This video has been sponsored by Squarespace. Diabetes mellitus, often referred to as just diabetes is a group of disorders characterized by elevated blood sugar levels There are three major types of the disorder referred to as just Type 1, Type 2 and Gestational. In Type 1 Diabetes, the body produces little to no insulin, which is a hormone that plays a major role in blood sugar regulation. Without insulin, cells have a very hard time taking in glucose and it causes it to build up in the blood. In most cases of Type 1, the insulin-producing beta cells of the pancreas are destroyed, usually by the body’s own immune system. The exact reason why this happens is not yet known. However, it’s believed that genetics play a large role and that exposure to certain environmental factors like viruses can act as a trigger. People who have type 1 diabetes need to closely monitor their blood glucose level and control it by insulin injections. In Type 2 Diabetes, insulin is still produced, but the cells just stop responding to it properly. When this happens, the condition is referred to as insulin resistance. Because of this, the pancreas has to start overproducing it just to maintain normal sugar levels. Initially this isn’t a huge problem But as the disorder progresses, the insulin producing cells can get worn out and stopped working properly. Most cases of type 2 are managed using a combination of proper diet, exercise and anti-diabetic medication. Injecting insulin is usually only needed in the late stages of the condition if the pancreatic cells are damaged. Like type 1, the cause is a combination of genetics and external factors. However, unlike, type 1 these factors are much more controllable. Obesity, lack of exercise, poor diet, and stress are some of the biggest factors that contribute to it. By avoiding these, you won’t necessarily escape your genetic fate, but you can greatly reduce the risk. Anyway, the last type is gestational diabetes. During pregnancy, some hormones from the placenta blocked the action of the mother’s insulin which can lead to insulin resistance. To overcome this, the mother needs to produce significantly more insulin than normal. if she already had some insulin resistance or problems making insulin, glucose can start building up leading to gestational diabetes. This occurs in about five to ten percent of mothers, but after birth, it usually goes back to normal. In any case, out of all these forms, type 2 is the most common, representing about 90% of all diabetes cases. All types, though, share one major and obvious symptom, which is increased urination. This was first recognized by the Egyptians and the Indians way back in around 1500 BC. Then a thousand years later, in around 250 BC, a Greek physician coined the term diabetes. It was derived from the Greek word meaning ‘to pass through’ or ‘siphon’, which was in reference to the way that liquids seemed to just pass through the body. This increase in urination happens because the level of sugar in the blood is way too high. Normally, the kidneys reabsorb pretty much all of the sugar from the urine and none is lost However in diabetics, there’s way too much of it and the reabsorption system is overloaded. Because of this, sugars, most notably glucose, are able to make it past the kidneys, and due to osmosis, they pull more water along with them. The earliest and only diabetes tests for a long time was to taste the patient’s urine . If it were sweet the person was likely diabetic. This unique characteristic eventually led to it being called ‘diabetes mellitus’ where ‘mellitus’ literally means ‘sweet like honey’. This pee-tasting method continued for hundreds of years, but it obviously wasn’t ideal. It took until 1841 for Karl Trommer to develop the first chemical-based test, which I’m sure a lot of people were thankful for. I’m gonna show you guys how it worked, and because I want this video to be as accurate as possible, I’m gonna be using real pee from a diabetic friend. For comparison purposes, I got two samples: one when her blood sugar was high, and one when it was normal. Just as a fun fact when I was planning this video, I was extremely close to trying the classic taste test myself, but I’m sorry guys when the time came I just ‘chickened’ out. Anyway for Trommer’s test I need to make two solutions. The first is about a 5% solution of potassium hydroxide, which is made by mixing 0.5 grams with 10 mL of water. The KOH dissolves very quickly, and it disappears with just a little bit of swirling. The second is a 10% solution of copper sulfate, which is made by adding 1.1 g to 10 mL of water. I again swirl it until it all disappears, but this time it takes a little bit longer. Now to test it out, the high sugar urine is mixed with about a third of its volume of the KOH solution. Then to this, the copper sulfate solution is added dropwise with continuous mixing Every time it’s added, a small amount of greenish solid initially forms, which is copper (II) hydroxide. However, in strongly basic solutions, like potassium hydroxide, the copper (II) hydroxide is slightly soluble, so it dissolves with a little bit of mixing. The goal now is to keep adding it very slowly just until the solid stops redissolving and the solution is saturated with the copper hydroxide This exact point is often hard to tell though, and it’s pretty easy to overshoot.. In any case, I eventually start to see some solids persist, so I take the tube off