This is the contents of a message thread in Section 4 (Hypoglycemia) in the diabetes forum (GO DIABETES) of Compuserve. It was written by Barrett Chapin, MD, who tells us his specialty is endocrinology. It is posted with his permission. If you have a question for him, he has requested that you post them on the Hypoglycemia Section of the Compuserve Diabetes forum. I used to have his email address posted here, but he was getting to much email to respond to each one. So, to remove frustration by both parties (with me in the middle to need to use the procedure above) (Another alternative: join our email mailing list referenced on the previous page -- the one that got you to this page. Barry is not on it, but it is an option if you can't get to Compuserve) Don McCullough 24-Apr-96 15:54:18 Sb: Understanding HG Lesson1 Fm: Barrett Chapin, MD To: [F] Mona Oliver As promised a little bit about Hypoglycemia (HG). More in the future (as time allows). The goal of this message is to provide the basics of what occurs in ones body in the regulation of glucose and hypoglycemia. I am trying to write for the layperson. Please, let me know if it is too complicated or I use words that you do not understand. To understand HG you must understand what is happening in the body. I will break things down into sections on each organ system. I will start with the brain, then insulin, then the digestive system and food, and finally the liver. THE BRAIN. The brain is the major player in hypoglycemia. The brain depends on glucose (sugar) for fuel. It has very little ability to store any glucose and depends on a constant supply from the the glucose concentration in the blood. Just as the brain requires oxygen and extracts it from the blood, the same thing occurs with glucose. Without enough glucose (or oxygen) the brain goes into a coma. Our bodys evolved in this way over a long time and beacuse of the importance to keep the organism alive, we have some protective mechanisms to warn us of hypoglycemia and prevent it from happening (this last sentence is my opinion, but it makes for a better story). The brain senses the glucose concentration and will cause things to happen when it drops too low. When the glucose concentration goes down to the 60s mg/dl there are several hormones that are released to help drive the glucose back up. These are called the counterregulatory hormones and consist of glucagon (the hormone most effective at raising glucose), epinepherine, norepinepherine, growth hormone, and cortisol. The level at which these processes occur, have some variability between people. When the glucose concentration drops to the mid-50s mg/dl most people begin to sense things from the counterregulatory hormones that are released (mostly from epinepherine and norepinepherine - "the fight or flight hormones"). These symptoms are called the autonomic symptoms of hypoglycemia and include shakiness, pounding/racing heart, nervousness, anxiety, perspiration, tingling, feeling hungry, and sensing that the blood sugar is low. At about 5 mg/dl below the autonomic symptoms (usually at a blood sugar of about 49mg/dl) the ability of the brain to work properly is noticed by the individual. These are called the neuroglycopenic symptoms and include confusion, fatigue, drowsiness, warmth, difficulty speaking, incoordination, and odd behavoir. It can progress to coma, seizures, and death at glucose levels in the 30s mg/dl or below. Be aware that the glucometers that people use for diabetes are most accurate in the low 100s and have very poor accuracy when it is reading concentrations below 60 mg/dl. Additionally there is quite a bit of individual variation, so don't think you are safe until you get to the 30s, because you may not be. INSULIN. As I have mentioned there are several hormones that will raise the glucose level, with glucagon being the most effective. Insulin is the only hormone that will lower glucose (for medical people - I know that you know that insulin-like growth factors can also lower glucose, but I want to keep this simple). Insulin is made in the pancreas, and I repeat, is the only hormone that lowers glucose. The pancreas senses glucose levels under about 80 and releases only a low level of insulin. After you eat and the glucose level goes up the pancreas senses this and releases insulin in order to lower the glucose. THE DIGESTIVE SYSTEM AND FOOD. Food can be divided into 3 component parts - Protein, Fat, and Carbohydrate. Carbohydrates are sugars. The body runs on glucose, one of the forms of sugar. Your small intestine will absorb the carbohydrate from your food. Most of the absorbed carbohydrate will be in the form of glucose. The rate of absorption will depend on what it came from. Some carbohydrates are absorbed more slowly that others. The term "complex carbohydrates" refers to