Hypoglycemia represents a significant problem for those with diabetes who require insulin or any of the insulin-secreting medications used to control diabetes. We know from the Diabetes Control and Complications Trial (DCCT) here and the U.K. Prospective Diabetes Study (UKPDS) here that control of blood glucose (BG) leads to a lower incidence and progression of long-term microvascular diabetes complications in persons with type 1 and type 2 diabetes, respectively. It is likely that maintenance of normal BG over a lifetime of diabetes would eliminate the microvascular complications and reduce the risk of macrovascular disease substantially. However, achieving normal BG without hypoglycemic episodes is quite difficult in the vast majority of persons with diabetes. In fact, hypoglycemia is the limiting factor in the glycemic management of diabetes. It causes both morbidity (illness or disability) and fatalities. For persons with type 1 diabetes (T1DM) depending on the study you look at, about 4-10% will die from hypoglycemia. Therefore, for persons with diabetes taking either insulin or insulin-secreting medication, hypoglycemia needs to be understood, respected, and avoided as much as possible in order to live a healthy life with diabetes.
In healthy humans, blood glucose (BG) is tightly regulated by several hormones and organs. The principle hormones that regulate BG are insulin, amylin, and glucagon and the principle organs that influence BG are the liver, muscle, and fat. Insulin is an anabolic hormone that facilitates movement of glucose into the liver, muscle, and fat cells to both stimulate the oxidation of glucose (conversion of glucose to ATP) and to store glucose as glycogen in muscle and liver and to convert glucose to fat in fat cells. Conversely, glucagon is a catabolic hormone that facilitates the breakdown of liver glycogen into glucose (glycogenolysis) as well as the production of new glucose molecules (gluconeogenesis) to be released into the blood stream. Amylin is a regulatory hormone secreted by the beta-cells in response to increasing glucose and/or amino acids in the blood stream. Amylin secretion signals the neighboring alpha-cells to reduce their glucagon secretion. See Table 1 below.
The beta-cells in islets of Langerhans in the pancreas secrete insulin and amylin in response to increasing BG and amino acid levels after a meal and conversely decrease insulin and amylin secretion in response to decreasing BG. Because the alpha-cells are located right next to the beta-cells in the islet of Langerhans in the pancreas, the insulin concentration can increase up to 100 times that of peripheral blood to suppress glucagon secretion. Amylin is co-secreted with insulin to suppress glucagon secretion as well. This suppression of glucagon helps to control the increase in post-meal BG which is necessary to shut off glucose production by the liver while the post-meal glucose and amino acids are cleared from the blood stream. Similarly after a meal, the insulin concentration reaching the liver via the portal vein (which connects the pancreas to the liver) is normally in high concentration (up to 3-4 times that of peripheral blood) to suppress the liver's production of glucose. Thus, liver glucose production after a meal is suppressed by both the reduction in glucagon and increase in insulin reaching the liver from the pancreas.
Conversely in the setting of low BG, the beta-cells reduce their insulin and amylin secretion. This reduction in insulin and amylin concentration around the neighboring alpha-cells, stimulates glucagon secretion. Again, blood leaving the pancreas in the portal vein goes directly to the liver. The liver responds to both the decrease in insulin concentration (first mechanism) and increase in glucagon concentration (second mechanism) by increasing glycogenolysis and gluconeogenesis which both increase BG to correct hypoglycemia. There is a third mechanism that will help correct hypoglycemia that is rarely evoked in persons who are metabolically healthy (non-diabetics). This is discussed below.
Hypoglycemia can be defined as an abnormally low plasma glucose concentration that exposes the individual to potential harm. Since persons with diabetes use blood glucose meters that are calibrated to give results in line with plasma glucose concentrations, I will use the term blood glucose (BG) to be equivalent to plasma glucose. A single value of BG that defines hypoglycemia is actually difficult to justify. For example in persons with poorly controlled diabetes, a BG value of 120 mg/dl (6.7 mmol/l) may result in typical symptoms of hypoglycemia whereas in persons with excellent glycemic control and especially those following a ketogenic diet may not experience symptoms until the BG falls below 50 mg/dl (2.8 mmol/l). More on this below, but first we should discuss why are those with T1DM and type 2 diabetes mellitus (T2DM) at risk for hypoglycemia?
As you likely know, a person with T1DM must inject exogenous insulin to control BG and to in fact survive at all. Only a minority of persons with T2DM need to use insulin. This is typically in a person with long-standing T2DM whose beta-cells have become exhausted or died out from overuse or glucose toxicity. This mechanism of beta-cells loss is quite different in T1DM which is due to autoimmune destruction of the beta-cells. However, the majority of persons with T2DM have enough beta-cells remaining to retain the normal feedback mechanisms described above to prevent hypoglycemia whereas virtually all persons with T1DM do not have enough beta-cells to effect the first two mechanisms that normally prevent hypoglycemia.
