Good Advice, Part 2

Oct 07 2008 Published by under Physiology/Pharmacology

So I've been thinking of ways to make some of my more science-y blogging come across to those with less in the way of science backgroud. There was a suggestion that I try categorizing the posts into easy, intermediate, and difficult, but I wouldn't want people to give up on something they may potentially find really cool just because it's labelled "hard", you know?
One way I thought of to help with this would be a series of really easy background posts on many of the topics that I write about. These would be things like different neurotransmitters and brain areas, as well as a couple of diseases that I happen to think are really cool. Thus, when I write the deeper, more science-y posts that contain these topics, I can link back to them, and you will know what I'm talking about. It's like wikipedia, only better because all of these things relate specifically to ME. And cannot be edited by people who may just want to change things for fun. These will, of course, be interspersed with other posts (I've got something awesome brewing on Aristotle, stay tuned).
So, without further ado, the first one of the things that I happen to like blogging about background posts...DIABETES.


Specifically, this is a diabetes mellitus post. There are several kinds of diabetes, but the most common are the two diabetes mellitus types (type I and II). I received most of this information from MY endocrine professors at the medical school, so I will try to find relevant citations, but most of them would probably be of the textbook variety. Still, I will add references where I can.
I'd like to start with some of the physiology of the pancreas, and how exactly your insulin is regulated on a day to day basis. From there, it will be easier to understand why diabetes has the symptoms and consequences that it does. So here it goes!
The Pancreas
Your pancreas is a very large gland located below your stomach and liver. It is differentiated into two main types of tissue. There are many large bulbs of tissue called the pancreatic acini, which surround littler bulbs of tissue called the islets of Langerhans. The pancreatic acini are mainly responsible for secreting digestive juices, and so I'm not going to talk about them here. The islets of Langerhans are made up of three different kinds of cells, which are conveniently named alpha, beta, and delta.
Alpha cells secrete glucagon, beta cells secrete insulin, and delta cells secrete somatostatin. Somatostatin is a very important molecule in many of the systems of the body, especially in growth, the gastrointestinal system, and in blood glucose regulation, but it's not technically one of the main players in this system, so we're going to concentrate for the time being on insulin and glucagon. (Somatostatin is pretty cool, though. For more information on it, try here, a pretty good bank of information from Colorado State University.)
So alpha cells, glucagon. Beta cells, insulin. I'll start with insulin, which will be something that most people recognize, even if they don't know what it does.
Insulin
Insulin is produced through a series of steps in the beta cells of the pancreatic islet. If you want to see how insulin is made, try here. For the biochemists out there, insulin has a molecular weight of 5808, and is made of two amino acid chains joined by disulfide linkages. What this means for people who are NOT biochemists, is that insulin is a honkin' big hormone.
Aside: Insulin goes through several steps on its way to being made, and the last one of these chops off something called a C peptide. The C peptide has been found to have some significant properties by itself, but it is also the major marker for when someone wants to measure how much insulin you have. Insulin is very fast acting, and is bound to receptors very quickly. So measuring insulin directly won't give you a correct idea of how much is out there. Instead, you measure the cut off C peptide, which sticks around for a little while. So most of the time, when doctors are measuring your insulin levels, what they're actually measuring is your C peptide levels. (End of aside)
What does insulin DO? It lowers your blood glucose levels. This may seem a little strange to some people, since I'm sure you've heard that low blood glucose is bad for you. But you'll see what I'm getting at soon. Your beta cells are stimulated to release insulin whenever your blood glucose levels get high, such as right after you eat a meal.
How does insulin work? As I mentioned above, insulin in a pretty big molecule. It doesn't just get released and go sliding into your cells. In order to have any effects, insulin has to bind to insulin receptors, which are on many of the cells in your body. When insulin binds to its receptors, the receptors change on the outside and on the inside of the cell, and it is these changes that make things happen. These insulin receptors become important later, when we talk about type II diabetes mellitus.
So what happens? It actually depends on where you are in the body. I'll go through a couple of the most important tissues, to give an idea of just how widespread and important these effects are.
Muscle
