CF-Related Diabetes and Impaired Glucose Tolerance
Cystic fibrosis related diabetes (CFRD) is our own special kind of diabetes. It is similar to type 1 diabetes in that the pancreas slowly stops excreting insulin into the blood stream. It is also like type 2 diabetes in that we have some degree of insulin resistance. Here I'd like to explain how blood sugar regulation is supposed to work in healthy humans, and then how it gets out of balance in some people with CF.
How Blood Sugar Regulation is Supposed to Work
Glucose is a monosaccharide (single sugar) and is the preferred energy source of cells. Much of the carbohydrates that we eat in our food are broken down into glucose by enzymes and gut bacteria. Glucose is absorbed from your food through the walls of your small intestine into the blood stream, and cells that need energy absorb that glucose from the blood. The body detects the amount of carbohydrate that you ingested, which triggers the release of an appropriate amount of insulin from the endocrine pancreas (a different part of the pancreas than the part that secretes digestive enzymes, which is called the exocrine pancreas). The body detects how much carbohydrate you have ingested in multiple ways: the sweet taste receptors on the tongue are stimulated, and once the food enters and moves through the stomach, glucose begins to be absorbed and is detected in the blood stream by glucose sensors in the pancreatic beta-cells. There are also peripheral glucose-sensing neurons in the small intestine, hepatic portal vein, carotid artery, and parts of the brain [1].
Insulin is a hormone secreted by your pancreas' beta-cells (part of the endocrine pancreas). Once your body has detected glucose in the blood stream, the pancreas excretes insulin into the blood stream, too. Insulin facilitates the movement of glucose out of your blood and into your cells, thus lowering your blood sugar (a.k.a. blood glucose). The beta-cells secrete insulin in two ways: a little bit all the time to maintain a basal level of glucose movement into the cells, and in response to carbohydrate ingestion at mealtime. Once insulin has moved glucose into the cell it is used in one of three ways: 1) immediate conversion into ATP (the basic unit of cell energy) and used to power the cell's processes, 2) conversion to glycogen, which is a multi-branched polysaccharide (complex sugar) and is stored inside the liver and other tissues for later use, 3) conversion to triglycerides (free fatty acids) for storage in liver, fat, and muscle cells. Storage of glucose is very important, because this acts as an emergency supply when our blood sugar may be too low. When insulin levels are too low in the blood, the alpha-cells of the pancreas secrete glucagon, a hormone that is kind of like the opposite of insulin. Glucagon causes glycogen stored in the liver and other tissues to be converted into glucose and excreted into the blood stream, thus raising your blood sugar (which can then be utilized by your cells).
Pancreatic Malfunction
In CF-related diabetes this normal physiological process of carbohydrate utilization breaks down. The main problem with CF glucose intolerance is that our endocrine pancreas slowly begins to malfunction, in addition to the malfunctioning exocrine pancreas that we take supplemental enzymes for. We don't yet know exactly why or how the endocrine pancreas stops working properly. The old theory was that because the ducts that move the pancreatic juices into the small intestine get clogged with mucus, these enzyme-containing juices get backed up and the pancreas inadvertently starts digesting itself. But this may not be so likely as the body has many safety mechanisms in place to prevent enzymes from being activated in the wrong place (i.e. outside of the small intestine). Newer research has theorized that the CF genetic mutation itself is responsible for causing the malfunctions of the beta-cells in the pancreas [2, 3]. So as the pancreas degrades, the ability for its beta-cells to produce insulin (and reflexively its alpha-cells to produce glucagon [1]) declines. Thus we can get both hyperglycemia (blood sugar too high) and hypoglycemia (blood sugar too low).
