lose consciousness because of too little glucose or hypoglycemia. Hypoglycemia is one of the worst-case scenarios that can happen to you. None of the free time sports activities will ever give you such a tsunami of (nor)adrenaline ((nor)epinephrine) as hypoglycemia. It will be so bad that it will make you feel you are going to die. Raised blood glucose, on the other hand, will rather make you feel comfortable. So, why would we need a hormone to lower our blood glucose and drive us to anxiety? Is lowering blood glucose really the major function of insulin in our bodies?

If we observe the relation between blood glucose and insulin a bit more carefully, we shall first find out that the story has a twist. Glucose is a major reason why insulin is released from the cells in a gland we call pancreas. Let us focus our attention to a person we put back into the wilderness. This person is likely feeling very hungry, his glucose is around 4 mM (around 80 mg/dl) and insulin is very low. But feeling hungry does not mean that the cells in his body have no food. It rather means the alarm rings because the food storages are emptying. This person is using proteins and fats to feed his cells in a process we call catabolism. Catabolism can run for tens of days, but after about a half of proteins is used, the structure and function of cells collapses, causing death. To prevent or at least delay such a scenario the body produces several hormones to keep glucose high enough so that any kind of food can further elevate blood glucose to drive the release of insulin and return the proteins and fats back to storages for the times to come. Insulin is an anabolic hormone. Therefore it will also drive glucose into cells for storage. So the only time that insulin lowers blood glucose is after a meal. This happens very rarely out there, in the wilderness, outside the comfort of our civilization.

Loosing ability to produce insulin is actually, very similar to having no food for a longer time. The body fights this situation by trying to boost insulin release by increasing glucose. Trying to prevent or delay wasting of proteins and fats is what it wants to achieve. So blood glucose is raising and raising…And raising even more, since the body has no ability to produce insulin. So, the raise in blood glucose leading to hyperglycemia is an innate defense mechanism of our bodies to stop loosing proteins and fats. When the ability to produce insulin is lost completely, adding insulin from outside sources is one of the solutions. But complete loss of ability to produce insulin is true only in a minority of hyperglycemias and diabetes cases. For all these different shades of gray, there are likely more convenient and safe solutions. Let us talk about the possibilities some other time…

Back to the natural environment

Let us start this blog with a mental exercise by sending a human being back to the natural environment where food is scarce and danger is lurking on every corner. To survive a human organism needs water and it must seriously save on proteins and fats on striving to catch/find food and avoid being eaten by potential predators. The hormone that helps saving with proteins and fats is insulin. If by chance our person would loose the ability to produce insulin, the poor being would start loosing proteins and fats until terminal starvation and death. But why aren't we worried about the poor man's blood glucose due to lack of insulin? Let us talk about that next time...