Obviously, your muscles need and use a lot of energy on a daily basis, even if you're not the type that goes out and runs miles and miles. But your muscles actually do not rely on glucose direct from your bloodstream most of the time. When you are in a fasting state (like when you wake up in the morning before breakfast), your muscles rely mostly on stored fatty acids and glycogen (which is a temporary way to store glucose). So most of the time, your muscle cells are actually not even permeable to glucose!
This is pretty important, because if your muscles were taking in glucose from your bloodstream to use all the time, you'd have a lot of trouble keeping your blood glucose levels high enough for other organs (like your brain) to function well. So your muscles are not normally permeable to glucose unless insulin is around.
In muscle cells, insulin causes a glucose transporter (GLUT4) to be moved to the cell membrane. So once insulin binds to muscle cells, the glucose transporters move to the membrane and start sucking up glucose from the blood. And for a brief time, your muscles will use glucose as their primary energy source.
Aside: This is why endurance athletes have those gels and Gatorades and things. They contain high levels of carbohydrates, which are broken down very quickly to glucose, and give your muscles a new source of energy. However, they work best when you need a burst of glucose into your blood, or when your muscles have already used up most of their fatty acid and glycogen stores. So seeing people chugging Gatorade after doing a mild 30 minutes on the elliptical machine is watching them take in calories and electrolytes to pretty much no real purpose. (end of aside)
Liver
Why liver? Well, your liver does a lot more than help you get over a night of heavy drinking. Insulin causes glucose to be transported into liver cells in the same way as in muscle. But once it gets there, the glucose is not used for energy. Instead it is, through a series of reactions, transformed into glycogen, which is a short term storage for glucose. Once the liver has all the glycogen it can hold, it begins transforming glucose into fatty acids, which are precursors to building up fat.
Aside: Ever wonder why people eat force-fed goose liver (foie gras)? This is why. When you force feed a goose (or any animal for that matter), their blood glucose is always really high. This means that their insulin levels are also high, which means that their liver stores a lot of glycogen. Since you're force-feeding the goose, glycogen levels quickly become maximal, and the liver switches over to producing fatty acids. Fat tastes good, and a fatty goose liver apparently tastes better. So this is why the best goose liver is from force-fed geese. (end of aside)
What is all this glycogen used for? The liver stores glycogen to be release into the blood stream as glucose when your blood glucose gets too low. It's the fast food joint of your body, to keep your blood glucose levels normal until you get a real meal.
Adipose tissue (fat)
Insulin is called a "fat sparing" molecule, and for very good reason. Insulin inhibits something called hormone sensitive lipase. Hormone sensitive lipase is involved in the breakdown of fat into triglycerides and other things that the body can use for energy. So when you inhibit hormone sensitive lipase, you stop the breakdown of fats, so insulin is a fat sparing compound.
Insulin also promotes transport of glucose into adipose (fat) cells, and then promotes the production of something called glycerol, which is one of the precursors to making more fat. This can cause your fat cells to grow, which is how insulin is fat promoting as well as fat sparing.
Ok, so now we know that insulin is secreted by beta cells, and is responsible for making sure the glucose in your blood is transported into the cells where its needed. Now we are going to look at the other major player, glucagon.
Glucagon
Glucagon is the arch-nemesis of insulin. Well, not really. It's more like the Sith to insulin's Jedi, or the Voldemort to insulin's Harry Potter. They are exact opposites in almost every way, but one cannot get along without the other. They bring balance to the force.
So where insulin is stimulated by high levels of blood glucose, glucagon is stimulated with blood glucose is LOW. Where insulin promotes glycogen being made and stored, glucagon promotes glycogen being broken down again and released into the blood as glucose. Where insulin promotes the making and storage of fat, glycogen causes fat to be broken down. In small amounts, this is fine, but in large amounts, (like in diabetes) the byproducts of fat metabolism will build up in the blood, causing a condition called ketoacidosis.
The practical upshot of all this is that glucagon takes care of you when your blood sugar is low. This is particularly important during fasting conditions. When you haven't eaten in a while and your blood sugar gets low, glucagon is released, promoting the breakdown of fatty acids and glycogen and releasing the resulting glucose into your bloodstream, so that you can keep functioning perfectly well until your next meal.