Glucagon is produced in two ways as well: in small amounts all the time, and in response to hypoglycemia. But in CFers with pancreatic exocrine insufficiency (i.e. reduced ability to excrete pancreatic enzymes into the intestines) glucagon production is impaired for unknown reasons [4]. This could either be a direct result of CFTR mutation, or could be the result of a broken feedback mechanism in relation to insulin production. Insulin and glucagon are supposed to counter-balance each other. In type 1 diabetes, where insulin production is also impaired, glucagon production is lacking not due to any physical malfunction of the alpha-cells, but because glucagon may be released in response to both hypoglycemia and falling insulin production. But for insulin-dependent type 1 diabetics, hypoglycemia induced by insulin injection does not stimulate this feedback mechanism correctly (because you can't un-inject yourself with too much insulin), and so glucagon is not released in response to hypoglycemia because insulin production doesn't drop as blood glucose gets too low [1]. Thus both type 1 diabetics and people with CFRD that get frequent bouts of hypoglycemia basically become glucagon deficient and increase our tolerance for hypoglycemic episodes (adrenaline and cortisol are released at lower and lower blood sugar levels) so that it's even harder to tell when we're getting hypoglycemic, further increasing the risk of life-threatening hypoglycemic episodes. These days I can't be without my glucometer near me at all times because I can no longer feel the symptoms of hypo until I'm below 50 mg/dL (which is pretty dangerous). However, I can increase my sensitivity to hypoglycemia if I go more than a week without going into a hypoglycemic dive. If blood sugar gets low enough one can pass out or go into a coma and die (if not rescued with glucose in time). For years I've made it a habit to always keep a snack with me to guard against "reactive" hypoglycemia (i.e. post-meal hypoglycemia from an insulin overshoot). For regular people, being "hypoglycemic" usually just means they're tired and hungry but their blood sugar is actually normal (within the range of 75-120 mg/dL). I describe hypoglycemia and reactive hypoglycemia further in this article.
For some CFers the process of pancreatic degradation is so slow that they can go their whole lives without developing diabetes or strange pancreatic behavior. For others, the process of degradation is quicker and CF-related diabetes (CFRD) develops in the person's teens or early adulthood. I developed diabetes when I was 24, which is a fairly common age to have this happen (and I had glucose intolerance for at least 5 years before that). Newer research is suggesting that treating glucose intolerance with insulin injections before it becomes outright diabetes may preserve a person's health for longer than waiting until CFRD develops. I personally believe this to be true and I wish I had done more work to control my blood sugar at an earlier age, as the negative physiological impacts of hyperglycemia are significant, as I describe below.
Insulin Resistance
Insulin resistance means that our body has a reduced capacity to use insulin to transport glucose into our cells. In a person with insulin resistance, the cells down-regulate the number of insulin receptors on cell membranes. This can happen in type 2 diabetes when a person eats so many carbohydrates that the pancreas secretes an extreme amount of insulin into the blood in order to deal with the onslaught of glucose in the blood. The body thinks the extremely high amount of insulin circulating in the blood must be some kind of mistake, so it essentially begins to reduce the number of "ears" (i.e. insulin receptors) it has to listen to the insulin. In CF and other chronic diseases (and also with long-term corticosteroid use, like prednisone) insulin resistance can develop when cortisol levels are very high, as when someone experiences significant emotional or physical stress (like chronic infection or illness) [5]. In both cases the body blocks the ability for insulin to work to remove glucose from the blood, leaving the blood stream with high levels of both insulin and glucose. Insulin resistance in CF can fluctuate with changing levels of infection and inflammation, and can also be modulated by exercise and avoiding excessive carbohydrate intake. One of the reasons why it is bad practice to perform a glucose tolerance test when someone is sick with a lung infection or in the hospital is that insulin resistance temporarily increases during that time of stress and can lead to a false positive for diabetes. So get your glucose tolerance test when you are healthy or in between lung infections. Cinnamon also helps increase insulin sensitivity, so taking cinnamon with a high carb meal can help.
