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

Learning medicine is hard work! Osmosis makes it easy. It takes your lectures and notes to createa personalized study plan with exclusive videos, practice questions and flashcards, and somuch more. Try it free today! In diabetes mellitus, your body has troublemoving glucose, which is a type of sugar, from your blood into your cells. This leads to high levels of glucose in yourblood and not enough of it in your cells, and remember that your cells need glucoseas a source of energy, so not letting the glucose enter means that the cells starvefor energy despite having glucose right on their doorstep.In general, the body controls how much glucoseis in the blood relative to how much gets into the cells with two hormones: insulinand 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 clustersof cells in the pancreas called islets of Langerhans. Insulin is secreted by beta cells in the centerof the islets, and glucagon is secreted by alpha cells in the periphery of the islets. Insulin reduces the amount of glucose in theblood by binding to insulin receptors embedded in the cell membrane of various insulin-responsivetissues like muscle cells and adipose tissue. When activated, the insulin receptors causevesicles containing glucose transporter that are inside the cell to fuse with the cellmembrane, allowing glucose to be transported into the cell.Glucagon does exactly the opposite, it raisesthe blood glucose levels by getting the liver to generate new molecules of glucose fromother molecules and also break down glycogen into glucose so that it can all get dumpedinto the blood. Diabetes mellitus is diagnosed when the bloodglucose levels get too high, and this is seen among 10% of the world population. There are two types of diabetes – Type 1 andType 2, and the main difference between them is the underlying mechanism that causes theblood glucose levels to rise. About 10% of people with diabetes have Type1, and the remaining 90% of people with diabetes have Type 2. Lets start with Type 1 diabetes mellitus,sometimes just called type 1 diabetes. In this situation, the body doesnt makeenough insulin. The reason this happens is that in type 1diabetes there is a type 4 hypersensitivity response or a cell-mediated immune responsewhere a persons own T cells attack the pancreas. As a quick review, remember that the immunesystem 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 bodyscells.It doesnt make sense to allow T cells thatwill attack our own cells to hang around, and so theres this process to eliminatethem called self-tolerance. In type 1 diabetes, there is a genetic abnormalitycauses a loss of self-tolerance among T cells that specifically target the beta cell antigens. Losing self-tolerance means that these T cellsare allowed to recruit other immune cells and coordinate an attack on these beta cells. Losing beta cells means less insulin, andless insulin means that glucose piles up in the blood, because it cant enter the bodyscells.One really important genes involved in regulationof the immune response is the human leukocyte antigen system, or HLA system. Although its called a system, its basicallythis group of genes on chromosome six that encode the major histocompatibility complex,or MHC, which is a protein thats extremely important in helping the immune system recognizeforeign molecules, as well as maintaining self-tolerance. MHC is like the serving platter that antigensare presented to the immune cells. Interestingly, people with type 1 diabetesoften have specific HLA genes in common with each other, one called HLA-DR3 and anothercalled HLA-DR4. But this is just a genetic clue right? Because not everyone with HLA-DR3 and HLA-DR4develops diabetes. In diabetes mellitus type 1, destruction ofbeta cells usually starts early in life, but sometimes up to 90% of the beta cells aredestroyed before symptoms crop up. Four clinical symptoms of uncontrolled diabetes,that all sound similar, are polyphagia, glycosuria, polyuria, and polydipsia. Lets go through them one by one. Even though theres a lot of glucose inthe blood, it cant get into cells, which leaves cells starved for energy, so in response,adipose tissue starts breaking down fat, called lipolysis, and muscle tissue starts breakingdown proteins, both of which results in weight loss for someone with uncontrolled diabetes.This catabolic state leaves people feelinghungry, also known as polyphagia. Phagia means eating, and Polymeans a lot. Now with high glucose levels, that means thatwhen blood gets filtered through the kidneys, some of it starts to spill into the urine,called glycosuria. Glycos refers to glucose, uriathe urine. Since glucose is osmotically active, watertends to follow it, resulting in an increase in urination, or polyuria. Poly again refers to a lot, and uriaagain 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 meansthirst. Even though people with diabetes arentable to produce their own insulin, they can still respond to insulin, so treatment involveslifelong insulin therapy to regulate their blood glucose levels and basically enabletheir cells to use glucose. One really serious complication with type1 diabetes is called diabetic ketoacidosis, or DKA. To understand it, lets go back to the processof lipolysis, where fat is broken down into free fatty acids. After that happens, the liver turns the fattyacids