Exogenous insulin is not an exact replacement for endogenous insulin primarily due to where exogenous insulin is injected. Exogenous insulin is injected into the subcutaneous fat rather than into the pancreas where the beta-cells used to be. This fact eliminates the above mentioned first two mechanisms that normally prevent hypoglycemia.
In those with insulin-requiring diabetes, if the exact correct amount of insulin could be injected into the subcutaneous fat, then hypoglycemia would not occur. However the reality is that the amount of insulin to be injected by a person with diabetes is simply a guess based primarily on ones recent BG response to their recent meals and physical activity. As pointed out in my article on T1DM here, carbohydrate is the primary dietary macronutrient that determines the post-meal BG. Thus, persons with diabetes who require insulin injections are taught to estimate their insulin dose based on the amount of dietary carbohydrate in their meals. This number is difficult to estimate as is how much glucose the body actually absorbs after eating a given amount of dietary carbohydrate. This method then leads to both an underestimation of the true insulin requirement resulting in hyperglycemia or an overestimation of the true insulin requirement resulting in hypoglycemia. Occasionally, the guess is just right and the resulting BG is normal. In the case of overestimation of the insulin dose, hypoglycemia results from the lack of the above mentioned mechanisms (reduction in beta-cell insulin and amylin secretion and increase in alpha-cell glucagon secretion). This is called hyperinsulinemic hypoglycemia or iatrogenic hypoglycemia in medical speak.
There is a third mechanism that corrects hypoglycemia in non-diabetics in the unlikely event that the reduction in insulin and amylin secretion and increase in glucagon secretion are not sufficient to raise BG and is the only mechanism that remains intact in those with insulin-requiring diabetes. It is the sympathetic nervous system and which secretes epinephrine (adrenaline), norepinephrine (noradrenaline), and acetylcholine while the adrenal glands secrete epinephrine. Epinephrine and norepinephrine stimulate glucose production by the liver and also result in the signs and symptoms of hypoglycemia including increased heart rate, blood pressure, and palpitations. The sympathetic nervous system also secretes acetylcholine which causes sweating and anxiety as well as stimulating liver glucose production. Thus recovery from hypoglycemia is dependent on the hepatic (liver) response to epinephrine, norepinephrine and acetylcholine and/or the person’s own recognition of the symptoms of hypoglycemia causing them to take one or more glucose tablet(s) or liquid or food if glucose tablets are not available.
Hopefully the above clearly explains why hypoglycemia almost invariably occurs in persons with T1DM and in those with T2DM who require insulin and/or medications that stimulate insulin secretion and why hypoglycemia is the greatest barrier to achieving near-normal glycemia. In addition to insulin, other medications used primarily for T2DM (but occasionally in T1DM as well) can also precipitate hypoglycemia. These medications will be reviewed below.
As mentioned above, dietary carbohydrate has the greatest effect in raising the post-meal BG. All of the Diabetes Associations recognize this and are most are slowly and subtilly "allowing" the use of low carbohydrate diets for those with diabetes here. However, it is really common sense that a low carbohydrate diet would both improve glycemia control and reduce hypoglycemia because reducing the major BG-raising dietary component (carbohydrates) and decreasing the meal-time insulin dose effectively reduces the potential error between BG-raising and BG-lowering effects. Dr. Richard Bernstein calls this the "law of small numbers". These two studies confirm that this is the case here and here. However, a low carbohydrate ketogenic diet does NOT eliminate hypoglycemia and therefore we must employ additional strategies to keep hypoglycemia to a bare minimum.
Achieving a degree of glycemic control that minimizes the risk of developing the long-term complications of diabetes is obviously desirable. These diabetic complications include, but are not limited to, both microvascular complications (neuropathy, retinopathy, diabetic nephropathy) and macrovascular complications (heart disease, stroke, peripheral vascular disease) which can result in blindness, kidney failure, amputations, and cause a reduction in health-span and life-span. However, believe it or not, there is no research that reveals what level of glycemic control is necessary to avoid these complications.
