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- Often times wethink of diabetes mellitus as a chronic disease thatcauses serious complications over a long period of timeif it’s not treated properly. However, the acute complicationsof diabetes mellitus are often the most serious, and can be potentiallyeven life threatening. Let’s discuss one of the acutecomplications of diabetes, known as diabeticketoacidosis, or DKA for short, which can occur in individualswith type 1 diabetes. Now recall that type 1 diabetes is an autoimmune disorder.
- And as such, there’s anautoimmune destruction of the beta cells in the pancreas, which prevents the pancreas from producing and secreting insulin. Therefore, there is anabsolute insulin deficiency in type 1 diabetes. But what exactly doesthis mean for the body? To get a better understanding,let’s think about insulin requirements as a balancing act with energy needs. Now the goal here is tokeep the balance in balance. As the energy requirementsof the body go up, insulin is needed to takethe glucose out of the blood and store it throughout the body. Normally in individualswithout type 1 diabetes, the pancreas is able toproduce enough insulin to keep up with any amountof energy requirement. But how does this change issomeone has type 1 diabetes? Well since their pancreascannot produces as much insulin, they have an absolute insulin deficiency. Now for day-to-day activities, this may not actually cause any problems, because the small amountof insulin that is produced is able to compensate andkeep the balance in balance. However, over time, astype 1 diabetes worsens, and less insulin is able to be produced, then the balance becomes slightly unequal. And this results in thesub-acute or mild symptoms of type 1 diabetes such as fatigue, because the body isn’t able to match these energy requirements. But what happens if the bodyis placed in a state of stress, such as with an infection?
- Now these stress situations require a tremendous amount of energy, and the balance ends upgetting tipped to a point where the body is far frombeing able to compensate. And this is the situation in which diabetic ketoacidosis occurs. And when this happens,metabolically speaking, the body goes into a starvation state. Now this is not necessarilya true state of starvation because someone with type 1 diabetes is still able to eatand bring in nutrients. However, without anadequate amount of insulin, the body is not able to utilizethese nutrients for energy. And in this sense, type 1diabetes can be thought of as a starvation in the face of plenty, as glucose is present, infact it’s present in excess in the blood, however the body is not able to utilize it for energy. So the body reacts as if it is starving, which in some senses it is.
- So how does thisstarvation metabolism then result in diabetic ketoacidosis? Well, first let’s start with the goal of starvation metabolism,and that is to preserve energy for crucial,life sustaining organs, and the most importantof which is the brain. And one thing you needto know about the brain, is that when it comes toenergy, the brain is very picky. The brain can’t utilizemany forms of energy. In fact, there are onlytwo forms of energy the brain can use, and these are glucose and ketones. And if it has to choose between the two, it prefers glucose. So the goal of starvation metabolism is to convert other forms of nutrients such as fat, protein and glycogeninto glucose and ketones. Now in order to understandthe clinical presentation of diabetic ketoacidosis, we need to discuss afew metabolic pathways that occur throughout the body.
- So I like to think of metabolism as being similar to a pawn shop. At a pawn shop, the goal is to convert different items of value, suchas precious stones or gold into a usable form ofcurrency in the form of cash. Now in metabolism, there aremany different forms of energy, such as proteins in muscle, and the triglycerides, or lipidsthat are in adipose tissue. However, as I just mentioned, they’re not usable by the brain. So they need to be convertedinto usable forms of energy, such as glucose and ketones. And this most commonlyoccurs within the liver, which can be thought ofas the metabolic pawnshop. And there are a few important pathways for the conversion of these energy sources into glucose and ketones, and these pathways aredriven by the interaction between many different hormones.
- Now, fortunately, thenames of all these pathways will help give us an idea of what they do. So we’ll start with proteolysis, which occurs within muscle cells. If we look at the name, lysisstands for the breakdown, and proteo stands for protein. So proteolysis is thebreakdown of proteins. And in this process,proteins are broken down into amino acids, which are then carried through the bloodstream to the liver, where they take part in gluconeogenesis, which we’ll discuss injust a minute, here. And similarly, Lypolysis occursin adipose, or fat tissue. Now lipo stands for lipids,which are another term for fats. And once again, lysisstands for the breakdown of. And in this process, the triglycerides that are within lipids are broken down into their componentparts, which are glycerol and free fatty acids.
