Diabetes for All
An Introduction to Our Normal Metabolism and
the Causes and Treatment of Diabetes
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We now experience a global diabetes epidemic. It is estimated that, worldwide, somewhere around 360 million people will have diabetes within 2030 if current tendencies continue. That will give far more patients than the medical professions will be able to treat. Diabetes is a serious illness with no cure, requiring life-long treatment. Luckily, a healthy life-style, a well-balanced diet and oral medication can markedly retard development of diabetes and diabetic complications if the illness is recognized in time. With proper care, those with diabetes can experience a good and long life.
Insight into normal metabolism and the problems that lead to diabetes are essential to attain good and health-winning results. Patients must learn to "manually perform" the integrating functions that hormones normally carry out. These pages are my attempt to provide a start for this process.
Common types of diabetes
What is this illness? Let us begin with two concise slides reproduced from literature from the American Diabetic Association (ADA). The first defines the most common forms of diabetes that are recognized today.
Type 1 diabetes was previously known as "Insulin-dependent diabetes" and follows a total collapse of the system that provides the body with insulin. This hormone is found in all animals and is essential for life. Somewhere around one person of 200 will develop type 1 diabetes during the first 20 years of life. People with type 1 diabetes must receive insulin for survival! Today insulin is given by injection although inhalation therapy is currently being evaluated.
Type 2 diabetes was previously called "maturity-onset-diabetes". As the name implies it developed most often in older people, often overweight people. Today we find the illness in younger people too, often in children and teenagers. There is a clear correlation between the global spreading of overweight and development of type 2 diabetes. People with type 2 diabetes produce more than enough insulin, but their organs just do not respond properly to the hormone.
Prediabetes is a kind of forerunner of type 2 diabetes. Usually, those with prediabetes or "glucose intolerance syndrome" do not experience any symptoms which tell them that they are in danger. Given time, they will most probably develop type 2 diabetes. There is a real danger here. The complications of type 2 diabetes can progress before the high blood sugar levels characteristic of type 2 diabetes are recognized.
Just what are those diabetic complications?
Several of the body's organs are especially sensitive to the high blood sugar levels seen in diabetes. These include the heart, the kidneys, the eyes, nerves and the small blood vessels called capillaries.
Heart disease: People with diabetes have a 2-3 times greater tendency to experience cardiovascular problems than "normal" persons. Because blood vessels are also affected by high blood sugar, these people may also experience brain hemorrhages and reduced circulation in their legs. The latter can lead to amputations. Pain from affected nerves may follow high blood sugar levels with time.
Kidney disease: The kidneys are rather delicately made-up organs. They are very active filtering systems, taking up useful compounds from the preurine and sending wastes out in the final urine. Damage here can give very serious results.
Eye Complications: The eyes are also very sensitive to high blood sugar. We shall see that the retina (or light-sensitive area in the eye) can easily be damaged by injury to capillaries followed by reduced blood flow. The lens is also sensitive to blood sugar levels and cataracts can develop following long periods with elevated blood sugar.
AMA, 2008: "THE BEST WAY TO AVOID THESE THREATS TO GOOD HEALTH IS TO MAINTAIN BLOOD SUGAR LEVELS SO NEAR NORMAL AS POSSIBLE".
Not that blood sugar alone is responsible for the complications of diabetes, but it is easy to measure and gives a good indication of the individual's metabolic situation.
Now, let us look at the body's energy system, its control elements and the fuel that drives it.
Hormones from the Pancreas Control Metabolism
The pancreas is a relatively large organ which is responsible for production of many of our digestive enzymes. These are sent to the intestine when needed. In addition, the pancreas has small groups of cells that produce hormones that control our metabolism. These are known as the Langerhans Islets, after the German doctor who discovered them in 1869. All animals have some form of these cell clusters, some fish have even separate organs comprised of Langerhans cell clusters. Three cell types can be identified here and we can take them in alphabetical order.
1. a or α-cells that produce the hormone glucagon.
2. b or ß-cells that produce the hormone insulin.
3. d or δ-cells, producing the hormone somatostatin.