carbohydrates with lots of bonds that makes them absorbed more slowly than pure glucose. This has been measured by some researchers and is called the "glycemic index" of a food. So "complex carbohydrates" have high "glycemic indexes", indicating that they are absorbed as glucose more slowly than simple sugars. THE LIVER. The liver's job is to keep the blood glucose concentration constant. After eating, the glucose concerntration stays up for 3-4 hours, so the liver needs to do nothing to maintain an adequate glucose concentration. When the meal is metabolized after the 3-4 hours, the liver maintains the glucose concentration by breaking down glycogen. Glycogen is a molecule made of many glucose molecules branched in different orientations. This process is called glycogenolysis and releases glucose when the body (brain) needs it. The other way that the liver maintains the glucose concentration when you haven't eaten for a while is called gluconeogenesis. Gluconeogenesis is the manufacture of glucose from other things, protein and fat. This is the major way the glucose concentration is maintained when fasting for a long time and when the glycogen stores run out. Enough for now. Maybe more in the next week or two. Here is lesson 2 of Understanding Hypoglycemia. This lesson is about what is considered normal from a medical standpoint. The medical laboratory definition of normal is the range of values that includes the middle 95% of the normal population. That didn't come out as clearly as I would have liked so let me show you with an example. The lab will take 100 normal people (none of them known to have a disease that effects the test being done). They will take the values of all the normal people, throw out the top 2.5% and the bottom 2.5% and call the remaining 95% their "normal range" for that test. In reality one does not have to take 100 or even 1000 people to define the normal range. One can use statistics to define it. By calculating the average (mean) and something called the standard deviation and assume the test is distributed in a Guassian Distribution, the normal range is 2 standard devations below the average to 2 standard deviations above the average. Trust me that a normal range can be calculated from a sample of people without disease, and will include 95% of of those disease free people. The normal range is a usefull concept but has some limitations. One limitation is that there are 5% of people without any disease (2.5% below the normal and 2.5% above the normal) who will be labeled abnormal. Another limitation is that some people with a disease that is being tested for may still fall into the normal range. This is because the definition of normal only used people without the disease. Put another way, some people with the disease may test as normal because there is some overlap of the people with the disease, with the test results of normal people. Okay, with that preface in mind, let's look at the normal plasma glucose level, derived from a population of normal individuals. This data comes from 52 premenopausal women and 12 men. If you want to look up the article it was written by TJ Mariwee and JE Tyson and is called, "Stabilization of Plasma Glucose During Fasting." and comes from the New England Journal of Medicine, volume 291, pages 1275-1278, in 1974. The normal values differ between men and women and will be presented separately. The normals are: WOMEN fasting 68-110 mg/dl 24 hrs fasting 34-81 mg/dl 48 hrs fasting 37-62 mg/dl 72 hrs fasting 15-68 mg/dl MEN fasting 66-111 mg/dl 24 hrs fasting 55-103 mg/dl 48 hrs fasting 50-99 mg/dl 72 hrs fasting 50-85 mg/dl. Let me reitterate, these come from normal individuals (no known diabetes and no hypoglycemic symptoms). I will make a comment on these figures. Some normal women can get very low glucose levels and have no hypoglycemic symptoms. Therefore a low glucose level does not give someone the diagnosis of hypoglycemia. So what do doctors consider proof of hypoglycemia? For the well accepted diagnosis of hypoglycemia, a patient needs to have something called "Whipple's triad." Whipple's triad is: 1) symptoms of hypoglycemia (see lesson one for these) 2) a low glucose level at the same time as the symptoms and 3) improvement and/or resolution of the symptoms with administration of carbohydrate (injected or eaten). Be aware that for #2 above, a glucometer level of glucose is not reliable below 60. And what is considered a low glucose? Most authorities agree that it should be a serum or plasma level less than 50 mg/dl in everyone, but some authorities advacate a glucose less than 40 mg/dl in a young person (less than 50 years old). I'll keep on going with more in the future. Please, pose questions on anything that was not clear. -Barry Okay, Mary, Lesson #4. Fasting Hypoglycemia. I'm going to do fasting