- And they are then carriedthrough the bloodstream to the liver to takepart in gluconeogenesis. And it’s important tonote that this process also produces some inflammatory cytokines, which will become importantin just a little bit, here. Now let’s move on to gluconeogenesis. If we look at the name,neogenesis stands for the creation of, andglucose represents glucose. So gluconeogenesis isthe creation of glucose, which as you recall, isone of the primary goals of starvation metabolism. So how does this work? Well, the amino acids fromproteolysis in the muscle cells and the glycerol and thefree fatty acids from the lipolysis in the adipose tissue undergo a series of metabolicreactions within the liver, that produce glucose. But this process is notperfect, and in order to create glucose from freefatty acids and glycerol, a by-product known asacetyl CoA is produced, and then utilized later inthe ketogenesis pathway. So we mentioned that the purpose of starvation metabolism is toproduce glucose and ketones. So the ketogenesis iswhere ketones come in here. And it’s the metabolicpathway for the creation of, or the genesis of ketones. And it utilizes the acetylCoA from gluconeogenesis, which then undergoes a series of reactions to produce ketones. Then the last pathway to mentionis that of glycogenolysis, which is the lysis, orbreakdown of glycogen. So glycogen is a storage form of glucose. And essentially all it is, is a polymer of many different glucose molecules, or a chain of glucose molecules that are linked to one another. And in glycogenolysis, glycogenis broken down into glucose, which is once again,one of the primary goals of starvation metabolism. Now as you can see, there’sa lot going on here, but by understandingthese metabolic pathways, we can gain a clearer understanding of the clinical presentationof diabetic ketoacidosis. So what is this clinical presentation? First off, someone in DKA is very sick, and likely became sick over afairly short period of time, maybe just a few hours to days. And they most commonly complain of abdominal pain, nausea, and vomiting. In addition, they are severely dehydrated, and therefore their skinmay appear cool and clammy.
- Then lastly, and mostalarming, many individuals in diabetic ketoacidosis willhave an altered mental status, meaning they may be confusedor even unconscious. So why do all of these symptoms occur? So nausea, vomiting and abdominal pain are pretty non-specific symptoms, but they are very commonin diabetic ketoacidosis, and these symptoms occur because of these inflammatory cytokines thatare released from lipolysis, and other metabolic processes. And then these cytokines irritate the gastrointestinal tract,resulting in these symptoms. Now, unfortunately, theloss of fluid from vomiting leads to the next clinicalsymptom, which is dehydration. However, the dehydration that occurs in diabetic ketoacidosisis extremely severe, and much more severe than what’s caused by the vomiting alone. But why exactly is this? Well, we discussed earlier that the goal of starvation metabolismis to produce glucose. So what’s the problem here? Well, remember, the patient has diabetes. And if there’s a deficiency of insulin, then the body is not ableto pull all of this glucose out of the blood to either store it or utilize it for energy. So the body is acting like it’s starving, and it continues toproduce all this glucose despite its not being able to use it. And the glucose then buildsup and builds up in the blood, resulting in hyperglycemia,or high blood sugar levels. Now when the kidneys are filtering blood, they are normally able to reabsorb all of the glucose that’s in the blood. However, at a certainpoint of hyperglycemia, the amount of glucose in the blood exceeds the kidney’sability to reabsorb it, and glucose begins tospill out into the urine. And this is a process called glucosuria. And glucose is an osmoticallyactive solute in the urine. This means that glucose sucks the water that’s in the bloodstreamout into the urine with it, and this is known as osmotic diuresis, or the loss of water due to an osmotically active solute. And it’s this osmotic diuresisthat causes the severe fluid loss and dehydrationin diabetic ketoacidosis that can lead to an altered mental status. Now once again, it’snot just the dehydration that causes the altered mental status in diabetic ketoacidosis. It is made worse becauseof the consequences of ketogenesis. So ketones, or ketone bodies,are an important source of energy for the brain and heart during times of starvation. However, they come at a trade-off, and that is that ketone bodies are acids, so they lower the pH of the blood, a process known as acidosis.
- And the body is able to bufferthis effect to an extent, however, in DKA, the ketones are produced in such large quantities that it overcomes the buffering ability of the body, and results in acidosis. And since it’s due to a metabolic process, it is known as a metabolic acidosis. And metabolic acidosisworsens altered mental status, and also if it’s severeenough, it may even cause cardiac arrhythmias, orabnormal heart rhythms, that can be fatal. So you can see here thatthe clinical presentation of diabetic ketoacidosis is directly tied to the underlying metabolism that’s caused by the starvation state, or perhaps, as we saidearlier, better put, the starvation in the face of plenty that occurs in type 1 diabetes. And anytime someone with type 1 diabetes presents with abdominalpain, altered mental status, and signs of dehydration, DKA, or diabetic ketoacidosis,should be very high in the differential forthe cause of their illness. And they will need to betreated quickly and aggressively with intravenous fluids and insulin, because if it’s left untreated, diabetic ketoacidosis can be fatal.