June 1, 2006

Death by Insulin: How Sweet it Isn't!!


By Dr. Howard Glicksman

Case Study
S. P. was a nurse who had a long history of depression. She had stopped her medication several months ago since her life had stabilized. However, with the discovery of her husband having an affair, a setback at work, and the terminal illness of her mother, she soon began to have feelings of unworthiness and hopelessness. She was working for a home health agency and was involved in the care of an elderly woman who had a heart condition brought on by her long history of insulin dependent diabetes. Her patient had just received her three month supply of quick-acting insulin. S.P. decided to take one of the bottles and in the privacy of her home she injected herself with the entire contents. Within several minutes she began to feel hungry, nervous, sweaty, shaky, and very weak. This rapidly progressed to her feeling dizzy, disoriented and confused, ultimately resulting in drowsiness, unconsciousness, coma, and finally death. Why did she die?

Cause of Death?
If your answer to this question is that S.P died from an overdose of insulin, I suppose you are right. After all that’s what I would put on the death certificate. But what I’m really looking for here is the mechanism underlying the cause of death. Only by understanding the pathophysiology of disease, dysfunction, and death, can one begin to appreciate the complexity of life and how easy it is for us to die and fall off the radar screen for the survival of the fittest. The strength of a chain is only as good as its weakest link.

In the case here of S.P, most people who are familiar with diabetes and insulin realize that since insulin is a hormone that is needed to keep the blood sugar (glucose) from going too high, then taking too much of it can cause a person’s blood sugar to drop too low. That’s exactly what happened here with S.P. Anyone who has ever experienced even a mild case of hypoglycemia can appreciate what S.P. initially began to feel when she became hungry, nervous, sweaty, shaky and a bit weak soon after taking the insulin. But because she had taken an overdose her blood sugar continued to sink to a new low. So low in fact that it killed her. But why exactly did she die?

Diabetes and Hypoglycemia
Before meals, especially in the morning, your blood sugar usually sits at between 70-100 mg/dL. When you eat, the gastrointestinal tract digests the food and begins to absorb sugar, fat, and protein, which is readily transferred to the bloodstream. The pancreas detects the rise in sugar and begins to send out insulin which is needed for the proper utilization and storage of glucose, particularly in the liver, the muscles, and the fat cells. In order to accomplish this task in these target cells, the insulin attaches to specific receptors on the cell membrane and facilitates the entry of glucose into the cell.

Over the next few hours, as the gastrointestinal tract continues to absorb more and more calories, and the body continues to use and store this new supply of sugar, the blood glucose level will tend to rise above the fasting level, usually topping out at about 110-120 mg/dL. If the pancreas cannot send out enough insulin to match the amount of sugar being absorbed, or the effectiveness of insulin out in the tissues is compromised, (insulin resistance) then one can readily see that after eating a lot of food, the blood sugar may rise far above 120 mg/dL because the ability of the body to use and store sugar is impaired. This in essence is what diabetes mellitus is all about. In general, there are two types (type I and type II).

Type I, or insulin dependent diabetes, generally refers to the situation where a person’s pancreas cannot secrete enough insulin to allow for the efficient uptake, usage, and storage of sugar in the body. If left untreated, the blood sugar can build up to very high levels, sometimes over 1,000 mg/dL. In addition to this decreased uptake of glucose in the tissues, there is also an increased breakdown of protein and fat resulting in loss of muscle mass, weakness, fatigue, weight loss, and dehydration due to the excessive loss of fluid through the kidneys brought on by these high sugar levels. Eventually, because of the impairment of glucose utilization by the tissues, alternative metabolic pathways become dominant which ultimately results in a build-up of acid in the bloodstream, causing death. Prior to 1921, when Banting and Best discovered isletin (insulin) at my alma mater, the University of Toronto, this was the plight of most diabetics.