These hormones are not sent to the intestine, but rather to the blood and, therefore, to all of the body's tissues. We shall concern us with glucagon and insulin in this discussion. A major point to be very clear over is that insulin and glucagon always work together as a team. This means that, together, they control metabolism and energy production. They resemble a car's brake and throttle. However, unlike the automobile's controls, these act at the same time. One foot on the gas, the other on the brake! A fine degree of control is achieved in this way. Sure, some energy is wasted and is dissipated as heat, but that helps to keep us warm. Even production and release of insulin-glucagon pair is coordinated. In almost all cases, increased release of one of these is reflected by a decrease in production and release of the other.
Note that in both type 1 and 2 diabetes only the ß-cells (or their function) are reduced or missing. The α-cells continue their production of glucagon and a very marked misbalance evolves.
Normal Hormonal Response to Meals
INSULIN: The graph at the left shows the response of the pancreatic ß-cells to meals. The upper curve show the levels of blood sugar (glucose). We see an increase in glucose in the blood after eating. It is important to note that the maximal concentration of blood glucose does not exceed 7-8 mmol/liter and that, between meals, the glucose level is between 4 and 5 mmol/liter. These are the "normal" values and are maintained by the insulin-glucagon "hormone pair". You can see on the lower curve to the left that insulin concentrations seem to follow the sugar curve; insulin is released and the concentration rises following an increase in blood sugar. The tops of the insulin curve come about one hour after meals.
Glucagon: That glucose/insulin picture is the usual one known to doctors and researchers. But there is something missing! Glucagon! Look at the panel and curves to the right. They follow just one meal but show about the same changes in glucose and insulin that we saw in the left-hand side of the figure. But look at the lower curve to the right. There you see the glucagon concentration before and after a meal: high before and low after the volunteer ate. The "between-meals" glucose level is supported by the high glucagon-low insulin situation. The limited rise in blood sugar after a meal is under control of a "high insulin-low glucagon system".
Now, think back to the ADA quotes cited above. No mention of glucagon there! And yet, the misbalance between these two hormones is the cause of the high fasting blood glucose levels seen in diabetes. And that overshoot in blood glucose after meals; another effect of that mismatch. Correct control of synthesis, release and destruction of both of these hormones is essential to regulate metabolism and to maintain normality!
Enter Amylin: Although not mentioned in the preceding figures and text, there is another hormone that is released from ß-cells simultaneously with insulin. This is called amylin and has been known for a long time. Recently it has been found that amylin seems to strengthen some of the effects of insulin. It curtails the rise in blood sugar after a meal by slowing uptake of sugar from the gut. It reduces hunger by acting at the brain, and it reduces secretion of glucagon by the α-cells. A drug, Pramlintide, with much of the same structure as amylin, is now coming into use to help control the metabolic disturbances seen in diabetes. So, control of glucagon release is becoming a part of treatment for diabetes. Click here for more information.
The "Energy System"
1. Where does the sugar in our body come from?
Food: If I ask you to tell me about sugar I expect that you will say "..well, it's kind of sweet..." and go on from there. In fact, most of the "sugar" in our environment is not sweet at all. It is rather tasteless, being tied up in long chains of glucose molecules or "sugar polymers". These are either starch as in potatoes and grain, or cellulose, found in food fiber and wood. We can forget the sugar in wood for now as we cannot digest it (it is a glucose polymer, but the links between the glucose molecules are a little special).
As you can see from the figure, bread contains starch and this is split into individual sugar molecules in the gut. The result of these reactions is release of glucose in the intestine and transport of this to the blood stream. The sugar in the starch molecule is identical with the sugar in our blood. Glucose, glucose and more glucose.
Table sugar, on the other hand, is made up of only two sugar molecules linked together, one glucose and one fructose. This glucose-fructose "dimer" is sweet. When sucrose (or table sugar) is eaten and digested, it also gives rise to glucose which is released to the blood stream. The fructose is carried to the liver where it enters metabolism in a special way. I will not take up that now. If you are interested, you can find more information here.