The Diabetes Control and Complications Trial (DCCT) published on September 30, 1993 in the New England Journal of Medicine here enrolled 711 persons with T1DM to the intensive insulin arm and 730 to the conventional arm of the study. They had two groups in each arm of the study, one without evidence of diabetic complications (the primary prevention group) and the other with evidence of diabetic complications (the secondary prevention group). The study showed that intensive insulin therapy was able to lower HbA1c from 9% to 7% by increasing doses of insulin, but no changes in diet, which significantly reduced the incidence and progression of diabetic retinopathy (by 76%), neuropathy (by 60%), and nephropathy (of albuminuria by 54%). This was the first large randomized clinical trial to demonstrate this benefit of improved glycemic control. However, this came at a price. The intensive insulin group suffered approximately three times as many episodes of severe hypoglycemia. Severe hypoglycemia is defined as an episode of hypoglycemia that requires the assistance of another person to recover from whether that comes in the form of someone giving the person with T1DM glucose tablets, a glucagon injection, calling 911, or requiring hospitalization (e.g. due to a seizure for example). Another complication of intensive insulin therapy in the DCCT was that at five years, patients receiving intensive insulin therapy gained a mean of 4.6 kg body weight more than patients receiving conventional therapy. Importantly, on secondary analysis, the DCCT could not identify any level of HbA1c that would maximize benefits (i.e. reduce complications) while at the same time minimizing risks (i.e. reduce hypoglycemia).
I have to interject at this point that these limitations of intensive insulin therapy without dietary intervention is where the low carbohydrate ketogenic diet is a potential game changer because glycemic control can be improved significantly with reduced insulin doses (not increased insulin doses as in the DCCT). More on this here and here.
In summary, the DCCT showed that improving HbA1c from 9% to 7% with increased insulin doses and no dietary changes significantly reduced the incidence and progression of long-term diabetic complications, but also resulted in a marked three-fold increase in severe hypoglycemia and a mean 4.6 kg body weight gain.
Unfortunately, we are still left with the question of how low should average BG or HbA1c be to both minimize the risk of long-term diabetic complications and hypoglycemia. I hope it is apparent that the lower the target BG even while on a low carbohydrate ketogenic diet, the more likely hypoglycemia is to occur due to the inherent variability created by using exogenous insulin. A definitive answer will require a long-term clinical trial that utilizes a low carbohydrate ketogenic diet. Until that trial is done, I think each individual will need to determine his/her own glycemic target in consultation with their physician. This glycemic target should be close enough to normal to prevent long-term complications yet at the same time, be safe. Now, we need to know what “normal” is and what “safe” is.
This study here of 21 healthy non-diabetic subjects wearing continuous glucose monitors (CGM) found that “the mean 24-hour interstitial glucose concentration under everyday life conditions was 89.3 ± 6.2 mg/dl (mean ± SD, where SD = standard deviation), and mean interstitial glucose concentrations at daytime and during the night were 93.0 ± 7.0 and 81.8 ± 6.3 mg/dl, respectively.” Whereas this study here of 74 healthy non-diabetic children, adolescents, and adults had a mean interstitial glucose of 98 ± 13.7 (mean ± SD) using a blinded CGM device for 3 to 7 days. A weighted mean of these 95 healthy persons from these two studies reveals that a normal BG is 96 ± 12 mg/dl (mean ± SD) and coefficient of variation is 12.5% (i.e. 12/96 = 12.5%). A mean BG of 96 mg/dl represents, in my opinion, the minimum target BG value to aim for since these healthy subjects would not be expected to develop diabetic complications. Aiming for an average BG less than 96 mg/dl would only increase the risk of hypoglycemia without providing any benefits (lower risk of diabetic complications). If this BG target of 96 mg/dl results in frequent or severe hypoglycemia, then the target average BG should be increased to whatever value is necessary to minimize hypoglycemia. You then might ask, “Does the increased BG variability of insulin-treated diabetes lead to the development of diabetic complications?” As you may know, BG does not stay in a narrow range in those with diabetes and this BG variability is easily measured by calculating the standard deviation (SD) of your BG readings. Unfortunately, no studies have examined the question: Does BG variability lead to diabetic complications? I think everyone with diabetes is striving to keep their BG variability as low as possible, but actually doing it is difficult. My SD before the ketogenic diet was 54 mg/dl and during the past six years on the ketogenic diet has ranged from 35 to 51 mg/dl over 1 year periods. You can see this is quite high compared the normal SD at 12 mg/dl. More details here.
