CF-Related Diabetes and Impaired Glucose Tolerance
The pancreas has two primary functions in the human body: to produce digestive enzymes (called the exocrine pancreas) and the secretion of insulin (called the endocrine pancreas). Cystic fibrosis often has trouble with both these pancreatic functions. In CF, trouble with the endocrine side of the pancreas can lead to impaired glucose tolerance or CF-related diabetes (CFRD). Approximately 50% of CF adults over the age of 30 develop CFRD, more common in the severe mutations [1]. CFRD is our own special kind of diabetes: it is similar to type 1 diabetes in that the pancreas has trouble excreting insulin into the blood stream, and is also similar to type 2 diabetes in that we may have some degree of insulin resistance. Here I'd like to explain how blood sugar regulation is supposed to work in healthy individuals and how it gets out of balance in some people with CF.
The Physiology of Blood Sugar Regulation
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 food through the walls of the small intestine into the blood stream, and cells that need energy absorb that glucose from the blood. The body detects the amount of carbohydrate ingested, which triggers the release of an appropriate amount of insulin from the endocrine pancreas. The body detects how much carbohydrate is 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 [2].
Insulin is a hormone secreted by the pancreas's beta-cells (part of the endocrine pancreas). Once the body has detected glucose in the blood stream, the pancreas excretes insulin. Insulin facilitates the movement of glucose out of the blood and into the cells, thus lowering the 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 it 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 which acts in the opposite way 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 the blood sugar (which can then be utilized by our cells).
In addition to glucose-dependent metabolism, the human body has evolved a secondary and alternative metabolic system for maintaining constant energy for the body's cells: ketosis. Ketones are a small molecules produced by the liver from fatty acids in times that the body does not have adequate access to carbohydrates as a fuel source. We've adapted this metabolic pathway as a response to the possibility of famine or prolonged periods of fasting. Certain traditional cultures who eat very little plant foods either seasonally or year-round dwell in a state of ketosis. For most people with adequate endocrine pancreas function, ketosis is a safe and healthy way to live. In fact, many people are using dietary ketosis to treat a variety of health issues associated with carbohydrate consumption (e.g. type 2 diabetes, autoimmunity, gut issues, etc.). One can induce ketosis by eating very few carbs (20-40g per day or less) for a long period of time. I myself use a ketogenic diet to treat my reactive hypoglycemia (it's the only thing that's worked)--more on that in this blog post. Ketones must stay within a narrow range to be considered safe. When ketones levels become too high they can acidify the blood causing seizures, coma, and death. This is called ketoacidosis and only occurs in people with type 1 diabetes if they do not use insulin. Thus insulin is always necessary for human survival, even in a state of ketosis.
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 for which we must take supplemental enzymes. 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. Yet newer research has theorized that the CF genetic mutation itself is responsible for causing the malfunctions of the beta-cells in the pancreas [3, 4]. I think this new theory is more likely, as I have personally worked with clients whose exocrine pancreases work normally (i.e. they don't need to take digestive enzymes) but have diabetes. So as the pancreas degrades, the ability for its beta-cells to produce insulin (and reflexively its alpha-cells to produce glucagon [2]) declines and we may need to take supplemental insulin injections. In CFRD we can have 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 [5]. 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 is released in response to both hypoglycemia (blood sugar below about 70 mg/dL) and falling insulin production. But for insulin-dependent type 1 diabetics, hypoglycemia induced by overdosing with injectable insulin does not trigger this feedback mechanism correctly because high insulin in the blood stops the release of glucagon, even if the blood glucose is too low [2]. Being in a state of hypoglycemia too often can increase our tolerance for hypoglycemic episodes so that it becomes harder to detect when we're getting hypoglycemic, further increasing the risk of life-threatening hypoglycemic episodes. This is called "hypoglycemia unawareness", and it was very troublesome to me for many years before I started the ketogenic diet; sometimes I wouldn't be able to tell that I was hypoglycemic until I got brain fog and a subtle weakness around 40-50 mg/dL. That's dangerous--if we can pass out, go into a coma, and if not rescued quickly enough we can die. These days I am dependent on using a continuous glucose monitor, and always have a glucometer with me as back up in case the continuous glucose monitor fails. We can increase our sensitivity to hypoglycemia if we control the diet and prevent hypoglycemic crashes, as I have done with a low-carb diet. However, I always keep a snack with me as well as glucose tablets, just in case. For regular people, they might feel "hypoglycemic" even when their blood sugar is normal (70-100 mg/dL), so what they actually mean is they feel weak and hungry. I discuss 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 endocrine problems. For others, the process of degradation is quicker and they might be diagnosed with CFRD in childhood or adolescence. Most CFers get diagnosed with CFRD in early adulthood. I developed diabetes when I was 24 but I had glucose intolerance for at least 5 years preceding. One study suggests 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 [6]. 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, which I describe below. It is possible that controlling the blood sugar earlier in this process with carb control and medication, putting less stress on the pancreas, may preserve endocrine function for longer.