Aside This is not to say that glucagon is a horrible thing, and it's release must mean you are STARVING. When we say fasting conditions, we usually mean the time right before breakfast in the morning, or right before a late dinner in the evening if you've had no snacks. Because glucagon causes fat breakdown when your blood sugar is low, some people say it is best to exercise in the morning before breakfast, when your body is technically fasting. Then your body will have to use your glycogen and fatty acid stores as a source of energy, and you will burn more fat. Unfortunately, with our current lifestyles, it's often the case that we aren't in a fasting state even in the morning. So you'd have to make sure you didn't stuff yourself after about 8pm the night before. (end of aside)
So now you know how both insulin and glucagon work, you can see that they keep blood glucose in a very delicate balance. When you eat and your blood glucose goes up, the pancreas is stimulated to release insulin, storing glucose away in your cells and using it for energy. When your glucose goes down, the pancreas is stimulated to release glucagon, which takes the stored glucose and releases it into the bloodstream to bring glucose levels back up.
And now we go into what happens when something in this goes WRONG...
Hypoglycemia
This is a condition when your blood sugar gets too low. It's often very rapid onset, and can result from fasting for too long, or from accidental administration of too much insulin in diabetics. Normal blood glucose is around 80-120 mg/dl, but many people can have between 60-80 mg/dl with no ill effects. But once you get below 60 mg/dl it's a different story.
Symptoms include: weakness, irritability, headache, chills, blurred vision, slurred speech, confusion, difficulty concentrating, hunger, and loss of consciousness. If you see someone with these symptoms, and they are still conscious, they need sugar immediately to get their blood glucose back to normal. People who are likely to get hypoglycemic symptoms (such as people on insulin) often carry things like glucose tablets or crackers on them just in case. If it gets bad enough they the person loses consciousness, they may sometimes need i.v. glucose administration.
Hyperglycemia
This is the main symptom in type I or type II diabetes mellitus. Unlike low blood glucose, high blood glucose (higher than 250 mg/dl) can take days to notice. This is what happens when you either have no insulin, or not enough insulin to take care of the glucose in your bloodstream. The glucose is there, but your cells don't have access to it. This means that your body will react as though it is starving. And in times of starvation, your body stimulates the release of glucagon. So your body starts breaking down glycogen and fats and pumping MORE glucose into your bloodstream.
Symptoms of hyperglycemia include: confusion, combativeness, dehydration, nausea, vomiting, rapid pulse, fruity breath, coma, and death. The only treatment for this is i.v. insulin as quickly as possible.
Type I Diabetes Mellitus
Until the last decade or so, type I diabetes was the type that everyone knew about. It's often referred to as juvenile onset diabetes, because symptoms usually first occur prior to or during puberty.
Type I diabetes is characterized by extreme hyperglycemia. This is because the patients have no insulin. None. They don't even have any beta cells. Type I diabetes is an auto-immune disorder (there is evidence that it's also genetic), where your body attacks its own cells. What we believe happens is that when a young adult or child has an illness, the body fights back and wins. But sometimes it fights back a little too enthusiastically, and ends up killing off its own beta cells in the process. Unfortunately, once your body has started killing off its own beta cells, it doesn't know how to stop. So the patient is unable to produce their own insulin.
The main symptoms are those of hyperglycemia, which I described above, as well as:
Polyuria: crazy amounts of peeing. High levels of sugars in your blood increase your serum osmolality, making your blood very concentrated. Your kidneys will try to filter this out to make your blood more dilute, which means you pee a lot. Also, because your body is trying to filter out all of this excess sugar, you will have glucose present in your urine, which is one of the tests for diabetes.
Polydipsia: crazy amounts of drinking. Due to all the filtration and polyuria, your body will become dehydrated.
Polyphagia: crazy amounts of eating. In diabetes, your blood glucose is plenty high, but you have no insulin! This means that none of that glucose is getting into your cells, and your body is telling your brain that you're ravenous! .
Ketoacidosis: This is a condition which causes a diabetic's breath to smell like Juicy Fruit. In times of extreme starvation, your body start breaking down fats and even proteins in very high amounts. The byproducts of these reactions are ketones. Normally your insulin would increase once you had sugars in the blood, and so you wouldn't get ketones. But people with type I diabetes have no insulin, so nothing blocks ketogenesis and you get a buildup of ketones in your blood. Since ketones are acidic, this changes the pH of your blood, and that's VERY bad. Ketoacidosis is pretty much the step right before a diabetic coma.
Type I Diabetes Treatments
No surprisingly, type I diabetes was a death sentence until about the 1920s. It was only when people discovered that you could cure diabetes in dogs by injecting them with pancreatic juices from other dogs that they realized diabetes could be treated. Until about the early 1980s, diabetics had to inject pig or bovine insulin, but now we have huge bacterial vats engineered to make insulin by the bucket-load. Not only that, diabetes was considered such a deadly disease that, when people patented insulin, they deliberately made it available non-profit. Insulin today is still only about $1 a dose, which is incredibly low. (if only they would do this for other horrible diseases...)