Cortisol plays a big role in insulin resistance. I recently had an "aha!" moment when I realized that the reactive hypoglycemic I get after a carb-filled breakfast is due to high cortisol levels in the morning. Many other CFers have this same problem, and after many years of trying to figure out what was going on, I have a hypothesis. If your circadian rhythm (your wake-sleep cycle) is on schedule, your pituitary tells your adrenals to send out a spike of cortisol in the early morning to wake you up. This spike of cortisol, however, also serves to reduce your cells' sensitivity to insulin. If we already have a background level of insulin resistance due to chronic illness or chronic stress, this AM spike in cortisol is going to have a significant impact on how you metabolize blood sugar in the morning. In order to test my hypothesis, I took glucose readings for several days eating various quantities of carbs in the morning for breakfast. What I found was that if I ate more than about 15 g of carbs, my blood sugar would peak at about 120-180 mg/dL and not start to decline until about 2-3 hours later, and then would suddenly crash. The more carbs I ate, the longer it took to crash but the harder the crash became. Taking insulin with breakfast would not change my blood glucose at all. That was the biggest clue in this puzzle. I could take double the amount of insulin I usually take for that amount of carbs and it wouldn't reduce the peak at all, but it would make the crash deeper. So what I deduced from this information is that my AM cortisol spike made my insulin resistance worse in the earlier hours of the day, but once the cortisol circulating in my blood went back down to a lower baseline level, my insulin sensitivity was normal again, usually by 1 or 2 pm. If I ate a lot of carbs during that AM period of insulin resistance, my pancreas would produce the right of amount of insulin but that insulin would be ineffective until my body chose to listen to it later in the day. Interestingly, if I eat a little low-carb snack for breakfast, like a bit of meat or a lot of nut butter, my insulin sensitivity improves earlier in the day. I hypothesize that this is because I always take bitters before meals, and bitters improves insulin sensitivity. So I could actually take bitters or drink something bitter (like dandelion root tea) and possibly have the same effect. However, when I am feeling really healthy and my diet is good and I'm decently active throughout the day, sometimes I can avoid AM reactive hypoglycemia even if I eat carbs in the morning, and this would be due to an improvement in my baseline insulin sensitivity when I'm feeling healthy. Cystagon has significantly improved my baseline insulin sensitivity to the point where sometimes I don't need to take any insulin at all with carby meals. Maintaining an active lifestyle is also really helpful in this regard, too.
Hyperglycemia
I've explained why hypoglycemia is bad, but what about hyperglycemia? Chronic high blood sugar can cause and exacerbate a number of problems including inflammation, infection, and damage to capillary beds. First of all, sugar is an oxidative substance, meaning that it introduces free radical electrons (ROS) into the body, which bind to molecules and cells causing damage to them. The damage that sugar oxidation causes to your tissues triggers an inflammatory response in the body to clean up the damage and battle the culprit. Some of the worst damage that sugar oxidation causes is to the walls of your smallest capillaries, especially those in your kidneys and eyes. This is why diabetics need regular screenings for kidney and eye damage. But they can also damage other capillaries, including the capillaries of the bronchial arteries which feed oxygen to the lungs. This is an important point, because it has the potential to be related to hemoptysis, a common complication of bronchiectasis (I discuss hemoptysis further in this article). The barrier between the capillaries that exchange gases in the bronchioles and alveoli is very thin and permeable, which puts this barrier at higher risk of damage by oxidative forces like hyperglycemia. High blood glucose also raises the glucose concentration in CF lung fluid (i.e. mucus), which is very dangerous because that can directly provide sugar for the bacteria that live in our airways. In a 2007 study, people with CF had significantly higher levels of glucose in their lung fluids than normal people, and patients with CFRD and hyperglycemia had even more glucose in their lung fluid that non-diabetic CFers. Not only that, but the inflammation caused by the hyperglycemia causes the junctions between our respiratory epithelial cells to weaken, allowing further infiltration of glucose into lung fluid [6].
In the early stages of glucose intolerance and diabetes, we can better regulate our blood sugar by controlling our diet and limiting sugar and carbohydrate intake. I will explain this more in the Blog and the sections on diet and nutrition.