Insulin Resistance
Insulin resistance is when the body develops 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 extremely high 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) [7]. 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 a glucose tolerance test when you are healthy or in between lung infections. Cinnamon, bitter melon, and several other herbs can increase insulin sensitivity. Taking cinnamon with a high carb meal can help lower blood glucose, but should not be used if you experience reactive hypoglycemia.
Cortisol plays a big role in insulin resistance. Cortisol is a hormone that keeps us awake and alert, and it reduces inflammation in the body. Because humans are diurnal (awake in the day) cortisol is produced in the daytime in opposition to melatonin, the sleep hormone produced at night. This is called the circadian rhythm. Cortisol levels are highest in the morning and midday, if the circadian rhythm is normal. I recently had an "aha!" moment when I realized that for some, reactive hypoglycemia is more common in the morning when cortisol levels are highest. There are other factors involved with this, including that the typical Western breakfast contains a lot of carbs, and that eating carbs on an empty stomach can cause a rush of glucose into the blood when a malfunctioning pancreas cannot keep up with producing insulin on time (in CFRD, insulin production may be delayed). Having hypoglycemia in the morning 1-2 hours after breakfast is one of the first signs of glucose intolerance and insulin resistance. One solution is to avoid eating carbohydrates, especially sugars, in the morning and instead choose a breakfast rich in protein and fat.
Early on in my diabetes journey, 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 spike at about 120-180 mg/dL. If I was sedentary, my blood sugar would crash about 2 hours later below 70 mg/dL, leaving me weak, shaky, and hungry. 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, but it would make the crash deeper. So what I hypothesized 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 in the morning, my pancreas would produce the right of amount of insulin but delayed, and due to insulin resistance it would be ineffective until a little later in the day. I have found that having reactive hypoglycemia in the morning sets up a roller coaster of multiple peaks and crashes for the rest of the day. This can be prevented by avoiding carbs in the morning. As my diabetes got worse over the years, and after starting Symdeko and then Trikafta (CFTR modulating drugs), my reactive hypoglycemia only got worse, leading to multiple crashes throughout the day (up to four) where I used to only have one in the morning. A ketogenic diet fixed this. In addition, it's important for diabetics of all types to have an active lifestyle with daily exercise because exercising muscles uptake glucose from the blood without the use of insulin. So, many times when I expect that a meal will cause me hyperglycemia (and then a crash afterward) I go on a walk immediately afterward to burn off some of those carbs.
Hyperglycemia
I've explained why hypoglycemia is bad, but what about hyperglycemia? Hyperglycemia is when the blood sugar goes above the normal physiological range (70-120 mg/dL) for too long. Healthy people can have occasional, transient blood sugar above 120 mg/dL if they eat a lot of sugars all at once, but it usually doesn't last for more than an hour. Chronic high blood sugar can cause and exacerbate a number of problems including inflammation, infection, and damage to capillaries (very small blood vessels) in the eyes, kidneys, fingers, and toes [8]. Sugar is an oxidative substance, meaning that it introduces free radicals (radical oxygen species, ROS) into the body, binding to molecules and causing damage. The damage that sugar oxidation causes to the tissues triggers an inflammatory response in the body to clean up the damage and battle the culprit. This is especially problematic in heart disease when the oxidative damage that sugar does to our blood vessels causes the body to respond to this damage by patching the wounds in the blood vessels with cholesterol, a process called atherosclerosis. A sad fact is that for more than 70 years mainstream medicine has misdiagnosed atherosclerosis and heart disease as problems caused by dietary cholesterol and fat, when in fact they're primarily caused by sugar! Controlling carbohydrate intake is an effective treatment for reducing and preventing cardiovascular disease [9, 10]. Heart disease is much more common in diabetics due to the link with chronic hyperglycemia [11].