HG before postprandial HG because I know there are far more postprandial HG's in the forum, and I want to make sure everyone knows the dangers of fasting HG. Fasting Hypoglycemia Fasting Hypoglycemia occurs more than 5 hours after the last meal. The treatment is entirely dependent on what the cause is. There are many causes. For the sake of organization, I will break down the causes of Fasting Hypoglycemia into 6 groups. Each group has several causes within the group. The 6 groups are: 1) drugs 2) organ failure 3) hormonal deficiencies 4) non-beta cell tumors (tumors other than insulinoma) 5) excess insulin states 6) congenital and enzymatic disorders (hypoglycemia in kids) Drugs. There are many drugs that have been reported to cause hypoglycemia. The most common and obvious are insulin and sulfonylureas. These are also sometimes the hardest to diagnose when the patient is not a diabetic and has a psychiatric illness that is causing them to use these diabetes medicines when they don't have diabetes. The next most common drug cause of HG is alcohol. It causes fasting hypoglycemia in alcoholic with liver disease by preventing them from making glucose through gluconeogenesis. Alcohol is also a cause of postprandial HG in non-alcoholics by increasing the release of insulin to a given amount of carbohydrate (as you will see in the next lesson). I will just list the other drugs most commonly implicated in Fasting Hypoglycemia to aviod boring you -- Pentamidine, Beta-blockers, quinine (in high doses), quinidine, salicylates (aspirin, especially in children), sulfonamides, disopyramide, propoxyphene, and haloperidol. Organ failure. The patient with organ failure knows he/she has organ failure because they are sick and have seen a doctors, so don't worry that you have undiagnosed organ failure if you have Fasting Hypoglycemia. Liver failure, kidney failure, heart failure, and sepsis (an overwhelming infection) all fit in this category. Hormone deficiency. Adrenal Insuffiency, severe hypothyroidism, and hypopituartism can all cause Fasting Hypoglycemia. The good news is that the HG goes away when these disorders are treated with hormone replacement. Non-beta cell tumors. Large cancers can cause hypoglycemia usually because they make a molecule called IGF-II (insulin like growth factor, 2). This molecule has the ability to act like insulin and lower glucose. Like organ failure, patients with these tumors usually don't have hypoglycemia as their first symptom. Most of these patients are sick when they develop HG. Insulin excess states. There are 3 of these and all are rare. Insulinoma, a tumor of the pancreas beta-cells that make insulin, has an incidence of one in a million. Some people make antibodies to insulin that prevents insulin from being broken down, but the insulin still works normally, so the insulin lasts too long. And some people make an antibody to the insulin receptor, leaving the receptor in the "on" position as if insulin were attached to it. Congenital & enzyme defects. I am not a pediatrian so I am not well versed in these causes of hypoglycemia. I will list the major causes, but it is no more than reading a list from a book for me, because I have no experience with any of them. Neonatal hypoglycemia, congenital enzyme deficiencies, ketoic hypoglycemia of childhood, galactosemia, and hereditary fructose intolerance. A normal baby of a diabetic mother may have hypoglycemia at birth. This would be under "neonatal hypoglycemia" and come from the child having a beefed up pancreas making alot of insulin due to the mother having higher than normal glucose during the pregnancy. That's the only childhood HG that I know about. I'll say it one more time in case you were not paying attention. If you have Fasting Hypoglycemia. That is hypoglycemia that occurs 5 hours or more after the last time you ate, GO SEE A DOCTOR! -Barry Reactive hypoglycemia. Formerly called functional hypoglycemia, and sometimes called postprandial hypoglycemia, reactive hypoglycemia is hypoglycemia occuring within 5 hours of eating. There are 4 types of true reactive hypoglycemia. They are: 1) from early NIDDM (type II diabetes) or glucose intolerence 2) alimentary hypoglycemia 3) alcohol induced and 4) ideopatic (a fancy word for "unknown cause" I will go through each cause sequentially. Glucose intolerence and early diabetes is usually accompanied by high insulin levels (compared to non-diabetic people) and an insulin release that occurs for a prolonged period after eating. This excess insulin can cause hypoglycemia after eating, even though the insulin doesn't work as well. Characteristicly the hypoglycemia from this cause occurs 3 - 5 hours after eating. A doctor can check you for glucose intolerence or diabetes with a fasting glucose and a glucose tolerence test (you drink 75 grams of