*******************************
[1] http://2009.igem.org/wiki/images/f/f8/Freiburg09_McCrimmon_R_DiabeticMedicine_2008_25_513.pdf
[2] Cystic fibrosis-related diabetes is due to functional abnormalities in beta cells. <http://www.rxpgnews.com/cysticfibrosis/Cystic_fibrosis-related_diabetes_is_due_to_functio_4659_4659.shtml>
[3] http://www.eje-online.org/content/172/4/R131.full
[4] Spontaneous hypoglycemia in patients with cystic fibrosis. <http://eje-online.org/content/156/3/369.long>
[5] Cystic Fibrosis-Related Diabetes and Abnormal Glucose Tolerance: Overview and Medical Nutrition Therapy. <http://spectrum.diabetesjournals.org/content/15/2/124.full>
[6] Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis. <http://jap.physiology.org/content/102/5/1969.full>
How Blood Sugar Regulation is Supposed to Work
Glucose is a monosaccharide (single sugar) and is the preferred energy source of cells. Much of the carbohydrates that we eat in our food are broken down into glucose by enzymes and gut bacteria. Glucose is absorbed from your food through the walls of your small intestine into the blood stream, and cells that need energy absorb that glucose from the blood. The body detects the amount of carbohydrate that you ingested, which triggers the release of an appropriate amount of insulin from the endocrine pancreas (a different part of the pancreas than the part that secretes digestive enzymes, which is called the exocrine pancreas). The body detects how much carbohydrate you have ingested in multiple ways: the sweet taste receptors on the tongue are stimulated, and once the food enters and moves through the stomach, glucose begins to be absorbed and is detected in the blood stream by glucose sensors in the pancreatic beta-cells. There are also peripheral glucose-sensing neurons in the small intestine, hepatic portal vein, carotid artery, and parts of the brain [1].
Insulin is a hormone secreted by your pancreas' beta-cells (part of the endocrine pancreas). Once your body has detected glucose in the blood stream, the pancreas excretes insulin into the blood stream, too. Insulin facilitates the movement of glucose out of your blood and into your cells, thus lowering your blood sugar (a.k.a. blood glucose). The beta-cells secrete insulin in two ways: a little bit all the time to maintain a basal level of glucose movement into the cells, and in response to carbohydrate ingestion at mealtime. Once insulin has moved glucose into the cell it is used in one of three ways: 1) immediate conversion into ATP (the basic unit of cell energy) and used to power the cell's processes, 2) conversion to glycogen, which is a multi-branched polysaccharide (complex sugar) and is stored inside the liver and other tissues for later use, 3) conversion to triglycerides (free fatty acids) for storage in liver, fat, and muscle cells. Storage of glucose is very important, because this acts as an emergency supply when our blood sugar may be too low. When insulin levels are too low in the blood, the alpha-cells of the pancreas secrete glucagon, a hormone that is kind of like the opposite of insulin. Glucagon causes glycogen stored in the liver and other tissues to be converted into glucose and excreted into the blood stream, thus raising your blood sugar (which can then be utilized by your cells).
Pancreatic Malfunction
In CF-related diabetes this normal physiological process of carbohydrate utilization breaks down. The main problem with CF glucose intolerance is that our endocrine pancreas slowly begins to malfunction, in addition to the malfunctioning exocrine pancreas that we take supplemental enzymes for. We don't yet know exactly why or how the endocrine pancreas stops working properly. The old theory was that because the ducts that move the pancreatic juices into the small intestine get clogged with mucus, these enzyme-containing juices get backed up and the pancreas inadvertently starts digesting itself. But this may not be so likely as the body has many safety mechanisms in place to prevent enzymes from being activated in the wrong place (i.e. outside of the small intestine). Newer research has theorized that the CF genetic mutation itself is responsible for causing the malfunctions of the beta-cells in the pancreas [2, 3]. So as the pancreas degrades, the ability for its beta-cells to produce insulin (and reflexively its alpha-cells to produce glucagon [1]) declines. Thus we can get both hyperglycemia (blood sugar too high) and hypoglycemia (blood sugar too low).