The alveoli of the lungs are surrounded by capillaries which are responsible for oxygen exchange, and I suspect that hyperglycemia may negatively impact these capillaries. This could be an additional reason why blood sugar must remain under control in cystic fibrosis--we don't need anything else to harm our lungs! The barrier between the capillaries that exchange gases in the bronchioles and alveoli is very thin and permeable, which puts it at higher risk of damage by oxidative forces like hyperglycemia. Hyperglycemia may have some connection to hemoptysis (the breakage of blood vessels in the lungs causing coughing up of blood), a common complication of bronchiectasis (I discuss hemoptysis further in this article). More research needs to be done on this connection. One study showed a correlation between hyperglycemia and risk of developing pulmonary tuberculosis in which hemoptysis is common [12]. Another study showed "that hyperglycemia in mice lacking functional CFTR disrupts airway glucose control, exaggerates pulmonary neutrophilic infiltration in response to a bacterial challenge, and reduces lung bacterial clearance over time"--in other words, in a mouse model of CF, hyperglycemia led to increased inflammation, infection, and reduced mucus clearance in the lungs [13]. High blood glucose has been shown to raise 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 leads to the weakening of the junctions between our respiratory epithelial cells, allowing further infiltration of glucose into lung fluid [14] and possibly even contributing to the development of hemoptysis.
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 discuss this more in the Blog and the sections on diet and nutrition.
*******************************
[1] Moheet, Amir, and Antoinette Moran. "CF‐related diabetes: containing the metabolic miscreant of cystic fibrosis." Pediatric pulmonology 52.S48 (2017): S37-S43.
[2] McCrimmon, R. "The mechanisms that underlie glucose sensing during hypoglycaemia in diabetes." Diabetic medicine 25.5 (2008): 513-522.
[3] Acharya, Sanjukta. “Cystic Fibrosis-Related Diabetes Is Due to Functional Abnormalities in Beta Cells.” RxPG News, 10 July 2006, www.rxpgnews.com/cysticfibrosis/Cystic_fibrosis-related_diabetes_is_due_to_functio_4659_4659.shtml.
[4] Barrio, Raquel. "Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues." European journal of endocrinology 172.4 (2015): R131-R141.
[5] Battezzati, A. L. B. E. R. T. O., et al. "Spontaneous hypoglycemia in patients with cystic fibrosis." European journal of endocrinology 156.3 (2007): 369-376.
[6] Dobson, L., et al. "Clinical improvement in cystic fibrosis with early insulin treatment." Archives of Disease in Childhood 87.5 (2002): 430-431.
[7] Brunzell, Carol, and Sarah Jane Schwarzenberg. "Cystic fibrosis-related diabetes and abnormal glucose tolerance: overview and medical nutrition therapy." Diabetes Spectrum 15.2 (2002): 124-127.
[8] Ruderman, Neil B., Joseph R. Williamson, and Michael Brownlee. "Glucose and diabetic vascular disease 1." The FASEB journal 6.11 (1992): 2905-2914.
[9] Halton, Thomas L., et al. "Low-carbohydrate-diet score and the risk of coronary heart disease in women." New England Journal of Medicine 355.19 (2006): 1991-2002.
[10] Bazzano, Lydia A., et al. "Effects of low-carbohydrate and low-fat diets: a randomized trial." Annals of internal medicine 161.5 (2014): 309-318.
[11] Chait, Alan, and Karin E. Bornfeldt. "Diabetes and atherosclerosis: is there a role for hyperglycemia?." Journal of lipid research 50 (2009): S335-S339.
[12] Qiuzhen, Wang, et al. "Hyperglycemia Is Associated With Increased Risk of Patient Delay in Pulmonary Tuberculosis in Rural Areas." Journal of diabetes 9.7 (2017): 648-655.
[13] Hunt, William R., et al. "Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes." American Journal of Physiology-Lung Cellular and Molecular Physiology 306.1 (2014): L43-L49.
[14] Baker, Emma H., et al. "Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis." Journal of applied physiology 102.5 (2007): 1969-1975.
The Physiology of Blood Sugar Regulation
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 food through the walls of the small intestine into the blood stream, and cells that need energy absorb that glucose from the blood. The body detects the amount of carbohydrate ingested, which triggers the release of an appropriate amount of insulin from the endocrine pancreas. The body detects how much carbohydrate is 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 [2].
Insulin is a hormone secreted by the pancreas's beta-cells (part of the endocrine pancreas). Once the body has detected glucose in the blood stream, the pancreas excretes insulin. Insulin facilitates the movement of glucose out of the blood and into the cells, thus lowering the 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 it 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 which acts in the opposite way 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 the blood sugar (which can then be utilized by our cells).