So, once more. The sugar we find out in nature is mostly the same sugar that we have in our blood and various organs.
Liver: We continue to utilize sugar between meals, so we must have an "internal" source of glucose. The liver is our "normal" internal sugar factory. It can either replace blood sugar from its own stores or, when these are reduced, produce glucose from various building blocks. More about this in the next section.
Where does the sugar in our body go?
It's well and good that sugar from fruit and grain gets into our bodies, but what happens to it thereafter? Let's look at a model of our "Sugar Central" or, more correctly, blood sugar. The barrel represents the storeroom of sugar in the body. Food provides input in good times (read "after a meal"). There are three major routes out of that storeroom:
1. To the liver. Here excess sugar from meals is stored to cover sugar shortages between meals and to make fat from excess sugar. Transport of sugar goes both to and from the liver. The liver fills the "Sugar Central" between meals.
2. To the brain. The brain is completely dependent upon sugar combustion for its supply of energy, in any case under normal conditions. It uses really huge amounts of sugar, something I will come back to soon.
3. To muscles and fat tissue. At least 40% of the body is comprised of skeletal muscles. These can use both fats and sugar to supply energy. The rate of sugar uptake and burning follows physical activity; more work; more sugar burned. Muscles do take up and store glucose to cover future activity but they cannot release sugar back to the blood stream or "Sugar Central". Fat tissue stores surplus sugar as fat. About half of this comes from the liver, the rest is made by fat itself.
How is all of this moving about of sugar controlled?
We can take the simplest system first and that is the brain. Now, there is nothing simple about the brain, except that it has a very large and constant need for sugar. I'll explain that statement. We all know what happens if the brain does not get oxygen. We have only a minute or two before we black out or worse things happen. What happens when we cannot breathe? Our brains cease to function simply because without oxygen the brain cannot use sugar! No burning of sugar, no energy, no you and me! This is true whether we sit in a chair, ride a bike, take an examination or simply sleep. Some part of your brain is working full-time all the time. In fact, the brain uses about 5 grams of glucose every hour throughout the day. That is a little more than two sugar bits every hour! It has the capacity to empty the circulation for glucose in 60-90 minutes. That little brain of ours (about 2 % of our total body weight) accounts for about 25% of the body's total energy consumption (equal to 450-500 kcal/day).
The brain's glucose uptake and burning is NOT regulated by hormones. We could not exist with swinging glucose uptake and brain activity, thinking clearly after a meal and cloudily between.
We can take a look at uptake of sugar from blood to skeletal muscles. These tissues make up at least 40% of the body, even in slim women. More than 50% of the body weight of men is muscular. Muscles have the capacity to rapidly take up large amounts of sugar from the blood, just because of their size. However, between meals resting muscles take little sugar from the blood. It is work that turns on that uptake.
1. Insulin: Insulin has several important functions in our muscles. One is to "open the door" for glucose entry. Surprisingly, sugars do not "just" enter our tissues; they are too big! To get around this, most of our organs have portals or "doors" that can be activated and opened by hormones or metabolism. Thus, after a meal, insulin, released from ß-cells to the blood, travels to the muscles, opens these "sugar transport doors" and the sugar streams in. It is then either burned to provide energy, or stored for use later.
2. Work: Muscles can use both fat and sugar as fuel for energy production. The more work a muscle does, the more fuel it must use. Some of this fuel is always sugar and "sugar-burning" is greatly increased in short-term hard activity (for example, a sprint or weight-lifting). At first, muscles use stored sugar, but after some few minutes they begin to take up and burn blood sugar. In fact, our muscles can take up so much sugar that there is too little left to support brain activity. More about that later on.
The whole picture after a meal
Let me try to put the "ins and outs" of sugar metabolism together. First, we shall look at the situation after a meal. Here, blood sugar rises as food is digested and absorbed in the gut. This results in a rising insulin level and a pronounced fall in the secretion of glucagon. Insulin opens the sugar doors (increases uptake of glucose) in muscles and fat pads. The fall in glucagon puts a stop to sugar release from the liver.
The brain just keeps on taking up glucose as though nothing had happened.
