Transcription
The most well-known and clinically important complications of diabetes can be divided into two major groups: acute complications and chronic complications. I will begin with the acute complications.
First, let's discuss diabetic ketoacidosis. This is an acute complication of diabetes and a very important one. It is most commonly seen in type 1 diabetes, and make note of this: type 1 diabetes. Diabetic ketoacidosis usually develops when a person is not receiving sufficient insulin therapy, is not adhering to treatment consistently, or when the body is under severe stress and requires more insulin than usual. For example, during infections or when diabetes remains untreated for some reason.
To understand the mechanism of diabetic ketoacidosis, we need to return to the process of lipolysis. So, when fats are broken down, they are converted into free fatty acids, which are transported to the liver. The liver then converts these fatty acids into ketone bodies. Examples of ketone bodies include acetoacetic acid and beta-hydroxybutyric acid. Although you do not necessarily need to memorize those names, what is important is that ketone bodies can be used by cells as an alternative source of energy. As we discussed earlier, when glucose cannot be effectively utilized, the body begins to break down fat. Ketone body production is one of the main ways cells obtain energy from those fat reserves. At first glance, this may sound beneficial. However, ketone bodies also have an important negative effect. They lower blood pH. In other words, they make the blood more acidic. That is why this condition is called ketoacidosis. In fact, diabetic ketoacidosis is a form of metabolic acidosis. And since we have already discussed metabolic acidosis, I will not repeat the details here.
One additional point: this process generally does not occur in type 2 diabetes to the same extent because patients with type 2 diabetes usually still produce at least a small amount of insulin. Even a modest amount of insulin helps suppress lipolysis. And one of insulin's important functions is precisely to prevent excessive ketone body formation. And here you can see also a whole range of symptoms and signs that may result from diabetic ketoacidosis. As I mentioned earlier, many of these should already be familiar to you because we discussed them when talking about metabolic acidosis. One example is the characteristic rapid, deep breathing. Another important feature is severe dehydration. Large amounts of glucose are lost in the urine, and as we discussed before, water follows glucose osmotically. This leads to substantial fluid loss. The deep, rapid breathing is a compensatory response to metabolic acidosis. The body attempts to remove the excess carbon dioxide through the lungs in order to partially compensate for the increased acidity of the blood.
One particularly characteristic symptom of diabetic ketoacidosis, which is not typical of metabolic acidosis in general, is that the patient's breath often has a sweet or fruity odor. This occurs because ketone bodies are broken down into acetone, and acetone is exhaled through the lungs. In other words, the body is trying to eliminate it. Additionally, patients may also experience abdominal pain, nausea, vomiting, and in severe cases of diabetic ketoacidosis, disturbances of consciousness may occur, including apathy, confusion, or reduced alertness, and in very severe cases, coma. One additional complication that is not shown here is the development of cardiac arrhythmias, which may occur as a consequence of hyperkalemia.
It is also important to note that poorly controlled diabetes is often associated with a weakened immune system. As a result, these patients become more susceptible to infections. One common example is candidiasis, but more broadly, they may become vulnerable to infections that are typically seen more often in individuals with some degree of immunodeficiency. In that sense, poorly controlled diabetes can sometimes make patients appear clinically similar to individuals with an impaired immune system. One particular important infection is mucormycosis. The term mycosis already suggests that it is a fungal infection. Mucormycosis is a potentially life-threatening fungal disease caused by fungi of the order Mucorales, which also includes organisms related to common bread molds. It often begins in the paranasal sinuses and can cause extensive tissue necrosis. From there, it may spread into surrounding structures, including the brain, resulting in very severe damage. And besides mucormycosis, other fungal infections can also pose a significant threat to diabetic patients, especially those whose diabetes is poorly controlled.
The second acute complication I want to discuss typically affects patients with type 2 diabetes. This condition usually develops when blood glucose levels become extremely high, often above 30 millimoles per liter. And this is called hyperosmolar hyperglycemic state. At first, the name may sound rather intimidating, but if we break it down, it becomes much easier to understand. So, hyperosmolar means that the blood osmolarity is excessively high. Hyperglycemic means that there is too much glucose in the blood. So, the name is actually quite descriptive. Such an extreme concentration of glucose in the blood leads to severe cellular dehydration. Remember that glucose is a polar, osmotically active molecule. This means that it promotes osmotic movement of water. When there's a very high concentration of glucose in the bloodstream, water is drawn out of the cells and into the blood vessels. As a result, cells lose water and become dehydrated. This is why the blood becomes hyperosmolar. And of course, the condition is called hyperglycemic because there is an extremely high concentration of glucose in the blood. In other words, the blood contains so many dissolved glucose molecules that water begins to leave the cells, causing them to shrink and become dehydrated.
