Lecture 5 - Diabetes mellitus

One important systemic disease that we definitely need to discuss is diabetes mellitus. It is a condition in which glucose cannot be transported effectively from the blood into the cells. As a result, blood glucose levels become elevated while the amount of glucose available inside the cell is insufficient. Since glucose is an essential source of energy for cells, the inability of glucose to enter the cells means that the cells experience an energy deficit. Even though glucose may be present very close to them in the bloodstream, glucose unfortunately cannot simply enter the cell on its own. It requires assistance.

So first we will briefly review how this mechanism works under normal conditions and then we will move on to the different types of diabetes. First let's once again briefly review normal glucose metabolism in the blood. To begin with, there's always some glucose present in the bloodstream. Depending on the country, blood glucose may be measured in mg per 100 ml or deciliter, and that is the case in Romania, as far as I know. But in Latvia and Finland, more millimoles per liter are used. A normal blood glucose concentration, and this may also vary from country to country, is approximately from 3.9 to 5.9 millimoles per liter. So I should also mention that this reference is the Latan reference, and it was increased or rather adjusted in 2024. Now, it was previously a little bit lower, 3.5 to 5.5 millimoles per liter, but modern reference values are, as you see, somewhat higher.

Now we will also discuss the fact that blood glucose levels are regulated primarily by two hormones: insulin and glucagon. Of course, other hormones also influence glucose metabolism, but insulin and glucagon are the two most important regulators. And here also, a quick terminology reminder. If blood glucose levels are too low, the condition is called hypoglycemia. If blood glucose levels are elevated, which is the main topic we will discuss today, the condition is called hyperglycemia. And by the way, when blood glucose exceeds approximately 30 millimoles per liter, a diabetic coma may occur. Also, so that you don't get lost into all these different units, I will tell you right away how conversion from mg per deciliter into millimoles per liter works. Basically, if you have something in millimoles per liter, you take the number and multiply by 18. So let's say you have a glucose level of 5.00 in millimoles per liter times 18. This would be the 90 mg per deciliter. And it works, of course, the other way around. You can take mg per deciliter and divide them by 18, and you get back the value in millimoles per liter. So this is a quick life hack to not get lost in the units, because I will mostly use both unit systems in this lecture.

Returning to the regulation of blood glucose levels. I mentioned that this is controlled by two hormones: insulin and glucagon. Both of these hormones are produced in the pancreas, where there are specialized clusters of cells called the islets of Langerhans. The islets of Langerhans contain several different types of cells. The cells that produce the hormone glucagon are called alpha cells. The cells that produce insulin are called beta cells. I should also mention the delta cells. These produce a third hormone, somatostatin, which actually helps regulate the activity of the other two hormones we just discussed. We will also be talking about glycogen further on. And to avoid mixing up all these similar-sounding glyco-terms, what you can do is, firstly, remember that glucagon sounds similar to the word hormone. So glucagon is a hormone. Maybe this can help you remember when we're talking about the hormone and when we are talking about glycogen, which is simply the storage form of glucose. Anyway, let's return to the roles of these hormones.

So, first of all, insulin is critically important for the entry of glucose into cells. As I mentioned earlier, glucose cannot enter the cell on its own without assistance. When blood glucose levels rise, the pancreas automatically releases insulin, provided everything is functioning normally. Of course, as illustrated in the animation here, insulin acts like a key that unlocks the cell membrane's gates, so to speak, allowing glucose to enter the cell. But if we talk about this mechanism more seriously and a bit more realistically, here is what actually happens. Insulin lowers the level of glucose in the blood by binding to insulin receptors located in the membranes of insulin-dependent tissues. In the illustration here, insulin is represented by the small triangles. As the name suggests, insulin-dependent tissues are those tissues that require insulin for glucose transport into the cell. Examples include skeletal muscle cells and adipose tissue, so fat tissue. Once the insulin receptor is activated, a process is triggered inside the cell. Here you can see a vesicle. These vesicles contain glucose transport proteins. So when the receptor is activated, these vesicles fuse with the cell membrane, and the transport proteins become inserted into the membrane itself. These transport proteins have also specific names. For example, GLUT4 is one of these transporters. Once inserted into the membrane, they allow glucose to enter the cell. As a result, glucose is removed from the bloodstream, although of course not all of it, as we know. And the cells can then use this glucose as a source of energy for ATP production.