The important point to understand here is that the blood sugar levels after a meal are kept within acceptable levels (from around 4.5 to 8-9 mmoles per liter) due to the coordinated and controlled release of insulin and glucagon. If blood sugar was allowed to go over these limits we would loose sugar into the urine, one of the symptoms of diabetes.
...and between meals
Well, things have changed! Now the release of our two controlling hormones is reversed; a lot of glucagon is released from the α-cells and insulin secretion and blood levels is reduced. This completely alters the role of the liver. Instead of storing excess sugar it now releases it to the blood. Not only does the liver send out stored sugar, but it begins production of sugar from proteins and lactic acid. While the fall in insulin reduces blood sugar uptake in fat and muscles, the latter can take up large amounts of sugar if they perform hard work. This can be a problem in that muscles can take up so much glucose that the brain "starves". Remember, the brain must cover its energy needs by burning blood sugar, at least on a short-term basis.
Diabetes patients make use of this to lower blood sugar levels when these are too high. One can use exercise or a bike "to reduce high blood sugar!
Once again, the main actors that control blood sugar are...
...the liver and the hormone-producing cells of the pancreas with their products, insulin and glucagon. The liver takes up or releases sugar according to our needs and in response to these hormones. Our normal function is completely dependent on coordination here! You can pick up more details about this complex steering by clicking here.
That "normal" blood glucose level...
can be shown as in the next figure. The column is kind of a sugar-meter where the normal fasting level is about 4.5 mmoles/liter. The green area is the "ok" or normal blood sugar level, the red areas represent " unhealthy" fasting blood sugar concentrations. The stronger the red color, the less healthy are those glucose concentrations.
Look at the people with blood sugar levels between 4 and 9 mmoles/liter. They are happy regardless of whether their blood sugar levels are normal or high! Those with sugar levels in the 6-9 mmoles/liter range do not notice that they are in danger! They can go for years without even guessing that they have high glucose. However, the late and serious complications of type 2 diabetes develop at just these increased sugar concentrations. Occasional blood sugar testing is important, especially when relatives have diabetes. Early control can prevent or slow progress of diabetes complications.
Blood sugar levels below the normal (under 3,5-4 mmoles/liter) are sensed! Double vision, dizziness, qualm and eventually unconsciousness follow a marked fall in blood sugar levels. Now, episodes of low blood sugar levels, or hypoglycemia, are uncommon. But they do occur. Diabetics who use insulin or oral medications that release insulin occasionally receive too much insulin. This will lead to excessive sugar uptake in muscles and reduced release from the liver. So-called "feeling" can follow and this is quite unpleasant. More commonly, low blood glucose levels can follow sports competition. Look at the next picture.
Collapse in a race...
This is from a local Norwegian newspaper. "Ivar" had taken part in a 5000 meter race but could not complete it. He collapsed about 100 meters from the finish line, completely exhausted. What had happened?
He was so motivated that he disregarded the clear signs of falling blood sugar, running so hard and so determined that his muscles reduced his blood sugar levels below that needed by his brain. In a way, this is the right way to compete, but it is a question of timing. Come to the finish line with "normal" glucose levels, well, you could have run faster. Sprint too early, and you may not be able to finish. It's all a question of blood sugar levels...
What goes wrong in prediabetes and type 2 diabetes?
We have now seen that control of hormone secretion and good liver function is necessary to hold blood sugar levels in place, especially after meals and when exercising. This proceeds completely automatically in all animals. We never really think about this indispensable system. What happens if it goes wrong? How can that happen?
By and large we imagine that the increasing resting blood sugar levels seen in diabetes follows a fail in insulin production or secretion. In fact, that does not usually happen during the first period of the development of type 2 diabetes or prediabetes. As a rule, the body's tissues gradually lose their ability to respond normally to insulin. We develop what doctors call "insulin resistance". We can see this in the model to the left. Remember, the liver is a "sugar factory". It can make large quantities of sugar when needed. A coordinated balance between insulin and glucagon determines whether the liver will take up glucose from the blood or release it to the blood, thereby maintaining correct blood levels.
