Diabetes mellitus (type 1, type 2) & diabetic ketoacidosis (DKA)

In diabetes mellitus, your body has trouble moving glucose, which is a type of sugar, from your blood into your cells. This leads to high levels of glucose in your blood and not enough of it in your cells, and remember that your cells need glucose as a source of energy, so not letting the glucose enter means that the cells starve for energy despite having glucose right on their doorstep. In general, the body controls how much glucose is in the blood relative to how much gets into the cells with two hormones: insulin and glucagon.

Insulin is used to reduce blood glucose levels, and glucagon is used to increase blood glucose levels. Both of these hormones are produced by clusters of cells in the pancreas called islets of Langerhans. Insulin is secreted by beta cells in the center of the islets, and glucagon is secreted by alpha cells in the periphery of the islets. Insulin reduces the amount of glucose in the blood by binding to insulin receptors embedded in the cell membrane of various insulin-responsive tissues like muscle cells and adipose tissue. When activated, the insulin receptors cause vesicles containing glucose transporter that are inside the cell to fuse with the cell membrane, allowing glucose to be transported into the cell. Glucagon does exactly the opposite, it raises the blood glucose levels by getting the liver to generate new molecules of glucose from other molecules and also break down glycogen into glucose so that it can all get dumped into the blood. Diabetes mellitus is diagnosed when the blood glucose levels get too high, and this is seen among 10% of the world population. There are two types of diabetes – Type 1 and Type 2, and the main difference between them is the underlying mechanism that causes the blood glucose levels to rise.

About 10% of people with diabetes having Type 1, and the remaining 90% of people with diabetes having Type 2. Let’s start with Type 1 diabetes mellitus, sometimes just called type 1 diabetes. In this situation, the body doesn’t make enough insulin. The reason this happens is that in type 1 diabetes there is a type 4 hypersensitivity response or a cell-mediated immune response where a person’s own T cells attack the pancreas. As a quick review, remember that the immune system has T cells that react to all sorts of antigens, which are usually small peptides, polysaccharides, or lipids, and that some of these antigens are part of our own body’s cells.

It doesn’t make sense to allow T cells that will attack our own cells to hang around, and so there’s this process to eliminate them called “self-tolerance”. In type 1 diabetes, there is a genetic abnormality causes a loss of self-tolerance among T cells that specifically target the beta cell antigens. Losing self-tolerance means that these T cells are allowed to recruit other immune cells and coordinate an attack on these beta cells. Losing beta cells means less insulin, and less insulin means that glucose piles up in the blood, because it can’t enter the body’s cells. One really important genes involved in regulation of the immune response is the human leukocyte antigen system, or HLA system. Although it’s called a system, it’s basically this group of genes on chromosome six that encode the major histocompatibility complex, or MHC, which is a protein that’s extremely important in helping the immune system recognize foreign molecules, as well as maintaining self-tolerance.

MHC is like the serving platter that antigens are presented to the immune cells. Interestingly, people with type 1 diabetes often have specific HLA genes in common with each another, one called HLA-DR3 and another called HLA-DR4. But this is just a genetic clue right? Because not everyone with HLA-DR3 and HLA-DR4 develop diabetes. In diabetes mellitus type 1, destruction of beta cells usually starts early in life, but sometimes up to 90% of the beta cells are destroyed before symptoms crop up. Four clinical symptoms of uncontrolled diabetes, that all sound similar, are polyphagia, glycosuria, polyuria, and polydipsia.

Let’s go through them one by one. Even though there’s a lot of glucose in the blood, it can’t get into cells, which leaves cells starved for energy, so in response, adipose tissue starts breaking down fat, called lipolysis, and muscle tissue starts breaking down proteins, both of which results in weight loss for someone with uncontrolled diabetes. This catabolic state leaves people feeling hungry, also known as polyphagia. “Phagia” means eating, and “Poly” means a lot. Now with high glucose levels, that means that when blood gets filtered through the kidneys, some of it starts to spill into the urine, called glycosuria.

“Glycos” refers to glucose, “uria” the urine. Since glucose is osmotically active, water tends to follow it, resulting in an increase in urination, or polyuria. “Poly” again refers to a lot, and “uria” again refers to urine again. Finally, because there is so much urination, people with uncontrolled diabetes become dehydrated and thirsty, or polydipsia. “Poly” means a lot, and “dipsia” means thirst. Even though people with diabetes aren’t able to produce their own insulin, they can still respond to insulin, so treatment involves lifelong insulin therapy to regulate their blood glucose levels and basically enable their cells to use glucose. One really serious complication with type 1 diabetes is called diabetic ketoacidosis, or DKA. To understand it, let’s go back to the process of lipolysis, where fat is broken down into free fatty acids. After that happens, the liver turns the fatty acids into ketone bodies, like acetoacetic acid and beta hydroxybutyric acid, acetoacetic acid is a ketoacid because it has a ketone group and a carboxylic acid group.