Type II, or non-insulin dependent diabetes, generally refers to the situation where a person may be producing normal or almost normal levels of insulin but their tissues for some reason are not responding to insulin as efficiently as they should. Therefore as the sugar level rises after a meal, the tissues cannot remove the sugar fast enough to keep it controlled at what is considered the normal range. These people often feel well for many years and are not aware of their diabetes until the problem worsens and they begin to experience some of the symptoms felt by type I diabetics.

What we’ve described above occurs in the body in response to a rise in blood sugar that has taken place after eating a meal. In S.P’s case, she gave herself a lot of insulin without eating and she took much more than her body would require. Therefore, when the insulin was absorbed into her bloodstream it went to the liver, the muscles and the fat cells of the body and ordered them to take in sugar and store it. These cells didn’t know what was happening elsewhere in her body. They just followed commands as the hormones directed them. As far as they were concerned, when S.P.‘s body absorbed all of the insulin she had injected herself with, her tissues “thought” it was coming from the pancreas. So what happened? Her blood sugar plummeted and she died.

Diabetes/Hypoglycemia Redux
When someone has untreated diabetes they have lots, even too much sugar floating around in their bloodstream but some of the major tissues that need it are literally starving for it even though it is right outside their door. When someone takes too much insulin the sugar gets directed to these tissues for storage without considering that there are other tissues in the body that may need it for function and survival. Hence, the body must not only be able to control its blood sugar in order for all its organs to work properly, but also be able to put sugar where it is needed, when it is needed, otherwise, all is lost. So why does severe hypoglycemia cause irreversible death? What is the mechanism behind it ?

Death- The Final Common Pathway
Question: What is the final common pathway for most deaths, no matter the insult: a heart attack, pneumonia, or cancer ?

Answer: Cardiopulmonary arrest. Either your heart stops or your breathing stops or they both stop simultaneously? A heart attack may damage some of the heart but you are not going to die unless it also causes the heart to stop or your breathing to stop. Pneumonia can give you a fever, make it hard to breathe and can drop your oxygen level and put your carbon dioxide level into the stratosphere and put you into shock, but you won’t die until this combination of problems causes you to stop breathing or makes your heart stop. Cancer can kill in many ways depending on where it starts and how it spreads throughout the body. But even here unless your heart stops or your breathing stops, or they both stop at the same time, death will not take place.

Question: So what is likely to happen when cardiopulmonary arrest occurs and the person is not resuscitated within at least four minutes? (Remember, they didn’t have defibrillators, ventilators, and pressure support drugs while macroevolution was taking place)

Answer: Four minutes of anoxia causes brain death because the brain, being the organ in the body with the highest metabolic activity, is the most susceptible to lack of oxygen.

Question: So why is this so important and why would it be irreversible?

Answer: If the brain damage largely occurs in the upper areas of the brain (cerebrum) it is possible for the person to survive with significant cognitive dysfunction. (anoxic encephalopathy). But if enough damage occurs in the brainstem, then death will be permanent because the brainstem is the region which houses the respiratory and circulation control centers and the area for consciousness.

Put very simply, if your brainstem dies, you die because you can’t tell yourself to breathe and your circulation collapses. Therefore you will never be able to get enough blood and oxygen to your brain ever again---check-mate----game over.

Question: The brain is the most susceptible organ in the body to the lack of oxygen because it has the highest metabolic rate: what else is needed to provide energy for cells to function other than oxygen?

Answer: Glucose (sugar) is the other component that is acted upon by oxygen to provide the energy for brain function. The brain does not need insulin to take in sugar for energy like the liver and muscles do. But unlike the liver and muscles, which have the ability to store sugar as glycogen, the brain is almost wholly dependent on the sugar that’s readily available in the blood for its metabolism and therefore with sudden drops it can run into big trouble as we saw in the case study.