One more important point regarding glucose regulation: it is clear that after a meal, blood glucose levels rise. We refer to this as postprandial hyperglycemia or dietary hyperglycemia. So, as explained earlier, hyperglycemia simply means an elevated blood glucose level. By adding the term postprandial or dietary, we emphasize that this is a temporary physiological state, not a permanent condition. When blood glucose levels increase, specialized receptors detect this rise, which in turn stimulates the pancreas to release insulin through the mechanism discussed previously. Insulin promotes the uptake of glucose into cells. This process is particularly important in tissues with high energy demands, including the liver, adipose tissue, and skeletal muscles. A small but important detail in the liver: glucose can enter the cells without insulin, actually. Similarly, neurons in the brain are largely insulin-independent with respect to glucose uptake. This is a crucial protective mechanism. Even if insulin function is impaired, the brain does not immediately lose its energy supply because neurons are still able to obtain glucose and continue producing ATP. Also, the liver plays a central role in glucose metabolism. Overall, both the liver and skeletal muscles serve as major storage sites for glucose because not all glucose is used immediately for ATP production. Instead, excess glucose is stored in the form of glycogen. So, what is exactly glycogen? Essentially, glycogen consists of many, many glucose molecules linked together, forming a large and complex storage molecule. In this form, glucose can be stored as an energy reserve for future needs. When required, the liver and, to some extent, skeletal muscle can convert glycogen back into glucose. The released glucose can then be used for ATP production, providing the cells with the energy they need. So with the help of insulin, glucose is successfully transported to various tissues. And as I said, in particular, it is stored in the liver and skeletal muscles, where it forms glycogen reserves, the body's glucose stores. Of course, every storage system has its limited capacity. Once the glycogen stores are filled to their maximum capacity, they cannot take in any more glucose. And at that point, the remaining glucose is converted into fat stores and begins to be stored in the form of lipids rather than glycogen. And this does not happen only in adipose tissue. It can also occur in the liver itself, where excess nutrients may be converted into fat and deposited. All of these processes are coordinated and regulated, of course, by insulin.

And now let's talk a little about the function of glucagon. Broadly speaking, glucagon can be thought of as a hormone that has the opposite effect of insulin. If insulin helps glucose enter the cells, then glucagon acts in the opposite direction by helping to release glucose back into the bloodstream. Here we are mainly talking about the liver. Glucagon stimulates the liver to break down its stored glucose reserves and release glucose into the blood. One might wonder in what situations would such a hormone be necessary, because it's easy to understand why insulin is needed. After a meal, blood glucose rises and needs to be brought back down. But the opposite situation can also occur. There may be too little glucose in the bloodstream. For example, a person may not have eaten for a long time, whether intentionally or unintentionally. As blood glucose gradually falls, symptoms of hypoglycemia may begin to appear, such as dizziness, nausea, and other signs of low blood sugar, as it is called. In such situations, glucagon acts as a rescue hormone. It mobilizes the liver's glycogen stores, breaks glycogen down into glucose, and releases glucose back into the bloodstream. Of course, if you look at the picture here, in reality, the liver is richly supplied with blood vessels and it is not physically separated from the circulation the way it may appear in the diagram here. The illustration is simply meant to make the concept easier to understand. Then there is another situation in which glucagon may be useful: after a particularly large meal containing a lot of carbohydrates. A substantial amount of insulin may be released. Sometimes insulin removes glucose from the bloodstream so effectively that blood glucose begins to fall more than intended. In that case, glucagon once again comes to the rescue, releasing a small amount of glucose back into the circulation. In this way, insulin and glucagon work together to maintain a stable blood glucose concentration.

So once again, here is the same diagram and the same overall concept. The pancreas secretes both of these regulatory hormones. And while we're at it, let me remind you that the pancreas also produces digestive enzymes. Then, talking about hormones, glucagon is the hormone that converts glycogen back into glucose when the body is running low on glucose. And insulin, on the other hand, does the opposite. It promotes the uptake of excess glucose from the bloodstream into cells. And as I mentioned earlier, there is also a third hormone secreted by the pancreatic delta cells called somatostatin. I will not go into great detail about it here, since this is not a lecture on endocrinology. However, it is worth mentioning that somatostatin helps regulate both insulin and glucagon by preventing their excessive secretion and activity, because of course, it is also possible for these hormones to be released in excessive amounts.