This question is difficult to answer, but certainly the lower the better is the best bet. As will be discussed below, there is a potential benefit of a low carb ketogenic diet, namely nutritional ketosis, in protecting the brain from hypoglycemia. That said at any given time when hypoglycemia occurs, one can never know the extent to which ketones may provide some protection. Regrettably, it only takes one severe hypoglycemic episode to die. Therefore, the safest approach is to make every effort to avoid BG values below 70 mg/dl and to treat it with glucose tablet(s) below 70 mg/dl. Personally, I have been striving to keep my BG between 61 and 110 mg/dl more than 70% of the time and in addition spending less than 10% of time < 61 mg/dl. Although I am close to that goal every month, it has been difficult for me to achieve it consistently. I am working to improve it. For those who do not take insulin for diabetes, it may be difficult to understand how variable the glycemic results of taking insulin can be. For me, this has been the most frustrating part of having T1DM. For example, one day I may wake up with a BG of 90 mg/dl and take 3 units of Humalog with breakfast and get a postprandial BG of 110 mg/dl. The very next day, I may wake up with a BG of 97 mg/dl and take 3 units of Humalog with breakfast and get a postprandial BG of 67 mg/dl having eaten the same breakfast, lunch, dinner, and done very similar exercise type, intensity, and duration. This has happened much too frequently over the past 20 years. Thus, for me anyway, each dose of insulin is a guess and the BG results are not very predictable.
This was the first change that I became aware of after starting the ketogenic diet on Feb. 8, 2012. This started me down a path of investigation to try to understand it better. I personally have had BG values in the 30s mg/dl without symptoms. Please do not confuse this last statement as an indication that asymptomatic hypoglycemia is an acceptable or desirable condition. In fact, this is one of the reasons I decided to write this article on hypoglycemia. I am simply stating the fact that since starting my low carbohydrate ketogenic diet, and never before, I have had a significant reduction in the symptoms of hypoglycemia. However, I do not know how much of this reduction in symptoms is due to hypoglycemia unawareness and how much is due to the brain being able to use ketones as a fuel by following a ketogenic diet.
Hypoglycemia unawareness simply means that a person with diabetes who has an abnormally low BG is unaware of it because they are not experiencing any symptoms. Depending on the level of glycemic control (average BG), a person with diabetes will develop symptoms of hypoglycemia at different levels of BG. Persons with poorly controlled BG may develop symptoms of hypoglycemia when their BG falls below 120 mg/dl, for example. While those with tightly controlled BG, may not experience symptoms until the BG drops below 60-70 mg/dl. Hypoglycemia unawareness is even more of a problem when hypoglycemia is severe (< 50–55 mg/dl, < 2.8–3.0 mmol/l). Persons with diabetes may not recognize their own neuroglycopenic symptoms which include cognitive impairments, behavioral changes, and psychomotor abnormalities, and, if no action is taken to correct their BG, can result in seizure, coma, or death. The exact mechanism for hypoglycemia unawareness is still unknown. However, it is known to occur following previous episodes of hypoglycemia. The brain somehow adapts to these episodes of hypoglycemia and does not perceive subsequent episodes as an emergency and thus does not activate the sympathetic nervous system and adrenal glands which are in place to correct hypoglycemia by secreting epinephrine (adrenaline), norepinephrine (noradrenaline), and acetylcholine. This adaption is considered by experts in the field to be a double-edged sword here because on the positive side the brain does not perceive an emergency requiring secretion of epinephrine which is thought to be the most common cause of harm from hypoglycemia, i.e. lethal cardiac arrhythmias mediated by sympathoadrenal activation here. Another study here in rats found that 3 days of recurrent moderate hypoglycemia resulted in 62–74% less brain cell death after a subsequent episode of severe hyperinsulinemic hypoglycemia (BG 10-15 mg/dl) and were protected from most of the deficits in spatial learning and memory disturbances caused by severe hypoglycemia compared to the control rats.
On the negative side of this double-edged sword, the lack of symptoms is thought to lead to more episodes of hypoglycemia any one of which could be severe enough to result in death from neuroglycopenia i.e. not enough glucose for the brain to survive. It is this negative side that needs special attention because we know that depending on the study cited, between 4 and 10% of those with T1DM actually die from hypoglycemia. The majority of these persons die in their sleep which is a time when perception of hypoglycemia is additionally reduced. In addition to antecedent hypoglycemia and sleep, exercise and alcohol ingestion also lead to hypoglycemia unawareness. Although we can’t avoid sleep, and shouldn’t avoid exercise, we can avoid drinking alcohol and work to minimize hypoglycemic episodes. Like many persons with diabetes, I am a person with T1DM who is highly motivated to achieve BG values as close to normal as is safely possible. However if any of us die or are seriously harmed from hypoglycemia, we have just defeated our own goal of living a normal life-span without diabetic complications. Thus, minimizing or avoiding hypoglycemia is of paramount importance. If a person with diabetes is having frequent hypoglycemia, then steps need to be taken to reduce them. I will cover those steps below. Also, be aware that the hypoglycemia unawareness due to recurrent hypoglycemia is completely reversible by avoiding hypoglycemia for 3-4 weeks here. Resolving hypoglycemia unawareness is an important strategy for preventing future hypoglycemia.