How Low Can You Go?
So in order to try to prevent this from happening the body is equipped to try to warn you about when your blood sugar level is dropping dangerously low. It’s sort of like when your gas gauge on your car notifies you that you’re running out of gas and your car may die on you. When the blood sugar level drops below 60 mg/dL the autonomic nervous system will start telling you that you’re hungry and that you should eat something. About the same time you’ll start feeling sweaty, shaky, and nervous. If you don’t do something pretty quickly to correct the situation and the level nears 50 mg/dL, you’ll probably start to notice a headache, problems concentrating, dizziness, and some irritability. As the blood sugar continues to drop you will start to become weaker, have problems speaking, feel very drowsy, and you may experience seizures. At this point you’re in big trouble because if you can’t do something to raise the blood sugar, the body’s continued use of it is going to drop the level further and if it sinks much below 20 mg/dL you’re probably going to suffer irreversible brain damage, and very likely--death.

Case Summary
When S.P. decided to take a high dose of insulin her blood sugar level was probably running between 70-100 mg/dL. In the natural state, insulin is released from the pancreas in response to a sugar load (eating food). As the food is absorbed and the blood sugar rises, more and more insulin is sent out by the pancreas so that it will be used and stored in the liver, muscles and fat cells. This keeps the blood sugar from rising too high after a meal and usually settles down a few hours later.

But S.P. took this high dose of insulin without eating anything. She took as much insulin as would be expected for someone who was eating many huge meals without providing the sugar load to satisfy the demands of the insulin she gave herself. As this high dose of insulin attached itself to the insulin receptors in the liver, muscles and fat cells, they began to draw sugar in for use and storage causing the blood sugar level to drop. S.P. began to experience the early symptoms of hypoglycemia that is the warning from the autonomic nervous system. This was followed quickly by further neurological decline resulting in death because her blood sugar dropped so low that she suffered irreversible damage to her brain, particularly the brainstem.

But why did this happen? Why does having a low blood sugar, or even low oxygen for that matter, result in brain cell death? Yes, I know we’ve said that it’s due to the high metabolic rate of brain cells. But what exactly does that mean at the cellular level? In order for the brainstem to die, brainstem cells must die. How does that happen?

It seems to me that, as always, it comes down to having a firm understanding of not only total body function, but more importantly, cellular physiology since the body itself consists of cells. When one understands how the most vital cells in the body, the ones that allow us to be aware, that tell us to breathe, and that control the circulatory system, can so easily die if the other systems of the body aren’t functioning properly, then one can critically look at what evolutionary molecular biologists have to say and realize that a lot has been assumed and extrapolated at the expense of the known truth.

Life= Organized Dust in Water
All physical life forms, including our own, consists of cells. Each cell is surrounded by a structure called the cell membrane that separates it from the rest of the world. The cell substance consists largely of water which contains within it dissolved chemicals in specific concentrations which differ from the outside. It’s important that the cell maintain these chemical concentrations within certain limits for its survival.

Floating in this fluid are small structures which perform various functions within the cell that are related to cell preservation or the specific organ function in which the cell itself is located. e.g. the beta cell of the pancreas produces biomolecules for its ongoing survival, and insulin, which performs a function related to glucose metabolism.

In order to be able to preserve the integrity and overall function of the cell, it needs enough energy to perform these activities. It generally derives this vital energy from the breakdown of sugar (glucose) in the presence of oxygen. When either of these necessary components are not present in adequate supply, then the cell is at high risk of losing its ability to function properly, and even dying.

Since brain cells are highly susceptible to either glucose or oxygen deficiency due to their high metabolic rate, they are the cells with the highest risk for irreversible destruction in the face of hypoglycemia. Recall: as the blood sugar level dropped and continued its steep decline, S.P. experienced worsening symptoms of brain dysfunction; from problems concentrating and dizziness, to not being able to speak, to drowsiness, to coma, and then death. S.P.’s brainstem cells died because without enough sugar in the blood for them to readily access for their energy requirements (< 20 mg/dL) they could not maintain their integrity and therefore they died--and so did S.P. as a consequence!!

Recap
What we’ve said is that our bodies consist of trillions of cells each containing water and many chemicals which need the energy provided by sugar for survival and function. In other words, life is essentially organized water and dust. The most critical component for our survival is brainstem function because, among other things, without it we aren’t aware or awake, we don’t breathe, and our circulatory system collapses.