Recently, pharm companies have been working on developing insulin that you inhale (squirt up your nose like Flonase) as opposed to injecting, which would probably be a drastic quality of life improvement for many people. Unfortunately, it's also very hard to control the dose of insulin that way, which leads to problems with glucose control. So right now, you'll see most diabetics with little insulin syringes or insulin pumps on their waistbands. The insulin pumps can deliver timed doses of insulin without the diabetic having to calculate exactly how much they need.
Type II Diabetes
Type II diabetes is also known as adult-onset, though these days its being found in children as well . Type II diabetes is differentiated from type I in that people with type II diabetes still have beta cells that still produce insulin. Type II diabetes is instead the case where you don't have ENOUGH insulin. But because you still have insulin, it's a much slower onset and much harder to see than type I diabetes.
There are several reasons why you might not have enough insulin. In some people, their beta cells simply do not produce enough insulin, because the beta cells themselves are impaired. This can also happen as your body gets older. In some cases this is due to excessive amounts of adipose tissue. A lot of body requires a lot of insulin, and sometimes your pancreas cannot keep up. Finally, there are some cases where your insulin receptors on your various cells become desensitized. No matter how much insulin is there, they don't really sense it. Finally, scientists are finding many genes that may predispose certain people to developing type II diabetes.
Type II diabetes, like type I, is characterized by hyperglycemia. However, in type II diabetics, you will see an insulin response, but not enough of one to bring blood sugar levels down to normal. On the one hand, this is good, because it means that there is still insulin, and so people with type II diabetes are much less likely to suffer from ketoacidosis. But they still have the same problems with polyuria, polydipsia, etc.
Type II Diabetes Treatments
In severe cases of type II diabetes, the patients do have to take insulin. Also, there is also a theory that some forms of type II diabetes are a slow autoimmune disorder with a genetic predisposition that will, in time, destroy your beta cells and you'll end up with type I, in which case you will definitely need insulin.
Luckily, type II diabetics often have other options. Some patients can stop all symptoms of type II diabetes by decreasing their body mass. This is in the cases where insulin resistance in caused by excess adipose tissue. In other cases, cutting out foods from the diet that have a very high glycemic index (stuff that really makes your blood sugar spike, like foods high in sugars or carbohydrates), can also help to control glucose levels. In fact, most doctors recommend this to type I and type II diabetics, as a way to promote glucose control and hopefully have less up and down of insulin and glucose (whether or not this is beneficial is up for debate right now, but I haven't got time to go into it). Also, exercise is recommended, because exercise can make your cells more permeable to glucose even in the absence of insulin, so exercising regularly can help lower your blood glucose.
There are also various types of drugs out there that can help type II diabetics make the most of the insulin they've got. There are actually many drugs out there of various types, I'm just going to cover the current top four categories.
1)Solfonylureas and Meglitinides, which includes the drugs Tolinase,Glucotrol, Prandin, stimulate your pancreas to release more insulin than it would normally, which can help bring your blood glucose levels down.
2)biguanides (the best known drug of this type is Metformin), actually stops your liver from releasing glucose back into the bloodstream. It also stops some absorption of glucose you're your gut when you eat. However, for some reason these drugs leave a taste in your mouth like you've been sucking on a nickel.
3)Thiazolidinediones, a completely unpronounceable class of drugs that includes the trade name Avandia, a drug that lowers the insulin resistance of your muscles, so they are more sensitive to insulin and thus absorb more glucose.
4)Alpha-Glucosidase Inhibitors, which includes drugs like Precose and Glyset. These drugs break down sugars in your GI tract, as well as delaying food absorption, so less glucose gets into your blood stream in the first place. Unfortunately, due to decreased breakdown of food and sugars, side effects include massive amounts of diarrhea and gas.
Of course there are several other classes, but this post is getting VERY long, and I'm very tired. I realize diabetes is a really complicated issue with lots of strange effects and drugs and stuff going on, and I certainly could not cover all I felt I should, so feel free to ask me questions if you have them! If I cannot answer them, I can certainly find someone else who can!