However, at this point you may be asking “given that I follow a ketogenic diet and lack symptoms of hypoglycemia at levels of BG that previously caused symptoms, what value of BG do I use to define hypoglycemia?” Certainly, low BG values should not be accepted as “OK”, even if they occur without symptoms. The 2018 American Diabetes Association (ADA) Standards of Medical Care in Diabetes here uses < 70 mg/dl as a threshold to define “hypoglycemia alert value” (see Table 6.3 shown below). This hypoglycemia alert value signals the need to take a fast-acting carbohydrate (glucose tablet(s)) and to adjust the dose of glucose-lowering therapy. I use both of these recommendations since each and every insulin dose I take is adjusted based on my BG results in the previous several days in the context of physical activity. The difficult part of diabetes control is that these previous results can vary significantly from day to day such that each dose is in effect, a guess. Several years ago, I arbitrarily chose < 61 mg/dl (3.4 mmol/l) to define hypoglycemia for myself since I had to choose a value to calculate the frequency of and time during a 24 hour period spent with hypoglycemia to be able to report my results on my blog. However, that does not mean I currently feel a BG < 70 mg/dl is desirable and requires no treatment or no insulin dose adjustment.
Another topic of research that needs to be done is to measure the degree to which ketones created by the liver by following a ketogenic diet can act as a brain fuel and lead to a reduction in or lack of symptoms of hypoglycemia in those with T1DM. We know from the study done by Drenick et. al. here that in non-diabetic obese persons who fasted for 2 months and achieved blood beta-hydroxybutyrate (BHB) levels of 8 mM when given a single dose of insulin to induce severe hypoglycemia suffered no symptoms despite BG values as low as 9 mg/dl (0.5 mmol/l). However, the applicability of this study to those with diabetes following a ketogenic diet is questionable given that the BHB levels are typically in the 0.5 to 3 mM range from nutritional ketosis. Another study here in rats found that the cerebral metabolic rate of glucose utilization decreased by 9% for each 1 mmol/l increase in total plasma ketone body concentration in ketotic rats induced by 3 weeks of a ketogenic diet. “The brain’s ability to switch from glucose oxidation towards ketone bodies requires a type of ‘cerebral metabolic adaptation’. This process is not well understood but is thought to be highly associated with the duration and level of ketosis. Ketones are considered to supply up to 70% of the total energy demands once maximal metabolic adaptation occurs.” Another study here of 8 healthy male students found that mental alertness was significantly reduced by moderate hypoglycemia (40 mg/dl or 2.2 mmol/l) after an overnight fast while similar hypoglycemia did not reduce mental alertness after a 72 hour fast. BHB levels were not reported in the abstract (I did not purchase the full article). Finally in this study here, the effect of hyperketonemia on counter-regulatory hormone responses to hypoglycemia was examined in six healthy subjects. The peak adrenaline (epinephrine) response to hypoglycemia fell from 7.97 to 2.6 nmol/l during ketone infusion and the peak noradrenaline, cortisol and growth hormone responses were also significantly lower during ketone infusion at a rate of 3 mg/min/kg body weight which resulted in a 0.58 mmol/l BHB concentration which as you know is achievable with nutritional ketosis. In addition, the study found that the BG required to elicit the counter-regulatory hormone response was lower during the ketone infusion (BG was 2.5 mmol/l (45 mg/dl) during ketone infusion compared to 3.0 (54 mg/dl) mmol/l without ketones).
These data are quite suggestive that keto-adaption at levels of blood ketones achievable with nutritional ketosis may, in fact, be providing the brain with an alternate source of fuel making hypoglycemia less symptomatic and less dangerous. Of course, formal studies of persons with T1DM following a ketogenic diet long-term need to be done to confirm this potential beneficial effect of the ketogenic diet.