So we have briefly now gone through the basics of normal glucose metabolism, and now that we understand how things work under normal conditions, we can start discussing what happens when they do not work normally. We are now going to talk about diabetes mellitus and its two main types. I will present the classification into type 1 and type 2 diabetes. Although in modern clinical practice, there are now several recognized subtypes, especially within type 2 diabetes. However, for the purposes of this discussion, I will focus on the traditional distinction between these two major types and then briefly mention a few other diabetes-related conditions outside of this classification.

So, first of all, how do these two forms of diabetes differ? Looking at this image while I'm speaking, even without any prior knowledge, you can probably already start to identify and guess some of the differences. At the same time, there are also a number of features that the two conditions have in common. So these common features are the four classic clinical signs of diabetes mellitus. Of course, we are talking here about uncontrolled diabetes. The four signs are polyphagia, which is increased hunger; glucosuria, glucose in the urine; polyuria, excessive urination; and polydipsia, excessive thirst. Let's look at them one by one.

First, let's look at polyphagia. In uncontrolled diabetes, there is plenty of glucose in the bloodstream. As we already discussed, these are symptoms seen when diabetes is not properly controlled. So there's a lot of glucose in the blood, but it is unable to enter the cells. As a result, the cells are effectively starving. Of course, cells cannot simply remain in a state of starvation. They need energy to function. To compensate, the body begins to obtain energy from other sources. So adipose tissue starts breaking down its stored fat, a process known as lipolysis. And we have discussed this already. The suffix -lysis means breakdown or destruction. You may remember a similar term in hematology: hemolysis, destruction of red blood cells. And also, I have mentioned these specific organelles, lysosomes, specialized in breaking down substances. So whenever you see the term -lysis, it generally means that something is being broken down. In this case, lipo- fat, and lipolysis is breakdown of fat. But that is not the only process taking place. The body also undergoes proteolysis, meaning the breakdown of proteins. Although the cells in the picture may seem like smooth muscle tissue, this occurs particularly in skeletal muscle, which contains abundant protein reserves that can be used as an energy source. The name itself tells us what is happening: protein and -lysis, breakdown of proteins. Through both lipolysis and proteolysis, the body can generate the energy that cells desperately need. However, these processes also lead to weight loss in patients with uncontrolled diabetes. Fat stores are depleted, and over time, muscle mass also begins to decrease. Losing fat may initially seem desirable to some people, but losing muscle is certainly not. This accelerated breakdown of fats and proteins ultimately produces a persistent sensation of hunger. And this brings us back to the term polyphagia. Poly- meaning much, phagia- eating or food intake. In other words, polyphagia means excessive hunger or increased appetite. The patient feels hungry because, despite having high levels of glucose in the blood, the body behaves as if it is starving while simultaneously losing both fat and muscle tissue.

In addition, when blood glucose levels become very high, and we have already touched on this topic, the kidneys are no longer able to reabsorb all of the glucose. This occurs when the renal glucose threshold is exceeded, which is typically around 10 to 11 millimoles per liter, although the exact value may vary somewhat between individuals. So once blood glucose reaches this critical level, there is simply too much glucose for the kidneys to reclaim and return to the bloodstream. As a result, some of the glucose remains in the urine. And as we have already discussed, this phenomenon is called glucosuria. In other words, glucosuria is the presence of glucose in the urine. In addition to this phenomenon, we also observe polyuria. You already know that poly- means many or excessive, and -uria refers to urination. The reason for this is that glucose is osmotically active, similar to sodium. Where glucose goes, water follows. In this situation, glucose is not reabsorbed back into the bloodstream but is instead excreted in the urine. Because glucose remains within the nephron tubules, it draws water along with it. As a result, the volume of urine increases significantly. This excessive urination then is called polyuria. Up to this point, when discussing kidney disorders, we have often talked about the opposite situation: reduced urine output or even absence of urination. Here, however, the situation is exactly the opposite: too much urination. So, this is the third consequence that follows naturally. And the last one then is, if a person is losing excessive amounts of fluid through urination, they gradually become dehydrated. This leads to the final symptom then: polydipsia. Polydipsia means increased thirst. The person feels the need to drink continuously because the body is losing fluid and the cells are becoming dehydrated, as water is essentially being urinated away. So these are the four clinical signs: increased hunger, glucose in the urine, excessive urination, and excessive thirst, and these are found more or less in all forms of uncontrolled diabetes.