Without insulin we cannot survive because the body is unable to use and store sugar properly. However, death from lack of insulin is not due to hypoglycemia since the brain doesn’t need insulin to use sugar. What causes brain death in an untreated insulin dependent diabetic is the buildup of acid in the bloodstream which interferes with the metabolic activity of the cells, causing their death, and consequently, total body death.

But how does the pancreas know how much insulin to release to keep the blood sugar level just right so the brain and all the other organs of the body will still have enough for their energy needs while at the same time storing some of it away? Wouldn’t that be dependent on the number of beta cells and their sensitivity to rising blood sugar levels, and the number of insulin receptors and how much they react to the insulin message?

If there aren’t enough beta cells making enough insulin or enough insulin receptors on the target tissue reacting strongly enough to insulin, this results in diabetes type I and II as described above. But is it possible for the pancreas to make too much insulin or for the insulin receptors to over-react by causing too much of an uptake of sugar by tissues like the liver and the muscles to cause a drop in blood sugar that puts the brainstem at risk? What’s a body to do to prevent the blood sugar from going too low and causing death?

Life and Death Matter
Some evolutionary molecular biologists may claim that they can determine how insulin might have come into being in humans, and even how the insulin receptor may have fortuitously come along hundreds of millions of years before or afterward. But it requires the properly educated student to ask for an explanation that details not only how the life form in question used insulin or its receptor independent of each other’s existence for glucose control, but also how the other necessary components for blood sugar control came about and were added to the process. For as we’ll soon see it takes a lot more than just insulin and its receptor to accomplish glucose control in the body. A process that involves sensory devices that tell the body when it’s in trouble and prevents the brainstem from dying.

Control: Plan Beta
Insulin is produced and released into the bloodstream from the beta cells in the pancreas. The beta cell contains a glucose sensor mechanism on its cell membrane. When this sensor is activated by a rising blood sugar it effects changes within the cell to make it release insulin in direct correlation to this rise.

The cell membrane of the beta cell, like nerve and muscle cells, and for that matter all cells in the body, has a negative electrical membrane potential. What this means is that the inside of the cell is more negative than the outside of the cell. This happens because more positive ions (potassium--K+) tend to leak out of the cell than go back into it (sodium--Na+). This takes place through what is called ion channels within the cell membrane. A beta cell’s resting membrane potential is - 60 mV. You may recall that the neuron’s is usually about -70mV

The glucose sensor mechanism on the beta cell membrane barely reacts to low blood sugars. But as the blood sugar rises, usually over 100 mg/dL in response to having eaten, the glucose sensor becomes more activated. This activity eventually results in the reduction of potassium loss through the ion channel. Since the resting membrane potential is - 60mV because of the loss to the cell of positive ions (potassium K+), this reduced loss results in the membrane potential becoming less negative (depolarization). As the membrane potential rises to -40mV, this causes calcium ions (Ca++) to flood into the beta cell through (voltage gated) calcium ion channels which ultimately causes the release of insulin from the beta cell.

So one can readily see that as the blood sugar rises, stronger reactions occur within the glucose sensor mechanism of the beta cell causing the release of more and more insulin. But as insulin causes the uptake of sugar in the target tissue, the body continues to metabolize sugar for its energy needs, and the gastrointestinal system completes its absorption of what was eaten, the blood sugar level begins to drop back down again. With this drop the reactivity of the glucose sensor mechanism in the beta cells declines to negligible levels as the blood sugar drops below 70 mg/dL . This allows the loss of potassium ions through the ion channel to gradually pick up again and as the membrane potential becomes more negative, (goes from -40mV back to -60mV) the Ca++ ion channels close and the release of insulin diminishes to basal rates.

So it would seem that the beta cell’s very sensitive glucose sensor mechanism’s activity which drops off significantly when the blood glucose is below 70 mg/dL and increases when it rises above 100 mg/dL, is able to prevent the blood sugar from going too low but still allows the body to store sugar when it’s in excess, by controlling insulin secretion.