the stand and I place it in some near boiling water for a few minutes. If sugar is present, the color will change to yellow orange or red depending on the concentration. Okay, so now to explain how this works… Glucose is known as a reducing sugar, and it’s able to reduce the copper (II) hydroxide to copper (I) hydroxide, which is yellow. This newly formed copper (I) hydroxide is not very stable so it quickly degrades the copper (I) oxide, which is red. All of these color changes give rise to a nice spectrum of colors. After a few minutes, the test tube is removed from the water and allowed to cool to room temperature. The final result is based on the color and it can even be used to estimate the level of sugar that was present. Mine here is an orange-brown color which tells me that there was a lot of glucose. Just as a comparison, this is what it looks like when pee at normal sugar levels is used in this case. There’s no glucose to act as a reducing agent so the color shouldn’t change. However, it still does due to the presence of other normal things found in pee like uric acid and creatinine This is a pretty decent problem because it can either mean that there’s no sugar at all or a very small amount, it’s impossible to tell So people who are just minorly diabetic can’t really rely on it For the next several years, scientists tried to improve on Trommer’s method, and in 1849 Hermann von Fehling succeeded in developing a better test. This test solution must be prepared fresh from two separate solutions A and B. This is solution A and I’m making it by dissolving 7 g of copper sulfate in a 100 mL of water To make solution B, I add 35 grams of sodium potassium tartrate also known as Rochelle salt, followed by 100 mL of water. I mix it around and when most of it dissolves, I add in 10 grams of sodium hydroxide. Then, I stir this for a few minutes until it all dissolves. To make the actual Fehling solution, I just need to mix an equal amount of each When I do this the sodium potassium tartrate will chelate the Cu2+ ions to form a complex with a deep blue color. This complex is not very stable though, which is why it needs to be made shortly before using it. It’s placed in some boiling water and an equal amount of diabetic pee is mixed in. If glucose is present the copper in the complex will get reduced to copper (I) and will precipitate again as copper (I) oxide. Just like the Trommer’s test, it will go through a spectrum of colors, which can be used to estimate the glucose level After letting it cool to room temperature we can see the color that I get is quite similar. This time, when I test the normal pee, it doesn’t turn green or anything, but it does still slightly change colors. This color change, just like before, is caused by uric acid and creatinine, but it’s not nearly as bad, and because of this, unlike the Trommer’s test, it’s useful for everyone, whether they’re just minorly diabetic or severely. The Fehling solution quickly took over as the major way to test for glucose in urine for nearly half a century until 1907 when Stanley Benedict developed yet another method The main improvements were that it only required making one solution, and it was much more sensitive to small amounts of glucose. To make it, I just add 10 g of sodium carbonate, 17.3 grams of sodium citrate, and 1.7 g of copper sulfate to 100 mL of water. Then, I mix it around for a couple minutes until it all dissolves. In the solution, the copper ions will form a complex similar to the Fehling’s test, except in this case it’s complex with sodium citrate is a lot more stable, and it’s even less sensitive to other things that might be in the urine. After a couple minutes of mixing, I have a nice and clear solution, so it’s good to go. The typical test was to add 5 mL of the Benedict’s solution followed by 8 drops of pee. Then just like all the other runs, it’s mixed thoroughly, and I put it in some boiling water. I let it sit here for a few minutes and a nice color change occurs. Just like the Fehling solution, the copper in the complex is reduced to copper (I) and it precipitates as copper (I) oxide. The color of the copper (I) oxide is variable, and it depends on the concentration of glucose. Anyway, I take it out after a few minutes, and I let it cool to room temperature. Because this is still a Cu-based test, the color range is the same as the previous ones. However only a small amount of urine used here, so it didn’t go all the way to the orange-brown color. When I did it again with the control urine, there was practically no change in color This is way better than all the other tests that have shown so far, and it’s no wonder that it took over as the major method to test for diabetes This went on for about three decades until the 1940s when the Ames company developed a tablet form and test strips. When the tablet was dropped into a test tube of urine, it would generate its own heat and carry out the Benedict test The test strip was also made using the ingredients of the Benedict test, but it was a little bit easier to use because it just needed to be quickly dipped in. Then based on the color, they could be matched to a chart and the glucose concentration could be estimated. These products were really revolutionary because it was the first time that diabetes could be easily tested for, and monitored at home. However, they were still based on the old copper sulfate technology which often underestimated the amount