carbohydrate and have your blood drawn for glucose every 30 minutes until 2 hours have passed). Alimentary hypoglycemia occurs from a mismatch of insulin and carbohydrate and insulin which is usually due to having an abnormality of the stomach. Ordinarily, a meal sit in your stomach and is slowly released, so the carbohydrate absorption occurs over a prolonged period. For people who have stomach surgery to remove part of the stomach or who dumps most of the meal into the small intestine immediately, there is a very rapid absorption of the carbohydrate. This rapid carbohydrate absorption can be followed by a very brisk insulin release. The big insulin release can drive the glucose level very low. Of all the causes of reactive hypoglycemia, this can be the most dangerous. Alimentary hypoglycemia has been reported to cause coma and seizures. Characteristicly the hypoglycemia from this cause occurs 1/2 - 2 1/2 hours after eating. It usually does not occur without a history of partial or total gastrectomy (stomach surgery). Alcohol can cause FASTING hypoglycemia when alcoholics who have damaged their liver from years of alcohol abuse don't eat for a prolonged period. Nonalcoholics can get REACTIVE hypoglycemia from drinking alcohol and eating carbohydrate. Alcohol can cause an excessive release of insulin when taken with carbohydrate. The excess insulin can lead to you know what. Yes, hypoglycemia! The most common scenerio is when drinking alcohol and carbohydrate alone. It is said that a gin (alcohol) and tonic (pure carbohydrate) and a 50 gram biscuit (more carbohydrate) is a very effective stimulous for hypoglycemia (kids, don't try this at home). So if reactive hypoglycemia is your problem, cut out the alcohol. The final type of reactive hypoglycemia is ideopathic, in other words we don't know the cause. If you truely have hypoglycemia and Whipple's triad (see the 2nd lesson) is documented, and it occurs less than 5 hours after eating, and it is not due to diabetes or glucose intolerence, an abnormal stomach, or alcohol, then you have ideopathic reactive hypoglycemia. If you do not have Whipple's triad and you feel funny or sick after you eat, I would label you as the "postprandial syndrome." The postprandial syndrome is not true hypoglycemia, but you may feel better with the same diet that works for people with reactive hypoglycemia. In fact, I believe that the majority of people who think that they have reactive hypoglycemia, truely have a postprandial syndrome. But what's in a name, if you don't feel right because of what you eat and eating something else will make you feel better, then just do it. Which takes us to treatment of reactive hypoglycemia. The treatment is a dietary adjustment. Less carbohydrate and more slowly absorbed carbohydrate (more complex carbohydrates) in your diet means less insulin released and a lower peak of insulin following your meal, and consequently less bottoming out of glucose after the carbohydrates are absorbed. All the reactive hypoglycemia are treated with dietary changes. In summary, small frequent meals, less carbohydrates (which means more protein and fat), and more complex carbohydrates (foods with a greater glycemic index). I am no expert on diets, so I refer you to the library, both this one in the Hypoglycemia section of the CompuServe Diabetes Forum (I have found some very good diet recommendations there) or your public library (mine had a book on hypoglycemia, and dietary recommendations). -Barry 29-Apr-96 22:57:11 Sb: #586573-#Understanding HG lesson4 Fm: Barrett Chapin, MD To: Mary J. Hill >> Why do some docs deny the existence of postprandial hypoglycemia? << Maybe because they weren't taught about in their training (either medical school, internship, or residency). The topic is not emphasized in training because the cause is not life-threatening, and the treatment is dietary modification (something else that is not emphasized in training). From a doctors standpoint: Let's say you only have a finite amount of time to study. Would you study the things that are potentially fatal or the non-fatal things. Not a great excuse, but the best I could come up with. -Barry 07-May-96 23:20:13 Sb: #The final HG lesson Fm: Barrett Chapin, MD To: all Now for the final installment of Understanding Hypoglycemia. This episode is called, "the free doctor's visit." I will outline how I approach a patient with suspected (and documented hypoglycemia). It might save you a hundred bucks, it should help summarize the important points from the previous lessons. "Next ... Oh, Good Morning, Mrs. Smith ... How are you feeling? This is where you tell me the symptoms that sound like hypoglycemia. Such as, "I feel shakey, anxious, sweaty, etc. and it goes away about a half hour after I eat something." "hmmmmmm," I say, stroking my chin. "Tell me