Fast Anyone?
But we aren’t finished yet. We have only explained how the pancreas is able to control its release of insulin to prevent too much uptake of sugar into the target organs to prevent life-threatening hypoglycemia. This is all well and good when you are able to eat. But what happens overnight when you haven’t eaten for about 12 hours? Or what would have happened in bygone days when our homonid ancestors had to go a few days without eating while searching for food? How does the body keep the blood level in the right range for brain function when new calories aren’t coming in and you need to be active? In other words; how does the body go about releasing the sugar that insulin instructed the organs to store after a meal when it is really needed?

Herein lies another level of complexity that requires an adequate explanation by evolutionary biology. Not having enough insulin causes death and having too much insulin causes death. But it’s not insulin itself that directly kills the brain cells is it? Without insulin the brain cells die from acidosis. With too much insulin it’s the lack of sugar for energy which causes the brainstem cells to cease functioning and die.

So far all we’ve talked about is how the body takes sugar and stores it for future use. The next question is how does it access this stored energy when it needs it in order to prevent severe hypoglycemia and death? Remember, the body is simply organized water and dust that has to be able to place biologically significant chemicals where they are needed at the right time or else death occurs. The current thinking in evolutionary biology is that all of this came about by the random forces of nature: natural selection acting upon random mutation and cellular transformation. It is reasonable to assume that these forces may have had something to do with life as we know it. But does it make rational sense that these systems could have come about without the aid of intelligent agency? See what you think after you read on.

Control: Plan Alpha to the rescue
The pancreas not only contains beta cells that produce and secrete insulin, it also has alpha cells, which produce and secrete glucagon. Glucagon goes to the liver and, after attaching to the glucagon receptor, tells it to release the glucose that insulin made the liver store when it was in abundant supply in the bloodstream after a meal.

Glucagon also instructs the liver to start making its own sugar from other sources and tells the fat cells to release their energy into the bloodstream as well. In this way, the alpha cell of the pancreas, by way of the glucagon it produces and secretes, is the brain’s major protector from profound hypoglycemia and death.

Like the beta cell, the alpha cell membrane also contains a glucose sensor mechanism. But interestingly enough, its glucose sensor is just a bit different. In fact it operates in exactly the opposite way. Instead of being more reactive to higher levels of blood glucose the sensor on the alpha cell reacts more to lower and lower blood sugar levels.

Instead of really being turned on as the blood sugar rises above 100 mg/dL and almost turning off once the level drops below 70 mg/dL, like the beta cell monitor, the glucose receptor on the alpha cell starts to react as the blood sugar drops below 70 mg/dL and becomes more activated as the blood sugar continues to drop, peaking at about 20mg/dL.

Once the alpha cell glucose sensor mechanism swings into action it causes a chain reaction through some of the ion channels of the cell membrane that is not as yet completely understood. This results in the release of glucagon into the bloodstream.

In other words, the glucose sensor mechanism on the beta cell, that just happens to make a hormone (insulin) responsible for the uptake and storage of excessive sugar, responds specifically to increases in blood sugar. And the glucose sensor mechanism on the alpha cell, which just happens to make a hormone (glucagon) that prevents the blood sugar level from going too low and causing death, responds to declining blood sugar levels. Now isn’t that just amazing ?? What a coincidence !!

Not only that, but the glucose sensor mechanisms turn on the systems of insulin and glucagon secretion at the right time before damage can occur. Who would have thought that such an interdependent and irreducible system that is vital for life could have come about totally by the random forces of nature? Gives you a new understanding of the word “intelligence” doesn’t it?

In fact, both hormones, insulin and glucagon, are released from the beta and alpha cells respectively, at a basal rate throughout the day. With calorie intake and absorption of glucose, fat and protein, insulin release and production will deflect upwards and then come back to basal rates again. Likewise, with drops in blood glucose from total body activity, glucagon release and production in the alpha cells will increase and then drop again to basal levels as the need for more glucose in the bloodstream subsides after food.