Glucagon is produced in two ways as well: in small amounts all the time, and in response to hypoglycemia. But in CFers with pancreatic exocrine insufficiency (i.e. reduced ability to excrete pancreatic enzymes into the intestines) glucagon production is impaired for unknown reasons [4]. This could either be a direct result of CFTR mutation, or could be the result of a broken feedback mechanism in relation to insulin production. Insulin and glucagon are supposed to counter-balance each other. In type 1 diabetes, where insulin production is also impaired, glucagon production is lacking not due to any physical malfunction of the alpha-cells, but because glucagon may be released in response to both hypoglycemia and falling insulin production. But for insulin-dependent type 1 diabetics, hypoglycemia induced by insulin injection does not stimulate this feedback mechanism correctly (because you can't un-inject yourself with too much insulin), and so glucagon is not released in response to hypoglycemia because insulin production doesn't drop as blood glucose gets too low [1]. Thus both type 1 diabetics and people with CFRD that get frequent bouts of hypoglycemia basically become glucagon deficient and increase our tolerance for hypoglycemic episodes (adrenaline and cortisol are released at lower and lower blood sugar levels) so that it's even harder to tell when we're getting hypoglycemic, further increasing the risk of life-threatening hypoglycemic episodes. These days I can't be without my glucometer near me at all times because I can no longer feel the symptoms of hypo until I'm below 50 mg/dL (which is pretty dangerous). However, I can increase my sensitivity to hypoglycemia if I go more than a week without going into a hypoglycemic dive. If blood sugar gets low enough one can pass out or go into a coma and die (if not rescued with glucose in time). For years I've made it a habit to always keep a snack with me to guard against "reactive" hypoglycemia (i.e. post-meal hypoglycemia from an insulin overshoot). For regular people, being "hypoglycemic" usually just means they're tired and hungry but their blood sugar is actually normal (within the range of 75-120 mg/dL). I describe hypoglycemia and reactive hypoglycemia further in this article.
For some CFers the process of pancreatic degradation is so slow that they can go their whole lives without developing diabetes or strange pancreatic behavior. For others, the process of degradation is quicker and CF-related diabetes (CFRD) develops in the person's teens or early adulthood. I developed diabetes when I was 24, which is a fairly common age to have this happen (and I had glucose intolerance for at least 5 years before that). Newer research is suggesting that treating glucose intolerance with insulin injections before it becomes outright diabetes may preserve a person's health for longer than waiting until CFRD develops. I personally believe this to be true and I wish I had done more work to control my blood sugar at an earlier age, as the negative physiological impacts of hyperglycemia are significant, as I describe below.
Insulin Resistance
Insulin resistance means that our body has a reduced capacity to use insulin to transport glucose into our cells. In a person with insulin resistance, the cells down-regulate the number of insulin receptors on cell membranes. This can happen in type 2 diabetes when a person eats so many carbohydrates that the pancreas secretes an extreme amount of insulin into the blood in order to deal with the onslaught of glucose in the blood. The body thinks the extremely high amount of insulin circulating in the blood must be some kind of mistake, so it essentially begins to reduce the number of "ears" (i.e. insulin receptors) it has to listen to the insulin. In CF and other chronic diseases (and also with long-term corticosteroid use, like prednisone) insulin resistance can develop when cortisol levels are very high, as when someone experiences significant emotional or physical stress (like chronic infection or illness) [5]. In both cases the body blocks the ability for insulin to work to remove glucose from the blood, leaving the blood stream with high levels of both insulin and glucose. Insulin resistance in CF can fluctuate with changing levels of infection and inflammation, and can also be modulated by exercise and avoiding excessive carbohydrate intake. One of the reasons why it is bad practice to perform a glucose tolerance test when someone is sick with a lung infection or in the hospital is that insulin resistance temporarily increases during that time of stress and can lead to a false positive for diabetes. So get your glucose tolerance test when you are healthy or in between lung infections. Cinnamon also helps increase insulin sensitivity, so taking cinnamon with a high carb meal can help.