All patients with diabetes need to know how to manage BG during illness. The most common illnesses that lead to glycemic fluctuations include infections (most common are pneumonia and urinary tract infections) and gastrointestinal illnesses (some of which are caused by viruses) which often result in nausea, vomiting, reduced food and fluid intake, and diarrhea. These acute illnesses are a stress to the body which responds by secreting cortisol, growth hormone, glucagon, and epinephrine all of which increase BG. Occasionally, patients with diabetes are prescribed corticosteroid medications (e.g. prednisone, methylprednisolone) for various medical conditions. These medications are synthetic versions of the stress hormone, cortisol, and will increase BG often dramatically. Reduced food intake may modify the changes in BG as well. In the setting of illness, the goal is avoid both severe increases in hyperglycemia (and thus relatively reduced insulin levels) which can result in diabetic ketoacidosis (DKA) and to avoid hypoglycemia from overly aggressive increases in insulin doses in an attempt to maintain near-normal BG. The increases in stress hormones often require increased doses of insulin to control hyperglycemia, but accepting mild hyperglycemia (up to 200 mg/dl) during a short illness is much preferred to developing hypoglycemia from overly aggressive increases in insulin doses. Therefore when treating hyperglycemia during illness, it is best to maintain your usual basal insulin dose or increase it by no more than 10% every 4-7 days and use rapid-acting insulin doses to treat hyperglycemia. Rapid-acting insulin typically has a duration of action of 4-5 hours, so dosing it more frequently than every 4-5 hours should be avoided. This 4-5 hour window also varies with the person, so if you have measured BG repeatedly after taking your rapid-acting insulin and know when your BG has stabilized, you could use that time period instead. Taking rapid-acting insulin more frequently that this time period, is called insulin-stacking and can result in hypoglycemia as can an excess dose of rapid-acting insulin. Keeping BG in the 100-200 mg/dl (5.6-11.1 mmol/l) range during an illness should be adequate enough to prevent DKA. Obviously, mildly elevated BG during an illness will have no impact on long-term complications of diabetes. However, overly aggressive insulin doses during an illness can and has caused death from hypoglycemia.
On the flip side, a patient with insulin-requiring diabetes who is unable to eat or having difficulty eating during an illness may need to reduce their basal insulin dose while others may not. This really depends on how much of ones usual dietary intake can be tolerated and how much of a stress hormone response the body is mounting due to the illness. Remember even while fasting (not eating at all), humans need some basal insulin to prevent hyperglycemia. When stress hormones due to illness are being secreted, you can see that severely reducing or stopping basal insulin altogether can result in DKA.
Finally, If you do not feel you are getting control of your BG with the above guidelines, do not hesitate to seek medical attention (calling your physician or going to the emergency room). Developing either severe hypoglycemia or DKA during an illness is life-threatening and both are preventable in the hospital setting.
Additional medications other than insulin are used to improve glycemic control in those with T1DM and T2DM. These medications should be used in those with diabetes only after lifestyle changes have been made most importantly implementing a low carb ketogenic diet and regular physical exercise. The following two classes of diabetes medications work by increasing the secretion of insulin from beta-cells and thus are only used in those with T2DM: sulfonylureas and meglitinides. The remaining classes of diabetes medications do not cause hypoglycemia by themselves but can make hypoglycemia more likely when used with insulin, sulfonylureas, or meglitinides and include biguanides (metformin), thiazolidinediones, GLP-1 (glucagon-like peptide 1) receptor agonists, DPP-4 (dipeptidyl peptidase 4) inhibitors, SGLT-2 (sodium/glucose cotransporter) inhibitors, α-glucosidase inhibitors, dopamine-2 agonists, and pramlintide (Symlin). Please refer to the link to each medication or medication class to learn more about their use in diabetes and their potential to cause hypoglycemia.
From the discussion above, the exact target BG that will both maximize benefit (lowest risk of long-term complications) and minimize risk (lowest risk of hypoglycemia) is NOT exactly known. Each person with diabetes needs to discuss with their physician what their target BG value should be to first minimize the number and severity of hypoglycemic episodes. This is a safety-first approach. Once the number of hypoglycemic episodes is minimized, then one can begin to lower the target BG towards a normal average BG reading of 96 mg/dl. If the number/severity of hypoglycemic episodes increases, then the target BG should be increased to a higher value. Thus, the target BG should be titrated down toward 96 mg/dl (5.3 mmol/l), but not below, while minimizing the number and severity of hypoglycemic episodes.
When trying to reduce the number and severity of hypoglycemic episodes, one needs to look carefully at several variables.
First and most importantly, the basal and/or bolus insulin doses need to be reduced.
Remember that basal insulin (or the basal rate in those who use an insulin pump) covers one’s insulin needs between meals and overnight. The basal insulin dose is determined by the fasting BG results. Fasting hypoglycemia, especially occurring on more than one day, will require a reduction in the basal insulin dose. Generally, a 10-20% dose reduction every 4-7 days depending on which basal insulin is used is needed until the fasting BG normalizes. Because basal insulin preparations have a long half-life, it may take several days for the change in dose to affect the fasting BG result. Glargine (Lantus) requires about 4 days to reach a new steady-state effect after a dose change whereas insulin degludec (Tresiba) may require about 7 days. Thus, taking a snack at bedtime is prudent to prevent additional episodes of fasting/nocturnal hypoglycemia until a new steady-state has been reached and the fasting BG normalizes.