Beta hydroxybutyric acid on the other hand, even though it’s still one of the ketone bodies, isn’t technically a ketoacid since its ketone group has been reduced to a hydroxyl group. These ketone bodies are important because they can be used by cells for energy, but they also increase the acidity of the blood, which is why it’s called keto-acid-osis. If the blood becoming really acidic can have major effects throughout the body. Patients can develop Kussmaul respiration, which is a deep and labored breathing as the body tries to move carbon dioxide out of the blood, in an effort to reduce its acidity. Cells also have a transporter that exchanges hydrogen ions (or protons—H+) for potassium. When the blood gets acidic, it is by definition loaded with protons that get sent into cells while potassium gets sent into the fluid outside cells. Another thing to keep in mind is that in addition to helping glucose enter cells, insulin stimulates the sodium-potassium ATPases which help potassium get into cells, and so without insulin, more potassium stays in the fluid outside cells.

Both of these mechanisms lead to increased potassium in the fluid outside of cells which quickly makes it into the blood and causes hyperkalemia. The potassium is then excreted, so over time, even though the blood potassium levels remain high, overall stores of potassium in the body—which includes potassium inside cells—starts to run low. Patients will also have a high anion gap, which reflects a large difference in the unmeasured negative and positive ions in the serum, largely due to this build up of ketoacids.

Diabetic ketoacidosis can happen even in people who’ve already been diagnosed with diabetes and currently have some sort of insulin therapy. In states of stress, like an infection, the body releases epinephrine, which in turn stimulates the release of glucagon. Too much glucagon can tip the delicate hormonal balance of glucagon and insulin in favor of elevating blood sugars and can lead to a cascade of events we just described—increased glucose in the blood, loss of glucose in the urine, loss of water, dehydration, and in parallel a need for alternate energy, generation of ketone bodies, and ketoacidosis.

Interestingly, both ketone bodies break down into acetone and escape as a gas by getting breathed out the lungs which gives a sweet fruity smell to a person’s breath. In general though, that’s the only sweet thing about this illness, which also causes nausea, vomiting, and if severe, mental status changes and acute cerebral edema. Treatment of a DKA episode involves giving plenty of fluids, which helps with dehydration, insulin which helps lower blood glucose levels, and replacement of electrolytes, like potassium; all of which help to reverse the acidosis.

Now, let’s switch gears and talk about Type 2 diabetes, which is where the body makes insulin, but the tissues don’t respond as well to it. The exact reason why cells don’t “respond” isn’t fully understood, essentially the body’s providing the normal amount of insulin, but the cells don’t move their glucose transporters to their membrane in response, which remember is needed for glucose to get into the cell, these cells therefore they have insulin resistance. Some risk factors for insulin resistance are obesity, lack of exercise, and hypertension, and the exact mechanisms are still being explored. For example, an excess of adipose tissue—or fat—is thought to cause the release of free fatty acids and so-called “adipokines”, which are signaling molecules that can cause inflammation, which seems related to insulin resistance. However, many people that are obese are not diabetic, so genetic factors probably play a major role as well.

We see this when we look at twin studies as well, where having a twin with type 2 diabetes increases the risk of developing type 2 diabetes, completely independent of other environmental risk factors. In Type 2 diabetes, since tissues don’t respond as well to normal levels of insulin, the body ends up producing more insulin in order to get the same effect and move glucose out of the blood. They do this through beta cell hyperplasia, an increased number of beta cells, and beta cell hypertrophy, where they actually grow in size, all in this attempt to to pump out more insulin. This works for a while, and by keeping insulin levels higher than normal, blood glucose levels can be kept normal, called normoglycemia. Now, along with insulin, beta cells also secrete islet amyloid polypeptide, or amylin, so while beta cells are cranking out insulin they also secrete an increased amount of amylin. Over time, amylin builds up and aggregates in the islets. This beta cell compensation, though, isn’t sustainable, and over time those maxed out beta cells get exhausted, and they become dysfunctional, and undergo hypotrophy and get smaller, as well as hypoplasia and die off.

As beta cells are lost and insulin levels decrease, glucose levels in the blood start to increase, and patients develop hyperglycemia, which leads to similar clinical signs that I mentioned before, like polyphagia, glycosuria, polyuria, and polydipsia. But unlike type 1 diabetes, there is generally some circulating insulin in type 2 diabetes from the beta cells that are trying to compensate for the insulin resistance. This means that the insulin/glucagon balance is such that diabetic ketoacidosis doesn’t usually develop.