Now we can move on to the features that distinguish the different types of diabetes. First, let's discuss type 1 diabetes mellitus. This is an autoimmune disease, and I already mentioned it as an example in the first lecture when we talked about autoimmune disorders. It is also worth noting that autoimmune diseases often occur together. Therefore, when taking a patient's medical history, other autoimmune conditions are frequently found alongside type 1 diabetes. In this form of the disease, the immune system specifically targets and destroys the beta cells in the pancreas. The destruction of these beta cells begins early in life, although symptoms usually appear before the age of 30. In type 1 diabetes, the body's tissues remain highly sensitive to insulin, but there are too few functioning beta cells, and therefore insulin levels are just low. As a result, the cells do not receive the insulin they need. So the problem is not with the insulin receptors and not with the insulin sensitivity. The problem is a true deficiency of insulin. And histological samples typically show a destruction of beta cells and leucocyte infiltration in the islets of Langerhans. In most cases, we are mainly talking about lymphocytes with some contribution from macrophages, but predominantly lymphocytes. This reflects the underlying autoimmune inflammation and ongoing destruction of the pancreatic beta cells.

Now, if we talk about type 2 diabetes, which we will discuss in a little more detail, it typically develops after the age of 40. In type 2 diabetes, the body does produce insulin, but the tissues respond poorly to it. The exact biochemical mechanism explaining why cells become less responsive is not completely understood. However, we do know that certain factors can increase the reduced sensitivity of insulin receptors. One of these factors is the regular consumption of large amounts of carbohydrates, especially simple carbohydrates, meaning monosaccharides. When large quantities of simple sugars are consumed frequently, insulin is released repeatedly because it responds to the rise in blood glucose. Over time, the receptors gradually become less sensitive to insulin, and this reduced responsiveness is known as insulin resistance. In fact, type 2 diabetes is often referred to as insulin-resistant diabetes. In essence, the body may produce a normal amount of insulin, but the cells become unable to efficiently place the necessary glucose transport proteins into the membranes in response to insulin. The most important risk factor for insulin resistance is obesity. In addition, genetic predisposition also plays an important role. From a genetics perspective, type 2 diabetes is considered a multifactorial disease, meaning that both genetic and environmental factors contribute to its development. This means that neither genetics nor environment alone can completely determine whether a person will develop the disease, but both can significantly increase the risk. The genetic component has also been demonstrated in twin studies. For example, if one twin has type 2 diabetes, the risk for the other twin is substantially increased, even when environmental influences differ. At the same time, type 2 diabetes is generally regarded as a largely preventable disease, even in individuals with a strong genetic predisposition. This is because the major risk factors are largely modifiable, like excess body weight or frequent consumption of large amounts of carbohydrates or a sedentary lifestyle. So these are all factors that one can change in their life.

Now, because the tissues do not respond adequately to normal insulin levels, the body initially compensates by producing more insulin. The goal is to achieve the same effect and continue removing glucose from the bloodstream. And actually, for a period of time, this compensatory mechanism works reasonably well. The elevated insulin levels help maintain near-normal blood glucose concentrations. However, this compensation is not sustainable indefinitely. Over time, the pancreatic beta cells become overworked, and one could say that the beta cells eventually become exhausted. Their function gradually deteriorates, and they may ultimately begin to die. When this happens, insulin production starts to fall. This is why type 2 diabetes can be somewhat deceptive. Insulin levels vary depending on the stage of the disease. At the time of diagnosis, a patient may have very high insulin levels, normal insulin levels, or markedly reduced insulin levels. Therefore, insulin concentration by itself is not always a reliable test for diagnosing type 2 diabetes, and that is why we rely on blood glucose measurements and other diagnostic tests, which we will discuss a little later.

So, what is the situation with type 2 diabetes in some countries? Well, it seems that things are not looking particularly good. I did not spend much time discussing the numbers for type 1 diabetes, but I do want to emphasize them for type 2 diabetes because, as I said, this is a preventable disease. So, regarding Latvia, according to estimates from the Ministry of Health of the Republic of Latvia, approximately 7,000 new cases of diabetes are diagnosed each year. However, in recent years, the number has actually been closer to 8 to 10,000 new patients annually. So the figure of 7,000 may no longer fully reflect the current situation. Considering Latvia's relatively small population, this is a remarkably large number of new cases. Moreover, the total number of people living with diabetes is approaching 100,000 individuals. And if we also add patients with type 1 diabetes, that would contribute roughly another 10 to 20,000 people altogether. That means that the total number of people affected by diabetes in Latvia is very substantial. Now, when you stop and think about it, those numbers are quite striking, aren't they?