In addition to glucose-dependent metabolism, the human body has evolved a secondary and alternative metabolic system for maintaining constant energy for the body's cells: ketosis. Ketones are a small molecules produced by the liver from fatty acids in times that the body does not have adequate access to carbohydrates as a fuel source. We've adapted this metabolic pathway as a response to the possibility of famine or prolonged periods of fasting. Certain traditional cultures who eat very little plant foods either seasonally or year-round dwell in a state of ketosis. For most people with adequate endocrine pancreas function, ketosis is a safe and healthy way to live. In fact, many people are using dietary ketosis to treat a variety of health issues associated with carbohydrate consumption (e.g. type 2 diabetes, autoimmunity, gut issues, etc.). One can induce ketosis by eating very few carbs (20-40g per day or less) for a long period of time. I myself use a ketogenic diet to treat my reactive hypoglycemia (it's the only thing that's worked)--more on that in this blog post. Ketones must stay within a narrow range to be considered safe. When ketones levels become too high they can acidify the blood causing seizures, coma, and death. This is called ketoacidosis and only occurs in people with type 1 diabetes if they do not use insulin. Thus insulin is always necessary for human survival, even in a state of ketosis.
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 for which we must take supplemental enzymes. 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. Yet newer research has theorized that the CF genetic mutation itself is responsible for causing the malfunctions of the beta-cells in the pancreas [3, 4]. I think this new theory is more likely, as I have personally worked with clients whose exocrine pancreases work normally (i.e. they don't need to take digestive enzymes) but have diabetes. So as the pancreas degrades, the ability for its beta-cells to produce insulin (and reflexively its alpha-cells to produce glucagon [2]) declines and we may need to take supplemental insulin injections. In CFRD we can have 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 [5]. 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 is released in response to both hypoglycemia (blood sugar below about 70 mg/dL) and falling insulin production. But for insulin-dependent type 1 diabetics, hypoglycemia induced by overdosing with injectable insulin does not trigger this feedback mechanism correctly because high insulin in the blood stops the release of glucagon, even if the blood glucose is too low [2]. Being in a state of hypoglycemia too often can increase our tolerance for hypoglycemic episodes so that it becomes harder to detect when we're getting hypoglycemic, further increasing the risk of life-threatening hypoglycemic episodes. This is called "hypoglycemia unawareness", and it was very troublesome to me for many years before I started the ketogenic diet; sometimes I wouldn't be able to tell that I was hypoglycemic until I got brain fog and a subtle weakness around 40-50 mg/dL. That's dangerous--if we can pass out, go into a coma, and if not rescued quickly enough we can die. These days I am dependent on using a continuous glucose monitor, and always have a glucometer with me as back up in case the continuous glucose monitor fails. We can increase our sensitivity to hypoglycemia if we control the diet and prevent hypoglycemic crashes, as I have done with a low-carb diet. However, I always keep a snack with me as well as glucose tablets, just in case. For regular people, they might feel "hypoglycemic" even when their blood sugar is normal (70-100 mg/dL), so what they actually mean is they feel weak and hungry. I discuss 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 endocrine problems. For others, the process of degradation is quicker and they might be diagnosed with CFRD in childhood or adolescence. Most CFers get diagnosed with CFRD in early adulthood. I developed diabetes when I was 24 but I had glucose intolerance for at least 5 years preceding. One study suggests 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 [6]. 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, which I describe below. It is possible that controlling the blood sugar earlier in this process with carb control and medication, putting less stress on the pancreas, may preserve endocrine function for longer.
Insulin Resistance
Insulin resistance is when the body develops 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 extremely high 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) [7]. 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 a glucose tolerance test when you are healthy or in between lung infections. Cinnamon, bitter melon, and several other herbs can increase insulin sensitivity. Taking cinnamon with a high carb meal can help lower blood glucose, but should not be used if you experience reactive hypoglycemia.
Cortisol plays a big role in insulin resistance. Cortisol is a hormone that keeps us awake and alert, and it reduces inflammation in the body. Because humans are diurnal (awake in the day) cortisol is produced in the daytime in opposition to melatonin, the sleep hormone produced at night. This is called the circadian rhythm. Cortisol levels are highest in the morning and midday, if the circadian rhythm is normal. I recently had an "aha!" moment when I realized that for some, reactive hypoglycemia is more common in the morning when cortisol levels are highest. There are other factors involved with this, including that the typical Western breakfast contains a lot of carbs, and that eating carbs on an empty stomach can cause a rush of glucose into the blood when a malfunctioning pancreas cannot keep up with producing insulin on time (in CFRD, insulin production may be delayed). Having hypoglycemia in the morning 1-2 hours after breakfast is one of the first signs of glucose intolerance and insulin resistance. One solution is to avoid eating carbohydrates, especially sugars, in the morning and instead choose a breakfast rich in protein and fat.