13 responses so far

  • Russell says:

    How does diabetes cause peripheral neuropathy?

  • Tye says:

    As I understand it (lowly M1 student) neuropathy results from a few things stemming from diabetes.
    1. Vascular damage, neuronal function and blood supply are highly coordinated events, diabetes has been linked to vasoconstriction, basement membrane thickening, and hypoxia (neuronal ischemia)
    2. since neurons are insulin independent they can take in glucose without in diabetics. in hyperglycemia, the polyol pathway can become hyperactivated by a complex series of reactions which leads to depleted NAD+ which takes away the ability to keep reactive oxygen species from accumulating and damaging cells.
    3. high levels of intracellular glucose (neurons are insulin independent) can cause glucose to react with proteins in the cell which can destroy their functions.
    I'm sure there are far better explanations and probably more reasons, thought I'd throw that out there though.

  • Coturnix says:

    This should join the Basic Concepts collection that John Wilkins is taking care of....

  • HP says:

    I was diagnosed with Type II about a year ago, and I found it was nearly impossible to find any information about the disease that was aimed at an intelligent layperson. That is, most of the info I was given as a newly diagnosed diabetic was aimed at about a 6th-grade reading level, and when I went looking on my own, all I could find were highly technical papers in endocrinology journals. So, thank you for this, and please write more.
    To Tye, re. circulation and neuropathy: I take it then that the cartoon explanation I was given -- lots of glucose makes blood syrupy, and harder to push through small blood vessels -- is an oversimplification?
    Suggested topics:
    1) I'd like to know more about what goes on during deep sleep and after waking, in terms of the various chemical signals, etc., related to glucose, metabolism, alertness, etc. (My doctor told me that when I don't eat breakfast, my liver starts dumping glucose in order to wake me up, and that's why my numbers go up if I skip breakfast.)
    2. My mother (also Type II) recently had a bout of acute pancreatitis, which may or may not be related to taking the diabetes drug Byetta. From what I've read, the connection between Byetta and pancreatitis is unclear, with some claiming it's woo, although Mom's doctor seemed pretty confident there was a connection. What's your take on the current literature?