into ketone bodies, like acetoacetic acid and beta hydroxybutyric acid, acetoaceticacid is a ketoacid because it has a ketone group and a carboxylic acid group.Beta hydroxybutyric acid on the other hand,even though its still one of the ketone bodies, isnt technically a ketoacid sinceits ketone group has been reduced to a hydroxyl group. These ketone bodies are important becausethey can be used by cells for energy, but they also increase the acidity of the blood,which is why its called keto-acid-osis. If the blood becoming really acidic can havemajor 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 theblood, in an effort to reduce its acidity.Cells also have a transporter that exchangeshydrogen ions (or protonsH+) for potassium. When the blood gets acidic, it is by definitionloaded with protons that get sent into cells while potassium gets sent into the fluid outsidecells. Another thing to keep in mind is that in additionto helping glucose enter cells, insulin stimulates the sodium-potassium ATPases which help potassiumget into cells, and so without insulin, more potassium stays in the fluid outside cells. Both of these mechanisms lead to increasedpotassium in the fluid outside of cells which quickly makes it into the blood and causeshyperkalemia. The potassium is then excreted, so over time,even though the blood potassium levels remain high, overall stores of potassium in the bodywhichincludes potassium inside cellsstarts 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, largelydue to this build up of ketoacids. Diabetic ketoacidosis can happen even in peoplewhove already been diagnosed with diabetes and currently have some sort of insulin therapy. In states of stress, like an infection, thebody releases epinephrine, which in turn stimulates the release of glucagon.Too much glucagon can tip the delicate hormonalbalance of glucagon and insulin in favor of elevating blood sugars and can lead to a cascadeof events we just describedincreased glucose in the blood, loss of glucose in the urine,loss of water, dehydration, and in parallel a need for alternative energy, generationof ketone bodies, and ketoacidosis. Interestingly, both ketone bodies break downinto acetone and escape as a gas by getting breathed out the lungs which gives a sweetfruity smell to a persons breath. In general though, thats the only sweetthing about this illness, which also causes nausea, vomiting, and if severe, mental statuschanges and acute cerebral edema. Treatment of a DKA episode involves givingplenty 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, lets switch gears and talk about Type2 diabetes, which is where the body makes insulin, but the tissues dont respond aswell to it. The exact reason why cells dont respondisnt fully understood, essentially the bodys providing the normal amount of insulin,but the cells dont move their glucose transporters to their membrane in response, which rememberis needed for glucose to get into the cell, these cells therefore they have insulin resistance. Some risk factors for insulin resistance areobesity, lack of exercise, and hypertension, and the exact mechanisms are still being explored. For example, an excess of adipose tissueorfatis 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 insulinresistance. However, many people that are obese are notdiabetic, so genetic factors probably play a major role as well. We see this when we look at twin studies aswell, 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 dontrespond as well to normal levels of insulin, the body ends up producing more insulin inorder 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 growin size, all in this attempt to pump out more insulin. This works for a while, and by keeping insulinlevels higher than normal, blood glucose levels can be kept normal, called normoglycemia. Now, along with insulin, beta cells also secreteislet amyloid polypeptide, or amylin, so while beta cells are cranking out insulin they alsosecrete an increased amount of amylin.Over time, amylin builds up and aggregatesin the islets. This beta cell compensation, though, isntsustainable, and over time those maxed out beta cells get exhausted, and they becomedysfunctional, and undergo hypotrophy and get smaller, as well as hypoplasia and dieoff. As beta cells are lost and insulin levelsdecrease, 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 generallysome circulating insulin in type 2 diabetes from the beta cells that are trying to compensatefor the insulin resistance. This means that the insulin/glucagon balanceis such that diabetic ketoacidosis doesnt usually develop. Having said that, a complication called hyperosmolarhyperglycemic 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 concentrationof the blood.To help understand this, remember that glucoseis a polar molecule that cannot passively diffuse across cell membranes, which meansthat it acts as a solute. So when levels of glucose are super high inthe blood (meaning its a hyperosmolar state), water begins to leave the bodys cells andenter the blood vessels, leaving the cells relatively dry and shriveled rather than plumpand juicy. Blood vessels that are full of water leadto increased urination and total body dehydration. And this is a very serious situation becausethe dehydration of the bodys cells and in particular the brain can cause a numberof symptoms including mental status