However, a fall in the blood insulin level or a reduced reaction to the hormone by the liver will lead to an increase in blood sugar. Especially since glucagon secretion and its effect on the liver are unchanged in diabetes or prediabetes! In diabetes type 2, the liver continues to produce and release sugar in spite of the existing high blood sugar level.
The quote from the ADA above states that one should "maintain blood sugar levels as close to normal as possible".
Let's look at some evidence that supports this. The next figure shows data from three studies in groups of people especially prone to developing type 2 diabetes. This includes middle aged-elderly people in the USA, the Pima Indians of Arizona, and one of many Middle East populations. One of the "late diabetic complications" is reduced vision or blindness caused by damage to the eye or "retinopathy". The red columns in the drawing mark the blood glucose concentrations in people experiencing damage to the retina. In all groups, this can be seen when blood glucose concentrations are greater than 6 mmoles/liter. That is only slightly above the normal 4,5-5,5 mmoles/liter. That is why we say that people with slightly higher than normal blood sugar values are in danger. More information can be found here.
Insulin and glucagon control fat metabolism
We often think of diabetes as a problem concerning sugar metabolism. After all, we measure sugar in the urine and blood to see if we have diabetes. In fact, insulin is one of the hormones that regulate fat metabolism. Insulin is a major controller of both synthesis of fat in fat tissue and is the major control element that regulates release of fat to the blood.
This is shown in the drawing to the left. Here you see that glucagon, along with adrenaline and growth hormone, stimulate breakdown of fat in fat tissue. Insulin alone stands against this tide. The combination of glucagon stimulation and insulin's inhibition of fat release results in a balanced and appropriate release of fatty acids. They come when they are needed to drive energy generation in the body. What happens if the fat tissues become resistant to insulin?
Look at the next figure. The signal from insulin has become diminished. Fat tissues respond to glucagon stimulation with only partial control by insulin. They release excessive fatty acids and increase the amount of fat in the blood. We shall come back to the unhealthy results of this soon.
Overweight, obesity and type 2 diabetes
We have become used to the fact that overweight and obesity is all too common in the USA and Western Europe. Many will perhaps be surprised to learn that this is a global problem. Many Asiatic lands experience the same overweight problem that we do. Furthermore, there is a close relationship between overweight and development of prediabetes and type 2 diabetes. Not that all overweigh or obese people become diabetic. Nevertheless, somewhere between 5-10 % of the world's population will become diabetic given the obesity pattern we see today.
Type 2 diabetes develops over years
Type 2 diabetes takes a long time to develop, usually 10-20 years. Earlier, this "maturity-onset diabetes" was found primarily in older people. However, due to the wave of obesity seen in both parents and children, we now find youngsters with type 2 diabetes.
The figure show the typical progress of diabetes. The first period is marked by overweight and a gradual reduction in the response of the body's tissues to insulin. This is so-called "insulin resistance". Now, the body is not dumb! It is quite aware of this growing problem and meets the challenge by increasing secretion of insulin. In the beginning, this works well. Glucose levels are held within the normal limits by this "automatic" regulation. However, over time, a gradual increase in fasting blood sugar can be seen. At the same time the blood sugar "top" after meals increases. Unfortunately for the coming patient, pancreatic ß-cells seem to become exhausted or damaged with time. Production and secretion of insulin decreases and sugar levels increase to a level we term "type 2 diabetes".
The real danger here is that the tissue damage that follows type 2 diabetes builds up during the "prediabetic" period. It is, therefore, essential to monitor blood sugar levels a few times each year, in particular for those who have a history of diabetes in their families.
Summary, complications of type 2 diabetes
I have already discussed eye damage in type 2 diabetes. Perhaps the most serious problem for diabetic patients is the high risk for development of heart disease. People with type 2 diabetes have a 2-3 times greater risk for cardiovascular illnesses than "normal" persons. This follows their increased blood levels of sugar and fat. High fat levels in the circulation, especially LDL or low-density lipids, often are correlated with high blood pressure. Again, careful control of diet, motion and eventually oral medication can prevent or greatly reduce this risk. Monitoring of blood sugar levels and an awareness of the problem can be of great help.