  • Tye says:

    HP: yes I would say that it is quite a bit of an oversimplification. Glucose is a highly reactive (in the sense of signaling and metabolic pathways) molecule who's concentration greatly affects many pathways within the body. I'm sure there are those who are more qualified to speak about this than me but diabetes is a pretty complicated disease course in that it affects the basal metabolism of almost every cell in the body.
    Re your question 2: I didn't do a thorough search but remembered the FDA putting out a press release last year dealing with the Byetta/pancreatitis link so I've included it here for you. [url]http://www.medscape.com/viewarticle/564359[/url]

  • Type2 says:

    There's something of a trend towards getting Type 2 patients on insulin sooner than had been the normal practice. If you can control your blood glucose with diet and exercise, that's ideal. If that's not enough, oral meds and insulin work very well together. I started on insulin a few years ago, and I'm quite pleased with the results. (Since one of the things that can happen with Type 2 is your insulin-producing cells "burning out" from trying to produce more and more insulin, my doctor and I decides to stop my sulfonylurea (glipizide) in favor of injected insulin.
    I think most insulin users find the injections a minor hassle, but the pain is usually negligible. If I had a choice, I would much rather get rid of the finger-sticks than the injections.
    HP: I've had the same experience with the medical community's "Diabetes Education" efforts. Fortunately,there's a lot of intelligent stuff on the internet about Type 2. (Unfortunately, but not surprisingly, it's mixed in with a lot of garbage.) Try Googling for David Mendosa and for "diabetes blogs". If you have the patience, subscribe to misc.health.diabetes--there's a lot of good information, and people sharing their experiences (but you have to wade through trolls, spammers, nutcases, and the people swearing at the trolls, spammers, and nutcases).

  • scicurious says:

    Thanks for the info, Tye! I'd always heard that high glucose levels contributed to peripheral neuropathy by glomming together (that's totally the medical term) on axons, which somehow promoted degeneration, but it wasn't very well covered. I can look some stuff up and see what I can find.
    HP: To be honest, I really don't know anything about sleep/wake cycles and how those differ in diabetes. But Coturnix might know! He's the king of everything circadian.
    I can try to look up stuff about Byetta. Tye, I couldn't access that article you linked, got another option?
    Thanks so much for the great feedback, everyone!

  • You may appreciate some contemporary humanistic poetry on this abstruse scientific topic.

    I'd hate to think that the time-honored "two cultures" division was the fault of science bloggers.

    http://www.youtube.com/watch?v=HZI8DsouAK8

  • Tye says:

    here you go, a more recent FDA warning about "life-threatening pancreas problems linked to the type 2 diabetes drug Byetta after getting two reports of deaths and four other hospitalizations in Byetta users." - Aug 18, 2008

    and sorry about the ubb codes in the earlier comment, def not a computer person

  • Tye says:

    here you go, a more recent FDA warning about "life-threatening pancreas problems linked to the type 2 diabetes drug Byetta after getting two reports of deaths and four other hospitalizations in Byetta users." - Aug 18, 2008
    http://diabetes.webmd.com/news/20080818/fda-notes-two--byetta-deaths
    arrrrggh, my interwebz illiteracy is shining through.

  • marcella cabrera says:

    hi i am dibetic type 2 and had it since 1991 and im 44 years old had a breast cancer removed and just finished my chemo last july 2008 and now have nerve damage to botth my foot and hand im wondring if the indulin pump will be a help to get my sugar to stay in line i dont like alot of needles in me every day i take it 5 times a day
    8 unit of lantus and 8 unit of humlog at 8 am
    then 8 unit of humlogat 12 and 5 then again 20 lantus at 10 am and it is getting on my nerves to having to keep up with all this and out of reach of my 3 kids
    im trying so hard to keep in mind must keep shots update and papers of where my sugar is at
    i wonder if insulin pump will less my time of to much needs
    ???/

  • scicurious says:

    marcella: congrats on finishing your chemo! I really hope it turns out all right. As for the diabetes, I'm not a medical doctor (I'm a researcher), and so I can't really tell you what to or not to do. An insulin pump is certainly an option and may help you stick to your regimen, which might decrease future problems with nerve damage, etc. However, you should ask your doctor. It's possible that the type of insulin you're on doesn't work well with an insulin pump (the volume may be too high or something), and it's also possible that your health insurance may not cover such a costly item. But asking your doctor is always a good idea.

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