The meal-time bolus insulin dose is determined primarily by the composition of the meal, the pre-meal BG, and the change in BG after the meal (the difference between the post- and pre-meal BG) on previous days. Post-meal hypoglycemia will likely require a reduction in the meal-time insulin dose (assuming similar meal, exercise, and pre-meal BG).
The different basal and bolus insulin preparations and methods of administering and adjusting doses are covered in detail in our books (on the right or below).
Keeping one’s meals as consistent as possible from day to day will greatly improve the consistency of the BG response to one’s meals. Thus, I for example, attempt to keep the quantity and types of food I eat at each meal consistent from day to day so that the grams of protein, carbs, fat, and fiber remain relatively constant.
Similarly, I try to keep my exercise type, duration, intensity, and time of day that I exercise, consistent as well. Exercise has a very significant effect on one’s insulin sensitivity and therefore on the BG response to exogenous insulin.
Followers of my blog may know that my interest in the ketogenic diet had its origins when I was trying to improve my glycemic control to complete an ironman distance triathlon in 2012. I started training in swimming, cycling, and running in August 2007 and did my first sprint triathlon on Dec. 8, 2007. I progressively increased the distance each year completing my first olympic distance triathlon Nov. 9, 2008, and my first half ironman distance triathlon on Nov. 8, 2009. As the distance of training increased, I started having hypoglycemia which I obviously did not like so I started using sports nutrition products (sugar essentially) preemptively to prevent hypoglycemia. Over time, I noticed that I was developing hyperglycemia from these sports nutrition products. On Sept. 18, 2009, I had the highest HbA1c ever at 7.9% which I felt was due to this practice of using sports nutrition products. In 2011 I was hoping to complete an ironman distance triathlon, but felt the amount of time required to complete it (around 15 hrs) would require a better approach. I was concerned about both hypoglycemia and hyperglycemia occurring during the event, but hypoglycemia could have resulted in more dire consequences had I been unable to recognize the symptoms. Exercise is one of the known causes of hypoglycemia unawareness. I discovered through listening to the podcast, IM Talk about Dr. Loren Cordain, and the podcast, Jimmy Moore’s Livin’ La Vida Low Carb, about Dr. Richard K. Bernstein, Dr. Stephen Phinney and Dr. Jeff Volek and the ketogenic diet. I implemented it on Feb. 8, 2012. This was a game changer for me, not only for my life in general, but specifically my need for carbohydrate during exercise and the swings in BG were dramatically reduced. Rather than taking carbohydrate at the beginning of exercise, I measured my BG every hour during exercise and supplemented with carbohydrate only on an as needed basis. I stopped having hypoglycemia during exercise which gave me the confidence to complete the ironman distance triathlon on Oct. 20, 2012 in 15.5 hours. This was not a competitive time, but I was just happy to have been able to do it without hypoglycemia and a BG less than 200 mg/dl for the majority of the time. From this experience, I am convinced that the lower insulin doses and fat-adaptation that result from a ketogenic diet allow for improved glycemic control during endurance exercise. The endurance exercise also contributed to improved insulin sensitivity which allowed for additional lowering of insulin doses. One problem I noticed, however, was that the long endurance training did require a day or two of rest to recover which resulted in varying insulin sensitivity from day to day. So I noticed I was adjusting insulin doses more so than what I was doing prior to starting regular exercise. After completing the ironman distance triathlon in 2012, I was so excited about the accomplishment that I continued pushing my training and signed up for another ironman event in April 2013. However, soon before the event all that training finally caught up to me and I was having both knee and foot pains from iliotibial band syndrome and plantar fasciitis. I continued exercising with a lot of swimming and short bike rides. As you might guess I also increased the distance of the swims and did two 5 kilometer swims. These swims were completed on the ketogenic diet so I was not worried so much about hypoglycemia and had none to boot. I never did another triathlon and it took almost 3 years for the plantar fasciitis to finally go away. In Dec. 2014, I started weightlifting mainly to address recurrent low back pain which I had been having for years precipitated by lifting things, cycling, and chores that involved bending over. I started with powerlifting: deadlift, squat, bench press. After 3 months, I was again developing overuse injuries, now in my elbows and I had flared up a preexisting injury in my left shoulder doing the bench press. So I switched to olympic weightlifting in March 2015 and over time, my central back pain with radiculopathy consistent with a herniated disc did resolve. It took several years to figure out how much exercise I could do without overtraining and in the process figured out that exercising daily had the most stabilizing effect on my glycemic control. With a few exceptions, I found that olympic weightlifting which I would describe as high-intensity resistance exercise most commonly, but not always of course, increases my BG. The elevation has ranged from mild to rather extreme (an increase of about 120 mg/dl at most). I have accepted these increases as a normal consequence of the type of exercise that I enjoy. It is caused by release of the stress hormones cortisol, epinephrine, growth hormone, and glucagon which serve to release glucose from the liver and fatty acids from fat to supply energy to exercising muscles. This stress hormone effect definitely did not happen during my endurance training exercise since I was doing long-slow training, i.e. no sprinting. Initially, I took small doses of rapid-acting insulin to correct the BG elevations after weightlifting. Up to that point, I had been avoiding eating lunch for 17 years so as to avoid having to take insulin and thus avoid the chance of hypoglycemia after lunch. But because I was having to take insulin after weightlifting almost daily, I added back lunch (1/2 lb. of beef and two eggs) after my weightlifting session in the hopes of adding some additional muscle. So far, my muscle mass seems rather stable, but if I can prevent it from declining that will be a victory. If I stop exercising which sometimes happens due to an injury or travel, I develop hyperglycemia using the same insulin doses and thus require increases in insulin doses progressively each day that I do not exercise. After two weeks of no exercise, the insulin doses stabilize at a new higher dose. Several years ago this occurred and I had to increase my total daily insulin dose from 30 IU/day to 42 IU/day. This represents a 40% increase in insulin dosage due to the reduced insulin sensitivity from the cessation of exercise.