Early on in my diabetes journey, 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 spike at about 120-180 mg/dL. If I was sedentary, my blood sugar would crash about 2 hours later below 70 mg/dL, leaving me weak, shaky, and hungry. 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, but it would make the crash deeper. So what I hypothesized 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 in the morning, my pancreas would produce the right of amount of insulin but delayed, and due to insulin resistance it would be ineffective until a little later in the day. I have found that having reactive hypoglycemia in the morning sets up a roller coaster of multiple peaks and crashes for the rest of the day. This can be prevented by avoiding carbs in the morning. As my diabetes got worse over the years, and after starting Symdeko and then Trikafta (CFTR modulating drugs), my reactive hypoglycemia only got worse, leading to multiple crashes throughout the day (up to four) where I used to only have one in the morning. A ketogenic diet fixed this. In addition, it's important for diabetics of all types to have an active lifestyle with daily exercise because exercising muscles uptake glucose from the blood without the use of insulin. So, many times when I expect that a meal will cause me hyperglycemia (and then a crash afterward) I go on a walk immediately afterward to burn off some of those carbs.
Hyperglycemia
I've explained why hypoglycemia is bad, but what about hyperglycemia? Hyperglycemia is when the blood sugar goes above the normal physiological range (70-120 mg/dL) for too long. Healthy people can have occasional, transient blood sugar above 120 mg/dL if they eat a lot of sugars all at once, but it usually doesn't last for more than an hour. Chronic high blood sugar can cause and exacerbate a number of problems including inflammation, infection, and damage to capillaries (very small blood vessels) in the eyes, kidneys, fingers, and toes [8]. Sugar is an oxidative substance, meaning that it introduces free radicals (radical oxygen species, ROS) into the body, binding to molecules and causing damage. The damage that sugar oxidation causes to the tissues triggers an inflammatory response in the body to clean up the damage and battle the culprit. This is especially problematic in heart disease when the oxidative damage that sugar does to our blood vessels causes the body to respond to this damage by patching the wounds in the blood vessels with cholesterol, a process called atherosclerosis. A sad fact is that for more than 70 years mainstream medicine has misdiagnosed atherosclerosis and heart disease as problems caused by dietary cholesterol and fat, when in fact they're primarily caused by sugar! Controlling carbohydrate intake is an effective treatment for reducing and preventing cardiovascular disease [9, 10]. Heart disease is much more common in diabetics due to the link with chronic hyperglycemia [11].
The alveoli of the lungs are surrounded by capillaries which are responsible for oxygen exchange, and I suspect that hyperglycemia may negatively impact these capillaries. This could be an additional reason why blood sugar must remain under control in cystic fibrosis--we don't need anything else to harm our lungs! The barrier between the capillaries that exchange gases in the bronchioles and alveoli is very thin and permeable, which puts it at higher risk of damage by oxidative forces like hyperglycemia. Hyperglycemia may have some connection to hemoptysis (the breakage of blood vessels in the lungs causing coughing up of blood), a common complication of bronchiectasis (I discuss hemoptysis further in this article). More research needs to be done on this connection. One study showed a correlation between hyperglycemia and risk of developing pulmonary tuberculosis in which hemoptysis is common [12]. Another study showed "that hyperglycemia in mice lacking functional CFTR disrupts airway glucose control, exaggerates pulmonary neutrophilic infiltration in response to a bacterial challenge, and reduces lung bacterial clearance over time"--in other words, in a mouse model of CF, hyperglycemia led to increased inflammation, infection, and reduced mucus clearance in the lungs [13]. High blood glucose has been shown to raise 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 leads to the weakening of the junctions between our respiratory epithelial cells, allowing further infiltration of glucose into lung fluid [14] and possibly even contributing to the development of hemoptysis.
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 discuss this more in the Blog and the sections on diet and nutrition.
*******************************
[1] Moheet, Amir, and Antoinette Moran. "CF‐related diabetes: containing the metabolic miscreant of cystic fibrosis." Pediatric pulmonology 52.S48 (2017): S37-S43.
[2] McCrimmon, R. "The mechanisms that underlie glucose sensing during hypoglycaemia in diabetes." Diabetic medicine 25.5 (2008): 513-522.
[3] Acharya, Sanjukta. “Cystic Fibrosis-Related Diabetes Is Due to Functional Abnormalities in Beta Cells.” RxPG News, 10 July 2006, www.rxpgnews.com/cysticfibrosis/Cystic_fibrosis-related_diabetes_is_due_to_functio_4659_4659.shtml.
[4] Barrio, Raquel. "Management of endocrine disease: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues." European journal of endocrinology 172.4 (2015): R131-R141.
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