The causes of type 2 diabetes
The routine way of gaining control of something begins with learning how it works. We can then find and fix the fail. Unfortunately, the insulin/diabetes system is extremely complex. I have "borrowed" the drawing to the left from Trends in Biochemical Sciences from the 1980s. We can see that insulin in the circulation comes to a tissue, joins up with a receptor molecule on the cell's surface, and "then something happens". That is, a series of reactions follow the hormone-receptor coupling and lead to the final actions of the hormone. Lots of data have been compiled during these 20-30 years that have passed since that drawing was published. As I stated above, that information is extremely complex and has no place in this presentation. You can click here if you wish to go further with these details. In short, I can say that no one particular single metabolic abnormality can explain development of type 2 diabetes.
Let us look at some of the possible causes of type 2 diabetes.
We can begin at the pancreas and the Islets of Langerhans. If you look back to the figure about development of type 2 diabetes, you will see that these cells initially do produce lots of insulin. What you do not see is that there is a time lag in secretion of the hormone early on in the development of type 2 diabetes. People with prediabetes do produce enough insulin after a meal, but it comes too late. That is, sugar and fat metabolism is not well coordinated with meals in these persons.
The next point to be clear about is that about half of the insulin that the pancreas secretes goes right to the liver and is inactivated there. That means that only about 50% of the produced hormone ever reaches target tissues.
Professor Bergman made an interesting and seldom discussed point here. Insulin is much too large to just wander over the blood vessel's wall. It has to be transported by a carrier system, but this is not yet identified. (Click here to see the insulin molecule). When we determine insulin's effectiveness, we usually measure blood concentrations and look at the extent of the hormone's actions in the various tissues. Now, we know that changes in capillary wall permeability follow increased sugar and fat concentrations in blood. An important and unanswered question is therefore, "how much of that secreted insulin really reaches the places where it is supposed to act"? Do changes in the capillary wall reduce insulin concentration at target cells and lead to type 2 diabetes? Is "insulin resistance" in reality a result of insufficient insulin transport? Good unanswered question...
Once again, insulin resistance (a reduced effect of the hormone) is an important element in type 2 diabetes. Current knowledge just might be summarized by "then something does not happen". While we do know a lot about "what happens" we have not come so far that we can design medicine to correct weaknesses here. This may surprise you, but the mainstays of diabetes treatment today are drugs discovered quite by accident. Let's look at these.
Treatment of type 2 diabetes
Treatment of diabetes today falls into two main categories. The first and most important is to try to overcome insulin resistance, to get the body's tissues back to the stage where they give a normal response to insulin. Two main approaches are used today. The first is to improve the body's physical condition; to increase exercise and reduce overweight.
Reduce insulin resistance:
Diet and motion:
1. Brisk walking at least 30 minutes per day.
2. Eliminating or markedly reducing intake of foods that give high and sudden increases of blood sugar (so-called high glycemic-index foods) .
3. Increasing intake of whole grain foods, fruit and vegetables.
4. Matching eating habits and exercise with a gradual weight reduction of around 10% of the body weight. Most important here seems to be reduction in so-called central fat (apple-formed men). Central fat seems to be much more correlated to development of type 2 diabetes than the subcutaneous variety.
French lilac or Goats Rue has been used since the middle ages to treat "excessive urine production" or "polyuria". Actually, this was often treatment of diabetes, but the relationship between polyuria and metabolism was unknown then. Water extracts of the plant have been shown to contain guanidine, a biguanide, and this was found to be the plant's active component and responsible for reducing urine production. We now know that it did this by sensitizing the patient's insulin target tissues to the hormone. Today's "metformin" is a slightly modified analog of the plant extract. In fact, we now know how this class of insulin-sensitizers work. More about that later on.
In any case, it is both surprising and interesting that one the most commonly used antidiabetic agents was not designed out from modern research but is a carry-over from medieval medicine!