of glucose present and had a bunch of other issues. About fifteen years after this release though, the Ames company developed a completely new technology that was based on enzymes. They consisted of three main ingredients all fixed to the end of a strip. The first two were the enzymes glucose oxidase and peroxidase, and the third was a chromagen. A chromagen is basically a substance that can be converted into a dye or a colored compound So how exactly does it work? If glucose is present, it’ll be picked up by the glucose oxidase and converted to gluconic acid and hydrogen peroxide The secondary peroxidase enzyme then picks up the hydrogen peroxide and uses it to oxidize the chromagen, leading to a change in color This level of color change is then proportional to the amount of glucose that’s present. The major benefit of this method is that it’s extremely specific to glucose. All the copper sulfate based tests are sensitive to anything that can reduce copper (II) to copper (I) which isn’t just glucose. This actually makes them generally useful in a lot of other chemistry applications, but it can lead to some problems in diabetes testing. For example vitamin C, supplements and various other drugs often lead to false positives. The enzyme-based strips are still used today because they’re easy and convenient, but they do have a major downside Not counting any rare medical problems glucose only spills over into the urine when the kidney resorption limit is overloaded. So although the glucose in the urine is correlated to how much is in the blood, it’s not the same. On top of this, the reading that you get from urine will always lag behind the actual level in the blood, and it also won’t be able to report low levels of blood sugar. For this reason, a blood measuring system was eventually developed in the 1960s again by the Ames company. The early systems were very similar to the enzyme-based urine strips with just a couple differences. A different chromatin was used and the outside of the test pad was covered in a semi-permeable membrane that would block blood cells, but allow glucose to pass. These strips were popular for a few years but it was really hard to accurately correlate small color differences to glucose concentrations. So to reconcile this, the Ames company developed a machine in 1970 that could read the color with a lot more precision Although they worked quite well, they were difficult to use properly and they were also super expensive. For these reasons they weren’t marketed for the average consumer, and they were sold exclusively to doctors and hospitals. It then took until 1981 to work out most of its problems and for a proper home version to be released. However, by this time, a faster and more accurate technology was already being developed. This new type of meter was released in 1987 and it was the first one to be based on electrochemistry This test strip has many layers and it contains both enzymes and The system was a lot easier to use and it also needed less blood to be drawn. Over the years some improvements have been made and this is what they tend to look like nowadays. So blood is first drawn by using a little device that quickly shoots out and retracts a small needle. The drop of blood is then touched by a test strip that is preloaded in a glucose monitor. The blood is quickly pulled up the strip and several seconds later, it gives a reading on the screen. Since the initial release in 1987, commercial blood sensors haven’t changed very much. They’ve generally become more accurate and look nicer but the technology isn’t significantly different. The test strips either use glucose oxidase just like the old chromagen-based ones or another enzyme called glucose dehydrogenase. Each enzyme offers their own unique pros and cons, but generally work in the same way Both of them pick up glucose from the blood and convert it to gluconic acid. In doing so though, the enzyme receives a pair of electrons from the glucose and becomes reduced. The electrons are then given to a mediator compound, and the enzyme goes back to its active state, ready to accept more glucose. The now reduced mediator compound transfers the electrons to an electrode which generates an electric current that’s directly proportional to the glucose concentration This is picked up and interpreted by the meter, and several seconds later, It spits out a reading. For most people, this meter works well enough, but it still has two major downsides. It requires blood to be drawn which isn’t ideal and it isn’t continuous, so it needs to be done multiple times in the day. Some alternatives have been starting to appear but they’re still in their very early stages of development. A few companies offer a chip that can be implanted under the skin which continuously monitors glucose levels and transmits the data to a small device. If the patient is type 1 diabetic the system can be also coupled to an electronic insulin pump. Most of these systems have dedicated receivers for the data, but some are starting to work with smartphones. The ideal system is one that is completely non-invasive, and a lot of work has been put into its development. However, so far, nobody’s been able to make a product that is reliable and accurate. Some new and quite promising ones are supposed to launch in 2018, but we’ll just have to wait and see how well they actually work. A special thanks
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