Having said that, a complication called hyperosmolar hyperglycemic state (or HHS) is much more common in type 2 diabetes than type 1 diabetes – and it causes increased plasma osmolarity due to extreme dehydration and concentration of the blood. To help understand this, remember that glucose is a polar molecule that cannot passively diffuse across cell membranes, which means that it acts as a solute. So when levels of glucose are super high in the blood (meaning it’s a hyperosmolar state), water begins to leave the body’s cells and enter the blood vessels, leaving the cells relatively dry and shriveled rather than plump and juicy. Blood vessels that are full of water lead to increased urination and total body dehydration. And this is a very serious situation because the dehydration of the body’s cells and in particular the brain can cause a number of symptoms including mental status changes.

In HHS, you can sometimes see mild ketonemia and acidosis, but not to the extent that it’s seen in DKA, and in DKA you can see some hyperosmolarity, so there is definitely overlap between these two syndromes. Besides type 1 and type 2 diabetes, there are also a couple other subtypes of diabetes mellitus. Gestational diabetes is when pregnant women have increased blood glucose which is particularly during the third trimester. Although ultimately unknown, the cause is thought to be related to pregnancy hormones that interfere with insulin’s action on insulin receptors. Also, sometimes people can develop drug-induced diabetes, which is where medications have side effects that tend to increase blood glucose levels. The mechanism for both of these is thought to be related to insulin resistance (like type 2 diabetes), rather than an autoimmune destruction process (like in type 1 diabetes).

Diagnosing type 1 or type 2 diabetes is done by getting a sense for how much glucose is floating around in the blood and has specific standards that the World Health Organization uses. Very commonly, a fasting glucose test is taken where the person doesn’t eat or drink (except water, that’s okay) for 8 hours and has their blood tested for glucose levels. Levels of 100 milligrams per deciliter to 125 milligrams per deciliter indicates prediabetes and 126 milligrams per deciliter or higher indicates diabetes.

A non-fasting or random glucose test can be done at any time, with 200 milligrams per deciliter or higher being a red flag for diabetes. Another test is called an oral glucose tolerance test, where a person is given glucose, and then a blood samples are taken at time intervals to figure out how well it’s being cleared from the blood, the most important interval being 2 hours later. Levels of 140 milligrams per deciliter to 199 milligrams per deciliter indicate prediabetes and 200 or above indicates diabetes. Another thing to know is that when blood glucose levels get high, the glucose can also stick to proteins that are floating around in the blood or in cells. So that brings us to another type of test that can be done which is the HbA1c test, which tests for the proportion of hemoglobin in red blood cells that has glucose stuck to it – called glycated hemoglobin. HbA1c levels of 5.7% to 6.4% indicates prediabetes, and 6.5% or higher indicates diabetes. This proportion of glycated hemoglobin doesn’t change day to day, so it gives a sense for whether the blood glucose levels have been high over the past 2 to 3 months.

Over time, high glucose levels can cause damage to tiny blood vessels, called the microvasculature. In arterioles, a process called hyaline arteriolosclerosis where the walls of arterioles where they develop hyaline deposits, these deposits of proteins, and these make them hard and inflexible. In capillaries, the basement membrane can thicken and make it hard for oxygen to easily move from the capillary to the tissues, causing hypoxia. One of the most significant effects is that diabetes increases the risk of medium and large arterial wall damage and subsequent atherosclerosis, which can leads to heart attacks and strokes, major causes of morbidity and mortality for patients with diabetes.

In the eyes, diabetes can lead to retinopathy and evidence of that can be seen on a fundoscopic exam that shows cotton wools spots or flare hemorrhages – and can eventually cause blindness. In the kidneys, the afferent and efferent arterioles, as well as the glomerulus itself can get damaged which can lead to a nephrotic syndrome that slowly diminishes the kidney’s ability to filter blood over time – and can ultimately lead to dialysis.

Diabetes can also affect the function of nerves, causing symptoms like a decrease in sensation in the toes and fingers, sometimes called a stocking-glove distribution, as well as causing the autonomic nervous system to malfunction, and that system controls a number of body functions – everything from sweating to passing gas. Finally, both the poor blood supply and nerve damage, can lead to ulcers (typically on the feet) that don’t heal quickly and can get pretty severe, and need to be amputated.

These are some of the complications of uncontrolled diabetes, which is why it’s so important to prevent, diagnose, and control diabetes through a healthy lifestyle, medications to reduce insulin resistance and even insulin therapy if beta cells have been exhausted. In fact, many people with diabetes can control their blood sugar levels really effectively and live a full and active life without any of the complications. .

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