The all-important point to have in mind here is that treatment of type 2 diabetes should begin during the prediabetic period and that the goal cited earlier ("THE BEST WAY TO AVOID THESE TREATS TO GOOD HEALTH IS TO MAINTAIN BLOOD SUGAR LEVELS SO NEAR NORMAL AS POSSIBLE") is the only way to prevent or slow the progress of complications. Frequently, these treatments with diet, exercise and metformin become less effective with time. Drugs activating release of insulin from the pancreas are then used.
Activation of insulin release from the pancreas
While increasing tissue sensitivity to insulin is an effective starting point for treatment of type 2 diabetes, a second medication to stimulate insulin release from the pancreas is often used. Again, the most common drug here was not found following diabetes research but was a spinoff from studies on antibacterial sulfa drugs. A French scientist, Marcel Janbon, "just happened to notice" that one of the compounds his group studied lowered blood sugar levels. That was the beginning of treatment with sulfonylurea compounds or "SU-derivative insulin releasers". These offer inexpensive and effective treatment of type 2 diabetes as long as the pancreatic ß-cells work as they should. The disadvantage to SU-therapy is that these drugs release insulin directly. That is, insulin release follows drug use and becomes uncoupled from food intake and blood glucose levels. This can lead to inappropriately high insulin levels and a marked fall in blood sugar levels or hypoglycemia with "feeling bad" as a result.
A new clinical approach currently being tried out uses a hormone analog (Exenatide) to release insulin. This increases insulin release coupled to blood sugar levels. That is, the hormone alone does not release insulin but augments release after a meal. Exenatide is not an oral medication, but must be injected. It is also expensive. Recently some questions about the Exenatide's safety have been raised.
The history back of this drug is interesting. Click here if you are interested in Gila Monsters!
Insulin and type 2 diabetes
The problem with insulin-releasers is that they are dependent on functioning ß-cells. These often appear to become "worn-out" and oral medication becomes less effective.
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that people who no longer can stabilize their blood sugar with diet, exercise, metformin plus SU-derivatives should consider dropping oral medication and go over to insulin therapy. Again, time is the major problem for people with diabetes. They should get control over blood sugar levels as soon as possible to avoid late complications.
Sugar is a poison
Did I hear "no, now you are exaggerating" or "after all, sugar is FOOD; we may eat too much of it, but it is Food"! OK, I accept those comments. But the body's reactions to increased levels of blood sugar are not OK. Lets look more closely at the problems here.
1. Sorbitol accumulation in tissues
Sorbitol is a naturally occurring sugar that we make ourselves from blood sugar. Normally this is a man's job. Sorbitol is an intermediate product in the production of fructose that we find in semen. Sperm cells thrive with fructose and use it as "lunch" on their way to the women's egg.
The problem here is that many of the body's tissues can also make sorbitol but they do not convert it to fructose. And, being one of our usual sugars, it cannot cross cell membranes without a special carrier. There is the problem! We have no carrier for sorbitol! That glucose carrier cannot move sorbitol. Increased blood sugar (glucose) levels increase glucose uptake to tissues and that leads to sorbitol formation. Since there is no carrier for this sugar, it accumulates in our tissues, especially the lens of the eye and in nerves. The rise in cellular sorbitol pulls increasing amounts of water into cells and this is damaging.
Sorbitol is used quite safely as a non-caloric sweetener. It has just as many calories as the other sugars in our diet, but it is not absorbed in the gut. Again, there is no carrier for this sugar. As long as we keep the daily consumption of sorbitol under 4-5 grams it is completely safe. If we eat more, gas production by bacteria in the gut can become rather unpleasant!
2. Glucose reacts with proteins
Blood sugar is not chemically inactive. As you can see from the figure, glucose has what we call a double-bonded oxygen and these are quite reactive. They combine spontaneously with our body's various proteins and, in doing so, modify them. Proteins have a great number of functions; they build our body's tissues, transport oxygen and carbon dioxide, carry messages from organ to organ and help to digest the food we eat, and much more. Many of the late complications of diabetes are thought to follow binding of glucose to proteins. There is no known specificity to this glucose-protein binding. The reaction merely follows the concentration of blood sugar. More sugar, more bound to proteins.