The next steps in the process are similar to what we saw in diabetic ketoacidosis. Excess glucose is filtered into the urine. This leads to glycosuria, or glucose in the urine, followed by osmotic water loss, resulting in polyuria, excessive urination. Consequently, the body loses enormous amounts of fluid. This produces severe dehydration. The brain is particularly vulnerable because it is very sensitive to changes in osmolarity. Therefore, patients may develop lethargy, confusion or disorientation, and seizures, and eventually coma. Without treatment, the condition can ultimately lead to death.
So, what is the main difference between this condition and diabetic ketoacidosis? The key point is that this is not ketoacidosis. Significant ketone production does not occur because these patients usually still have enough baseline insulin to suppress lipolysis and ketone body formation with that. However, even without ketoacidosis, the extreme degree of cellular dehydration is by itself a very serious and potentially life-threatening problem.
Another acute complication that can occur in both types of diabetes, this time, is hypoglycemia. So far, we have been talking about hyperglycemia, high blood glucose, but the opposite can also happen. A patient may be treated for diabetes so aggressively that blood glucose falls too low. In other words, this is a potentially dangerous complication of diabetes treatment. Hypoglycemia most commonly occurs during insulin therapy because it is relatively easy to administer too much insulin or to administer it at the wrong time, causing blood glucose levels to drop excessively. However, some oral anti-diabetic medications can also cause hypoglycemia, meaning that this complication may occur in patients with type 2 diabetes as well.
The brain, and especially its neurons, is particularly vulnerable to hypoglycemia because glucose is its primary source of energy. If there is insufficient glucose available, hypoglycemia can result in irreversible neuronal injury. The symptoms of hypoglycemia can be divided into two categories. First, there are symptoms caused by the activation of the autonomic nervous system. As blood glucose falls, the body releases adrenaline and other stress hormones, and therefore, this leads to symptoms such as palpitations, sweating, tremor, nausea, and intense hunger. The feeling of hunger is particularly pronounced because the hypothalamic hunger centers respond to the lack of glucose and stimulate food intake. These symptoms serve as warning signs that more serious problems may soon develop.
The second category consists of neuroglycopenic symptoms. These are the most dangerous symptoms because they indicate that the brain is no longer receiving enough glucose. Early manifestations include dizziness, drowsiness, and weakness. As hypoglycemia worsens, patients may develop confusion, disorientation, behavioral changes, and ultimately, severe hypoglycemia can progress to coma. And the outcome may be even more serious if treatment is not provided. Therefore, without prompt recognition and treatment, hypoglycemia can be life-threatening. So, these would be then the main acute complications of diabetes.
Now let's move on to the chronic complications of diabetes. I think some of these will already be familiar to you, and you've probably heard about some of them before. Unlike the acute complications we just discussed, chronic complications develop gradually over many years of elevated blood glucose levels. Long-term hyperglycemia damages blood vessels, nerves, and various organs throughout the body. As a result, diabetes can affect multiple organ systems simultaneously.
First, let's discuss non-enzymatic glycation. In fact, you have already heard about this chronic complication, certainly at least twice during this course. And let me remind you that it is called non-enzymatic because glucose attaches covalently to other molecules without the help of enzymes. Up to this point, we have mostly been discussing situations where glucose binds to proteins. But in reality, non-enzymatic glycation can also occur with lipids. In other words, glucose can attach to lipids both inside cells and within blood vessels. Until now, we have mainly focused on what happens in the blood vessels. As a result, so-called glycated molecular complexes are formed, and these complexes are actually pro-inflammatory. They can damage cells and tissues, thicken basement membranes, and make blood vessel walls stiffer and more fragile.
Now, let's look at some examples of non-enzymatic glycation. I will not spend time on the first one because hyaline arterial arteriosclerosis has already been covered. If you have forgotten it, you can simply go back a few lectures and review it. As for the others, I will briefly discuss them. Diabetic retinopathy is a disease that affects the blood vessels of the retina. It develops primarily as a consequence of poor metabolic control, meaning inadequate long-term control of blood glucose levels. It is diagnosed by an ophthalmologist who can observe retinal hemorrhages and other characteristic changes during an eye examination. Uncontrolled blood glucose gradually causes progressive damage to the retina, which can eventually then result in complete vision loss. Fortunately, this outcome is largely preventable with proper diabetes management. However, once vision has been permanently lost, it generally cannot be restored. At that point, the goal is to prevent further progression.
Next is diabetic nephropathy. Here again, chronically elevated blood glucose gradually damages the small blood vessels of the kidneys, particularly those within the nephron's filtration system. The kidneys normally act as a filter that cleans the blood. When the glomerular capillary network becomes damaged, the filtration process becomes less effective. Substances that should remain in the blood may begin to pass into the urine. One of the earliest signs is the appearance of small amounts of albumin in the urine. Therefore, in patients who undergo regular urine testing, microalbuminuria can serve as one of the first indicators of diabetic nephropathy, and without treatment, the process may gradually progress to chronic kidney disease.