more ..." "blah, blah, blah, ... after I eat." Or "blah, blah, blah, ... when I don't eat." This is the next important bit of information. The relationship of the symptoms to eating. If the symptoms come LESS THAN 5 hours after eating, we are down the pathway of reactive hypoglycemia, and if the symptoms come when fasting or MORE THAN 5 hours after eating we are down the pathway of fasting hypoglycemia. Let assume the symptoms come LESS THAN 5 hours after eating - reactive hypoglycemia. Now I want to document it. If you have not had a venous glucose (blood test) done at the time of your symptoms. Fingerstick glucometer readings won't cut it (they are not reliable when less than 60 mg/dl). I will ask you what reliably brings out the symptoms (let's say it's comes 2 hours after you eat a plate of spaghetti). I'll have you eat the plate of spaghetti for lunch and come into my office afterwards. My nurse will put in an I.V., draw a blood test when you have symptoms, and call me. I will ask you some memory questions and calculations to see if you are thinking clearly (looking for neuroglycopenia), then give you some I.V. fluid with glucose, ask you more memory and calculation questions and measure your glucose level when you feel back to normal. If the first glucose (when you felt bad) was less than 50 mg/dl and the glucose brought you back to normal, you have documented hypoglycemia. If your symptoms are reproduced by someting that you have recognized and you can't bring them out on command, then I give you a lab slip for a glucose level. You are to rush to the lab when you get your symptoms (if possible) and I will see if the glucose level is less than 50 mg/dl. This is documentation enough for me with a reliable patient. You will notice that I do NOT use the 5 hour oral glucose tolerance test for diagnosis. I do not believe this test separates normal people from hypoglycemic people. 20-25% of normal people will become hypoglycemic (symptoms AND glucose less than 50) after a 5 hour glucose tolerance test. I don't do them and don't recommend you accept your diagnosis as hypoglycemic if that is how your doctor diagnosed you. Then I will look for early diabetes. Does anyone in your family have diabetes? Are you overweight? I do lab tests for fasting blood glucose, Hemoglobin A1c, urinalysis, and possibly a 75 gm oral glucose tolerance test with glucose levels every 30 minutes for 2 hours - I do not carry the test out for more than 2 hours). I'm looking for diabetes or impaired glucose tolerance. Do you drink alcohol with your meal? I'm looking for alcohol induced reactive hypoglycemia. Have you had stomach surgery or some other reason why food doesn't stay in your stomach after you eat. I'm looking for alimentary hypoglycemia. If those 3 things come up blank, and you have documented hypoglycemia, your diagnosis is ideopathic hypoglycemia. I refer you to the nutritionist and wish you well. You have nothing I can help you with, as I am a dietary ignoramus and I do not ant to hear the intimate details of your dietary history. I know you don't feel well, but I do not have the expertise to help you. It is my frustration at my lack of knowledge in this area that makes me callus. My defense mechanism, I suppose, as I'm human too. Okay, enough of my shortcomings. If your symptoms come when you DON'T eat, you have fasting hypoglycemia. I pull out my list of causes of fasting hypoglycemia, because there are too many causes for me to memorize (I don't want to miss any), and go through them one by one ... Drugs ..."nope" Organ failure ... "nah" hormone deficiency (my personal favorite) ... "doubt it, but I'll test for it because that's what I do best" big tumors ... "uh uh" excess insulin ... "hmmmm, can never rule that one out" congenital & enzyme defects ... "not if you are an adult." So I run some hormone tests, a TSH and a morning cortisol. While those are cooking in the lab, I see if I can get you to fast overnight to bring out your symptoms and get some blood tests with symptoms. I want a glucose level, insulin level, C-peptide, proinsulin level, and a test for sulfonylurias (either a blood test or urine test) ... all done with symptoms. This will help me sort out all the causes of excess insulin induced hypoglycemia. If you don't have symptoms after an overnight fast or couldn't bear the symptoms and HAD to eat before coming in for the tests, I will admit you to the hospital. You will not eat for as long as it takes to get the symptoms or 72 hours (3 days), whichever comes first. If you don't get the symptoms in 3 days, you don't have fasting hypoglycemia (except in rare cases which I won't go into here). Your treatment for fasting hypoglycemia will depend on what the cause was. So there you have your free evaluation, I'm sure it was worth the price of admission. :) -Barry