Each of these hormones’ activity lasts only a few minutes in the bloodstream as they are rapidly taken up by tissue such as the liver. Therefore in this way, the sum total of blood glucose management is controlled on a moment to moment basis by the ratio of insulin and glucagon in the bloodstream both of which are dependent on very complex and sensitive systems of production in the pancreatic beta and alpha cells respectively.

Reality/Truth Check
Shouldn’t evolutionary molecular biologists, who believe and teach that all of life came about exclusively by the random forces of nature without intelligent agency, have to explain, not only how these devices came into being and ended up on the right cells doing the right job, but also how the prior system(s) worked without them?

It seems to me that they conveniently omit these sticky details which ignores the pathophysiology of disease, dysfunction, and death, and leaves those who trust them with the belief that they indeed have worked all of these things out, when indeed, nothing could be further from the truth.

If the vital task of blood sugar control, especially the prevention of it going too low, resulting in brain death, is mainly dependent on the ratio of insulin and glucagon then how could such an important system develop one step at a time, if each of the two components are absolutely necessary for it to work? Are we to believe that insulin and glucagon just happened to come together in the same life form purely by chance?

And if so, how did life forms, that were multi-system organisms with complex body plans, use and store sugar in a way that would allow for their survival before this incredibly providential happenstance?

And then once insulin and glucagon and the systems that create them and allow them to function came into being, how did the body figure out how the ratio should affect glucose metabolism to allow for survival.?

Once again we are left to ponder how it is that the insulin and glucagon systems are able to secrete the right amounts of hormone in a particular set of circumstances that react appropriately in the tissues to allow for survival. Can the human body give itself an overdose of insulin? Ever heard of an insulinoma? It’s a benign tumor that produces and secretes insulin at its own discretion ie independent of the ambient blood sugar. Its hallmark presentation is a fasting hypoglycemia because even though the person hasn’t eaten overnight where normally there would be negligible insulin secretion, the insulinoma has run amok and is doing its own thing. Release of insulin in the face of fasting can have devastating consequences---like seizures and death no less.

All of this information about how the body controls its blood sugar for survival then logically points to the underlying premise that in evolutionary molecular biology it should not be considered adequate to have demonstrated the development of a particular system simply by formulating the genetic basis for the existence of one or more of its parts.

Detailing the genetics behind insulin, glucagon, their specific receptors, and the beta and alpha cell glucose sensor mechanisms, does not explain how they all could have come together in order to function purely by the random forces of nature. But beyond this, as is clearly demonstrated here, one still needs to explain how it is that the sensors are preset to go off at the right moment resulting in the release of enough hormone that ends up causing the needed effect in the target tissues, which allows for continued survival given the vicissitudes of physical human existence.

For the mere existence of parts should not assume function. And the mere existence of function should not assume survival capacity.

The human intellect requires a more detailed explanation than has so far been provided by evolutionary biologists given our understanding of disease, dysfunction, and death. It’s pretty easy to die so each and every system in the body better be functioning at tip top efficiency or else: death.

In my opinion, to just compare parts from different organisms without a deep understanding of the development of function, and then beyond this, that function’s capacity for survival, should be considered wholly inadequate for mankind to be able to believe in what is put forth by evolutionary biology. Indeed, maybe this is at the heart of why most people really don’t believe it despite the rhetoric from NeoDarwinists.

Next Time
We are all one heartbeat away from death. But how does the natural pacemaker in the heart do its job and can evolutionary biology explain its development? Wait and see !!

Dr.G.
drhglicksman@yahoo.com

Howard Glicksman M.D. graduated from the University of Toronto in 1978. He practiced primary care medicine for almost 25 yrs in Oakville, Ontario and Spring Hill, Florida. He now practices palliative medicine for a Hospice organization in his community. He has a special interest in how the ethos of our culture has been influenced by modern science’s understanding and promotion of what it means to be a human being. Comments and questions about this column or any of the previous ones are welcome at drhglicksman@yahoo.com

Copyright 2006 Dr. Howard Glicksman. All rights reserved. International copyright secured.
File Date: 03.01.06