And then the fourth complication is atherosclerosis, which primarily affects the large blood vessels. Now let me say a few more words about atherosclerosis. For patients with diabetes, one of the most important forms of atherosclerosis is that of coronary arteries. As a result, coronary artery disease develops. Make a note of this: coronary artery disease is the leading cause of death in people with diabetes. In other words, chronic hyperglycemia damages the coronary arteries and greatly increases the cardiovascular risk. If you need a refresher on coronary artery disease, you can also revisit the second lecture.
The next, the arteries of the legs are also frequently affected. This can lead to ulcers, tissue ischemia, gangrene. If blood glucose remains poorly controlled and the problem is ignored, the disease may ultimately result in amputation of one or even both limbs. In many cases, the severity of these complications is closely related to the patient's adherence to treatment. In fact, the same can be said for most diabetic complications. Good long-term glucose control significantly reduces the risk of these outcomes here. Unfortunately, not all patients are able to maintain optimal diabetes management consistently.
Well, and finally, there's another particularly dangerous form of atherosclerosis, which is the atherosclerosis of the cerebral arteries. When diabetes damages the arteries supplying the brain, the risk of stroke and transient ischemic attacks increases substantially. Some of these ischemic episodes may be temporary, but they remain important warning signs of cerebrovascular disease.
Now let's move on to another complication, or rather another mechanism of damage: osmotic cellular injury. Once again, we are dealing with osmotic balance and how this mechanism works. Normally, when glucose enters the cells, it is used in glycolysis and subsequently for ATP production. However, there are certain cells into which glucose can enter without the help of insulin. As I mentioned before, these are insulin-independent cells. In some of these insulin-independent cells, a specific metabolic pathway does not function the same way it does in other tissues. Under normal circumstances, glucose that is not immediately used for glycolysis can be converted into sorbitol. You may recognize that name. Firstly, the ending -ol suggests that it belongs to the family of alcohols, and that is indeed the case. Interestingly though, our taste buds perceive sorbitol as a sweet substance, which is why it is also used as an artificial sweetener. So, when glucose concentrations inside cells become very high, some cells convert glucose into sorbitol and then further convert sorbitol into fructose. However, it turns out that not all cells can efficiently perform this second step. Cells that are particularly limited in this regard include lens cells, retinal cells, and Schwann cells associated with neurons, and also certain renal epithelial cells. Most of insulin-independent cells are able to convert sorbitol further into fructose. Of course, in a healthy person, this is usually not a major issue at all because blood glucose levels do not become excessively elevated. Therefore, this mechanism mainly becomes relevant in poorly controlled diabetes.
So, what is the problem with sorbitol? Just like glucose, sorbitol is osmotically active. In fact, it may be even more osmotically active than glucose. This means that sorbitol attracts water. But in this case, the process occurs inside the cell. As sorbitol accumulates, water is drawn into the cell, and the consequences are: the cell begins to swell. And quite often, that means too much water enters the cell, and this swelling occurs.
Now let's look at some typical examples of the complications that can result from this process. So, if sorbitol accumulates in the lens of the eye and draws water into it, the result is often cataracts, meaning clouding of the lens. On the other hand, when talking about Schwann cells, let me remind you that Schwann cells are the cells that produce the myelin sheath around peripheral nerves. I should also remind you that the myelin sheath enables faster nerve impulse conduction. Now imagine what happens if these Schwann cells become damaged. This means that the amount and quality of myelin surrounding peripheral nerves decreases. The nerves most commonly affected are sensory nerves and nerves of the autonomic nervous system. This process, in which Schwann cells are damaged and can no longer maintain normal myelin production, is known as diabetic neuropathy. As a result, the most distal parts of the body gradually become less sensitive, and guess which parts are furthest from the body? The hands and the feet. Of course, this is why diabetic neuropathy is often described using the glove and stocking pattern. Patients may feel as if they are wearing gloves or socks because these areas have become numb or less sensitive. At the same time, these tissues become more vulnerable to injury. Also, foot ulcers commonly develop as a consequence of chronic damage, and furthermore, elevated blood glucose levels impair wound healing. Because of chronic hyperglycemia, wounds tend to heal more slowly. That is why at the very beginning, when discussing diabetes, I emphasized the importance of regular foot examinations to detect non-healing ulcers.
Then, damage to autonomic nerves can also produce a variety of gastrointestinal symptoms. For example, stomach motility may be reduced because parasympathetic nerve fibers no longer function optimally. And when gastric peristalsis slows down, patients may experience vomiting after meals, delayed gastric emptying, and constipation.
As you can see, diabetes is a very complex disease with many different complications. Considering the large number of people affected by diabetes, early diagnosis and patient education should be major priorities. Early detection, good glucose control, and adherence to treatment can significantly reduce the risk of these long-term complications.