Now, regarding Finland, the situation is not better. In Finland, diabetes is diagnosed in approximately 24,000 patients each year, and the total number of patients is approximately 424,000 people. Now, regarding Romania, well, Romania does not appear to have a national diabetes registry as detailed as Finland's THL registry. So, the figures are more often estimates or based on health insurance records. Reliable current annual incidence figures for type 2 diabetes alone are harder to find. So what I found was that 1.5 million patients were diagnosed in 2021. Unfortunately, especially in English, I couldn't find more recent numbers. And then the total number of patients could be around 1.1 to 1.8 million people, assuming that there are 1.1 million diagnosed diabetes two patients. But assuming that there are a lot of undiagnosed patients, the numbers could go as high as 1.8 to 1.9 million people overall. So actually, regarding the percentage of the total population, in Finland, it's around 7% of the total population. And it is somewhat similar in Latvia too, also 7%. Still, well, not a great number, but uh, still not a very good number. Actually, it is a very high number. But in Romania, the estimated number is well, 9 to 12% of the whole population of adults. So this is even a bit higher than Finland and Latvia.

Now, and I also promised to mention some other forms of diabetes. In addition to type 1 and type 2 diabetes, there are several other subtypes. One of the most important and one that is commonly tested is gestational diabetes. This is a condition that occurs only during pregnancy, in particular, during the third trimester. As pregnancy approaches term, some women may develop elevated blood glucose levels. This happens because the placenta produces large amounts of a hormone called human placental lactogen. According to current understanding, this hormone promotes insulin resistance. Some women, not all, but some, are unable to produce enough insulin to compensate for the effects of this placental hormone. As a result, blood glucose levels rise, and signs of diabetes begin to appear. Gestational diabetes may be a temporary condition, but unfortunately, not always. Its outcome depends partly on how well it's managed during pregnancy. Although management is not the only factor involved. In some cases, even when gestational diabetes is treated appropriately, diabetes may persist after delivery. Then diabetes can also develop secondary to other systemic diseases. And in addition, it can be caused by certain medications. One of the most common examples are corticosteroids, because corticosteroids can also induce insulin resistance.

Now, in here I have uh, one more summary comparing the two types of diabetes. Perhaps the one detail worth highlighting, which I have not mentioned yet, is the origin of the name diabetes mellitus. And the word diabetes comes from the Greek term meaning "to pass through," referring to the excessive urination or polyuria seen in the disease. And the second term, mellitus, comes from Latin and means "honey" or "honey-sweet." This refers to the presence of glucose in the urine. In fact, there was a time before blood glucometers existed when diabetes was diagnosed by examining, and historically, even tasting the urine. So, if you had been a physician in ancient times, long before modern laboratory tests, you might have found yourself tasting urine in order to diagnose diabetes. Fortunately, medicine has advanced quite a bit since then. And as for the rest of the comparison here, we have already covered the major points.

So now let's move on to diagnosis. So how do we diagnose diabetes? There are several methods. Naturally, all of them revolve around measuring blood glucose levels. But diagnosis is usually based on one or more of the first three methods mentioned in this table in combination with the final test, the glycated hemoglobin test. In any case, whether we are dealing with type 1 or type 2 diabetes, diagnosis is fundamentally based on assessing the amount of glucose in the blood. One of the most commonly used tests is the fasting blood glucose test. Many of you have probably undergone this test yourselves. It is performed after fasting, meaning that you should avoid food and drinks, except water, of course, for about 8 hours beforehand. Blood glucose then is measured, and ideally, the result should not exceed the current upper reference value of approximately 5.9. However, if the value is higher, there is no need to panic immediately. The exact number matters, but it may not necessarily indicate diabetes. And also, you have to remember there is a pre-diabetic state, which can still be reversed if a person changes their lifestyle and diet. Therefore, no diagnosis is based on a single test alone.