The protein depicted here is a normal red blood cell protein formed by combining glucose with hemoglobin. It is known as Hemoglobin A1c (HbA1c or A1C). There is a good correlation between blood sugar levels and glucose bound to hemoglobin. Since our red blood cells survive for about 100 days, the degree of glucose-binding to hemoglobin, (HbA1c) reflects the average blood glucose level for the prior three months.
This table shows the relationship between HbA1c levels and blood sugar levels. The green area shows the "good" data. The "normal" value for HbA1c is approximately 5 %. As you can see, there is a marked increase in HbA1c with elevated blood sugar levels.
We use HbA1c measurements to control the success of treatment of diabetes. The clinical goal here is to keep HbA1c levels below 7%. Almost half of the diabetes patients in the USA do not meet this goal! Note that 7% HbA1c correlates with a blood glucose level well over 7 mmol/liter. Think back to the figure about retinopathy. Blood glucose levels of 6-7 mmol/liter were absolutely in the area where many had eye damage! One really should strive to hold HbA1c levels as low as possible. The suggestion from the ADA and EASD that one should begin insulin treatment when oral medication ceases to be effective is based upon this data.
3. Interference with hormone signaling
This topic is extremely complex and I will just give an overview of some of its general aspects.
Once again, we have a situation where the mere increase in the amount of sugar in the blood will accelerate a common reaction in our cells. Again, we have the glucose carrier that transports glucose to our tissues. Its activity is directly related to the level of blood sugar. Amino acids, glutamine among others, are also taken up from the circulation. Normally, most of the sugar is used to provide energy to the cell, but a small percent combines with glutamine and forms hexosamines and an active compound (N-acetylglucosamine). The latter readily couples to proteins. Normal blood sugar concentrations permit only a marginal production of hexosamine and our organs function well with these levels. However, hexosamine and N-acetylglucosamine concentrations increase with increasing blood sugar and can interfere with cell function.
Recent research suggests that N-acetylglucosamine often couples to proteins that take part in hormone signaling. This alters or blocks normal messaging.
Integration or coordination of our numerous hormones (the list grows almost from week to week) is extremely important for our health and well-being. Some areas of importance are:
1. Stabilization and integration of the body's energy metabolism. That is, coupling together fat and sugar metabolism to provide the energy needed for short and long-term physical activity in all of our organs.
2. Control of growth and repair of our various organs.
3. Control of the body's metabolism and functions through the central nervous system. That is, maintenance of the healthy state through integration of signals to and from the brain.
4. The brain monitors our nutritional state and adjusts our appetite to stabilize this. The brain "knows" when we begin to lose weight and sharpens appetite to compensate for this.
To summarize, integrated hormonal regulation is essential for normal function of the body. Interference here may well be a major element in the long-term complications of diabetes.
Hormonal signaling and Mister 4-6
As I wrote above, this hormone-signaling thing is not easy to understand. At least three "nodes" are involved: these are the hexosamine signal system, the protein kinase system mTOR, and the adenosine monophosphate kinase (AMPK) signal system. Each has multiple components and they are interlaced.
Our bodies operate well when blood glucose levels are in the 4-6 mmoles/liter region. That implies that these three signal systems work together to hold blood sugar at this level. In addition, they are involved in regulation of growth and fat metabolism. Interestingly, research has shown that the positive effects of metformin come from interaction of the drug with the AMPK system. We can hope that medical research lead to further understanding of these signal systems. Perhaps new and better medications will be designed that work at specific sites in these systems.
How can you and I use this knowledge? I believe that most of us can come a long way by understanding that these elements find their correct actions and functions when resting blood sugar levels are between 4 and 6 mmol/liter. A healthy life-style and careful use of medication can help us hold blood sugar in this area.
1. Readers who want more information about hexosamine interference with normal metabolism can click here.
2. The American College of Endocrinology and the American Association of Clinical Endocrinology have recently published a statement concerning diagnosis and treatment of prediabetes. This is og major importance and can be downloaded here.