All this is a long way of saying that I have had a lot of experience with exercising with T1DM as an endurance athlete on both a high-carb and low-carb ketogenic diet and with high-intensity resistance training on a low-carb ketogenic diet. The lessons I have learned and the reading I have done on the topic include the following:
One of the most frequent questions I get is whether treating hypoglycemia with glucose tablets/liquid or food for that matter will interfere with ketosis. First, I hope I made it clear above that hypoglycemia is dangerous and therefore it is essential to treat both symptomatic and asymptotic hypoglycemia quickly and efficiently for one’s own safety. So whether ketosis is affected or not is irrelevant. Hypoglycemia should be treated immediately with anything that is available at the moment. Ideally, every person with diabetes, particularly T1DM, should be carrying glucose tablets/liquid with them at all times. These sources of pure glucose are best for rapidly raising BG and resolving any symptoms of hypoglycemia as quickly as possible. The longer the symptoms last, in addition to being unpleasant and risky, the more potential for more serious complications as well as overcorrection by consuming too much food or sugar. I would like to explain that sugar is sucrose which is a compound composed of one glucose and one fructose molecule. The fructose can be converted to glucose primarily in the liver, but the process is slow compared to the immediate absorption and utilization of glucose. This study here found the mean conversion of fructose to glucose was 41% ± 10.5 (mean ± SD) in 3–6 hours after ingestion. Thus, sugar is not equivalent to or as good as glucose for correcting hypoglycemia in persons with diabetes (only use it if glucose tablets/liquid are not available). To treat symptomatic hypoglycemia, take 2-4 glucose tablets (contains 8-16 grams glucose) and wait about 15 mins to see if symptoms are improving. If symptoms are not improving take 2-4 more tablets and seek additional help (e.g. glucagon injection) and/or medical attention. Note that the ADA here recommends using 3-5 glucose tablets (15-20 grams of glucose) initially. However, I found this usually results in hyperglycemia. Thus, each person needs to determine their own glucose dose because their body weight and insulin sensitivity will affect the dose of glucose needed to correct hypoglycemia. Taking excessive amounts of food, sugar, or even glucose tablets can result in hyperglycemia which will need to be treated with one or more additional insulin doses. This has and likely will happen to each and every person with diabetes, but these episodes can be minimized by following the above guidelines. Finally, glucose tablets are also best for correcting mild asymptomatic hypoglycemia. I typically use 1/2 or 1 glucose tablet (2-4 grams of glucose). The tablets are scored and easy to break in half. Liquid glucose can be used as well. Finally, recheck BG with your meter to confirm that the hypoglycemia has been corrected especially before driving a car or going to sleep.
Now for the question about what happens to ketosis in those following a ketogenic diet after treating hypoglycemia with glucose tablets. Taking just a few glucose tablets is not likely to affect ketosis at all. In fact because hypoglycemia in those with diabetes is a hyperinsulinemic hypoglycemia, the excess insulin itself is more likely to have already inhibited ketosis if it has been affected at all. You see, insulin inhibits the rate-limiting enzyme, HMG CoA synthase, required to make ketones. Treating hypoglycemia with glucose tablets will effectively use up the excess insulin and may restore ketone synthesis. Thus treating hyperinsulinemic hypoglycemia with glucose tablets will either improve nutritional ketosis or not affect it at all.
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