Cortisol plays a big role in insulin resistance. I recently had an "aha!" moment when I realized that the reactive hypoglycemic I get after a carb-filled breakfast is due to high cortisol levels in the morning. Many other CFers have this same problem, and after many years of trying to figure out what was going on, I have a hypothesis. If your circadian rhythm (your wake-sleep cycle) is on schedule, your pituitary tells your adrenals to send out a spike of cortisol in the early morning to wake you up. This spike of cortisol, however, also serves to reduce your cells' sensitivity to insulin. If we already have a background level of insulin resistance due to chronic illness or chronic stress, this AM spike in cortisol is going to have a significant impact on how you metabolize blood sugar in the morning. In order to test my hypothesis, I took glucose readings for several days eating various quantities of carbs in the morning for breakfast. What I found was that if I ate more than about 15 g of carbs, my blood sugar would peak at about 120-180 mg/dL and not start to decline until about 2-3 hours later, and then would suddenly crash. The more carbs I ate, the longer it took to crash but the harder the crash became. Taking insulin with breakfast would not change my blood glucose at all. That was the biggest clue in this puzzle. I could take double the amount of insulin I usually take for that amount of carbs and it wouldn't reduce the peak at all, but it would make the crash deeper. So what I deduced from this information is that my AM cortisol spike made my insulin resistance worse in the earlier hours of the day, but once the cortisol circulating in my blood went back down to a lower baseline level, my insulin sensitivity was normal again, usually by 1 or 2 pm. If I ate a lot of carbs during that AM period of insulin resistance, my pancreas would produce the right of amount of insulin but that insulin would be ineffective until my body chose to listen to it later in the day. Interestingly, if I eat a little low-carb snack for breakfast, like a bit of meat or a lot of nut butter, my insulin sensitivity improves earlier in the day. I hypothesize that this is because I always take bitters before meals, and bitters improves insulin sensitivity. So I could actually take bitters or drink something bitter (like dandelion root tea) and possibly have the same effect. However, when I am feeling really healthy and my diet is good and I'm decently active throughout the day, sometimes I can avoid AM reactive hypoglycemia even if I eat carbs in the morning, and this would be due to an improvement in my baseline insulin sensitivity when I'm feeling healthy. Cystagon has significantly improved my baseline insulin sensitivity to the point where sometimes I don't need to take any insulin at all with carby meals. Maintaining an active lifestyle is also really helpful in this regard, too.
Hyperglycemia
I've explained why hypoglycemia is bad, but what about hyperglycemia? Chronic high blood sugar can cause and exacerbate a number of problems including inflammation, infection, and damage to capillary beds. First of all, sugar is an oxidative substance, meaning that it introduces free radical electrons (ROS) into the body, which bind to molecules and cells causing damage to them. The damage that sugar oxidation causes to your tissues triggers an inflammatory response in the body to clean up the damage and battle the culprit. Some of the worst damage that sugar oxidation causes is to the walls of your smallest capillaries, especially those in your kidneys and eyes. This is why diabetics need regular screenings for kidney and eye damage. But they can also damage other capillaries, including the capillaries of the bronchial arteries which feed oxygen to the lungs. This is an important point, because it has the potential to be related to hemoptysis, a common complication of bronchiectasis (I discuss hemoptysis further in this article). The barrier between the capillaries that exchange gases in the bronchioles and alveoli is very thin and permeable, which puts this barrier at higher risk of damage by oxidative forces like hyperglycemia. High blood glucose also raises the glucose concentration in CF lung fluid (i.e. mucus), which is very dangerous because that can directly provide sugar for the bacteria that live in our airways. In a 2007 study, people with CF had significantly higher levels of glucose in their lung fluids than normal people, and patients with CFRD and hyperglycemia had even more glucose in their lung fluid that non-diabetic CFers. Not only that, but the inflammation caused by the hyperglycemia causes the junctions between our respiratory epithelial cells to weaken, allowing further infiltration of glucose into lung fluid [6].
In the early stages of glucose intolerance and diabetes, we can better regulate our blood sugar by controlling our diet and limiting sugar and carbohydrate intake. I will explain this more in the Blog and the sections on diet and nutrition.
*******************************
[1] http://2009.igem.org/wiki/images/f/f8/Freiburg09_McCrimmon_R_DiabeticMedicine_2008_25_513.pdf
[2] Cystic fibrosis-related diabetes is due to functional abnormalities in beta cells. <http://www.rxpgnews.com/cysticfibrosis/Cystic_fibrosis-related_diabetes_is_due_to_functio_4659_4659.shtml>
[3] http://www.eje-online.org/content/172/4/R131.full
[4] Spontaneous hypoglycemia in patients with cystic fibrosis. <http://eje-online.org/content/156/3/369.long>
[5] Cystic Fibrosis-Related Diabetes and Abnormal Glucose Tolerance: Overview and Medical Nutrition Therapy. <http://spectrum.diabetesjournals.org/content/15/2/124.full>
[6] Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis. <http://jap.physiology.org/content/102/5/1969.full>