Glucose can also be measured at any time of the day. In that case, however, it is important to consider whether the person has recently eaten or not. But anyone can perform such measurements at home using a glucometer. Even after eating, blood glucose, though, should not exceed 11 millimoles per liter. Under normal circumstances, postmeal hyperglycemia does not rise above these values, although the exact interpretation depends on the situation and what has been consumed. Of course, another method is the oral glucose tolerance test. In this test, a person drinks a standardized amount of glucose, and blood samples are then taken at specific intervals to evaluate how effectively the body can remove glucose from the bloodstream. After approximately 2 hours, blood glucose levels should have returned to the normal range. If they have not, the results are interpreted in the context of the individual clinical situation. Incidentally, this is a test that we sometimes demonstrate with students. Instead of giving though pure glucose, we may use different food products and then compare how various foods affect blood glucose levels, how high they raise it, and how quickly those levels return toward normal. So, this is something you may also experience in the nearest future.

And then the final and essentially indispensable test when evaluating diabetes is the HbA1c test, also known as the glycated hemoglobin test. So when blood glucose remains elevated for long periods, glucose begins to bind to proteins throughout the body, including proteins circulating in the blood. And one of these proteins is, of course, hemoglobin. This test measures the percentage of hemoglobin molecules that have glucose attached to them. This glucose-bound form is called glycated hemoglobin, which is where the test gets its name. If everything is normal, the HbA1c value should generally be 6.5% or lower. In other words, this is generally considered within the normal non-diabetic range. In this lecture's context, this test is an excellent diagnostic marker because glucose does not bind to hemoglobin overnight. Unlike a single blood glucose measurement, which only reflects the situation at that particular moment, this test provides information about long-term glucose control. After all, a normal glucose value today tells you very little about what happened yesterday, last week, or last month. And once glucose has attached to hemoglobin, that process cannot simply be reversed overnight. For this reason, the HbA1c test reflects the average blood glucose level over approximately the previous 3 months. Why 3 months? Because that is roughly the lifespan of a red blood cell. The glucose remains attached to hemoglobin until the cell itself is removed from circulation. And that is why glycated hemoglobin is such a valuable test in diabetes. It allows us to determine whether blood glucose has been elevated over the long term, rather than only at a single point in time. And as I mentioned earlier, this test is usually interpreted together with fasting glucose measurements, providing a much more complete picture of the patient's metabolic status. And of course, additional laboratory tests may also be performed, but we will not go into those in detail right now.

As for treatment, type 1 diabetes always requires insulin therapy because insulin production is either severely reduced or completely absent due to the destruction of beta cells. The treatment of type 2 diabetes, however, is quite different. First and foremost, it begins with lifestyle modification. This is because the disease is usually influenced not only by genetics but also by the patient's lifestyle. Lifestyle changes include increasing physical activity, improving dietary habits, and weight reduction when necessary. In addition, there is pharmacological treatment. The usual first-line medication is metformin, although other options are also available. In any case, each patient requires an individualized approach. This includes a personalized dietary plan, guidance from an endocrinologist or other healthcare professionals, and selection of the most appropriate medication for that individual. Insulin is added to treatment only if these measures fail to provide adequate glucose control. In other words, insulin is not usually started immediately in type 2 diabetes. The patient's condition is assessed first to determine whether insulin is actually necessary. Starting treatment of type 2 diabetes with insulin as the very first step would generally be considered inappropriate unless there is a specific clinical indication. And in addition, patients should also undergo annual screening for diabetic complications, which we will discuss later in this lecture. These evaluations should include an examination by an ophthalmologist to assess the eyes, regular urine testing, including checks for protein in the urine, assessment of glomerular filtration rate to monitor kidney function, and foot examinations to evaluate for neuropathy and diabetic ulcers. These follow-up assessments are extremely important because diabetes can significantly affect multiple organ systems, particularly the eyes, kidneys, and peripheral nerves.

And finally, to conclude, here's a photograph from the early 20th century. Before the discovery of insulin, type 1 diabetes was a truly devastating diagnosis. And in 1921, two scientists, Frederick Banting and John Macleod, played key roles in the discovery of insulin. For this achievement, they were awarded the Nobel Prize in Physiology and Medicine in 1923, just 2 years later. During that same year, pharmaceutical companies began producing insulin on a large scale. And as you can see in this image, we have a child with diabetes. And before insulin treatment, the effects of lipolysis and proteolysis are clearly visible. The child has lost both fat tissue and muscle mass due to severe metabolic consequences of untreated diabetes. However, after only 3 months of insulin therapy, the transformation is remarkable. The child appears healthy, well-nourished, and dramatically improved. In that sense, the discovery of insulin can truly be considered one of the greatest medical achievements of the 20th century. And with that historical perspective in mind, we can now move on to discuss the complications of diabetes.