changes. In HHS, you can sometimes see mild ketonemiaand acidosis, but not to the extent that its 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, thereare also a couple other subtypes of diabetes mellitus. Gestational diabetes is when pregnant womenhave increased blood glucose which is particularly during the third trimester.Although ultimately unknown, the cause isthought to be related to pregnancy hormones that interfere with insulins action oninsulin receptors. Also, sometimes people can develop drug-induceddiabetes, which is where medications have side effects that tend to increase blood glucoselevels. The mechanism for both of these is thoughtto be related to insulin resistance (like type 2 diabetes), rather than an autoimmunedestruction process (like in type 1 diabetes). Diagnosing type 1 or type 2 diabetes is doneby getting a sense for how much glucose is floating around in the blood and has specificstandards that the World Health Organization uses. Very commonly, a fasting glucose test is takenwhere the person doesnt eat or drink (except water, thats okay) for 8 hours and hastheir blood tested for glucose levels. Levels of 100 110 milligrams per deciliterto 125 milligrams per deciliter indicates prediabetes and 126 milligrams per deciliteror higher indicates diabetes. A non-fasting or random glucose test can bedone at any time, with 200 milligrams per deciliter or higher being a red flag for diabetes.Another test is called an oral glucose tolerancetest, where a person is given glucose, and then a blood samples are taken at time intervalsto figure out how well its being cleared from the blood, the most important intervalbeing 2 hours later. Levels of 140 milligrams per deciliter to199 milligrams per deciliter indicate prediabetes and 200 or above indicates diabetes. Another thing to know is that when blood glucoselevels get high, the glucose can also stick to proteins that are floating around in theblood or in cells.So that brings us to another type of testthat can be done which is the HbA1c test, which tests for the proportion of hemoglobinin 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 doesntchange day to day, so it gives a sense for whether the blood glucose levels have beenhigh over the past 2 to 3 months. Finally, we have the C-peptide test, whichtests for this byproduct of insulin production. If the level of C-peptide is low or absent,it means the pancreas is no longer producing enough insulin, and the glucose cant enterthe cells.For type I diabetes, insulin is the only treatmentoption. For type II diabetes, on the other hand, lifestylechanges, like weight loss and exercise, along with a healthy diet and oral antidiabeticmedications, like metformin and several other classes, can sometimes be enough to reversesome of that insulin resistance and keep blood sugar levels in check. However, if oral antidiabetic medicationsfail, type II diabetes can also be treated with insulin. Something to bear in mind is that insulintreatment comes with a risk of hypoglycemia, especially if insulin is taken without a meal. Symptoms of hypoglycemia can be mild, likeweakness, hunger, shaking, but they can progress to loss of consciousness and seizures in severecases. In mild cases, drinking juices, or eatingcandy, or sugar, may be enough to bring blood sugar up.But in severe cases, intravenous glucose shouldbe given as soon as possible. The FDA has also recently approved intranasalglucagon as a treatment for severe hypoglycemia. Ok, now, over time, high glucose levels cancause damage to tiny blood vessels, called the microvasculature. In arterioles, a process called hyaline arteriolosclerosiswhere 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 canthicken and make it hard for oxygen to easily move from the capillary to the tissues, causinghypoxia. One of the most significant effects is thatdiabetes increases the risk of medium and large arterial wall damage and subsequentatherosclerosis, which can lead to heart attacks and strokes, major causes of morbidity andmortality for patients with diabetes. In the eyes, diabetes can lead to retinopathyand evidence of that can be seen on a fundoscopic exam that shows cotton wool spots or flarehemorrhages – and can eventually cause blindness.In the kidneys, the afferent and efferentarterioles, as well as the glomerulus itself can get damaged which can lead to a nephroticsyndrome that slowly diminishes the kidneys ability to filter blood over time – and canultimately lead to dialysis. Diabetes can also affect the function of nerves,causing symptoms like a decrease in sensation in the toes and fingers, sometimes calleda 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 passinggas.Finally, both the poor blood supply and nervedamage, can lead to ulcers (typically on the feet) that dont heal quickly and can getpretty severe, and need to be amputated. These are some of the complications of uncontrolleddiabetes, which is why its so important to, diagnose and control diabetes througha healthy lifestyle, medications to reduce insulin resistance and even insulin therapyif beta cells have been exhausted. While type 1 diabetes can not be prevented,type 2 diabetes can. In fact, many people with diabetes can controltheir blood sugar levels really effectively and live a full and active life without anyof the complications..

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