Blood Sugar

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Introduction

Blood sugar is also known as (aka) blood glucose (BG), the two terms are used interchangeably.

The body, in particular the brain needs glucose. The brain needs glucose constantly, 24 hours a day, the brain can’t burn fatty acids like other cells in the body. The brain can use ketones as a source of fuel, it’s cleaner and more efficient than glucose, which is why metabolic flexibility (the ability to easily switch from burning glucose to ketones) or ketosis (when the body is almost completely fueled by fat/ketones) is often recommended for ApoE4s, see Ketosis and Ketogenic Diet. But the brain has special cells, glutaminergic cells, that can only burn glucose. So the brain cannot run on ketones alone. Under the best of circumstances, ketones can only provide about 2/3rds of what the brain needs to work properly.

While the brain does indeed need glucose, it doesn’t want too much of it. A person doesn’t need to eat sugar to provide glucose to the brain. Such foods are known as high glycemic, they are typically carbohydrates and sugar. But even people who follow a zero carb/zero sugar diet (a type of ketogenic diet not advocated for ApoE4s) are able to maintain acute mental clarity, this is because the body, primarily the liver, can make its own glucose, a process called gluconeogenesis. So eating glucose isn’t necessary to provide fuel the brain, in fact too much glucose is detrimental to the brain (discussed below).

I eat sugar and carbohydrates and my blood sugar levels are fine, so why worry?

As shown by the blue line, Blood Glucose levels can remain relatively normal while demand for insulin rises to keep glucose under control rise. If insulin resistant, blood glucose levels rise slowly over many years because the body is able to produce enough insulin, but at some point the pancreas can no longer produce sufficient insulin, blood glucose levels rise significantly and that’s Type 2 diabetes. This slow glucose ramp-up period is stressful for the body, health concerns are developing despite the “normal” blood glucose levels, even if Type 2 Diabetes never results. Graph source: Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study, (Tabák, A, et al, 2009 Figure 1, https://www.sciencedirect.com/science/article/pii/S014067360960619X
It’s hard to discuss blood glucose without including insulin.

The body wants blood glucose levels to be just right (metabolic homeostasis). Insulin is the hormone that works to keep blood sugar levels steady, neither too high (hyperglycemia) nor too low (hypoglycemia). But when insulin has been overworked, being asked to keep blood glucose levels under control for too long (a period of many years), insulin eventually “gives up,” blood glucose levels subsequently raise dramatically and that, very simplistically, is Type II Diabetes.

That insulin “breaking point” (when the blue line goes from a slow upward progression to a rapid upward trajectory) comes from overloading the body with glucose, so while the overall glucose numbers may look “good” (and the conventional wisdom of what is considered “good” is discussed below), glucose spikes from high glycemic foods are overworking the body. Add snacks to three meals a day or follow the faulty advice of consuming six small meals a day to “reduce glucose spikes” and this just asks the pancreas to constantly produce insulin, something it was not “designed” to do, it needs rest time.

These practices result in a person becoming insulin resistant. During this phase, when insulin is “overworked” and blood glucose numbers are “normal” but slowly rising, insulin receptors are getting damaged, they’re becoming numb (desensitized) to insulin, and they’re “downregulating” i.e. becoming fewer in number, the fat cells are expanding to a point where they can’t get any bigger, these overstuffed fat cells can’t get enough oxygen and inflammation results, the fatty acids look for other storage places, areas where fat were never meant to go: the abdominal cavity (visceral fat), other organs (liver, pancreas, kidneys), and muscle. So while blood glucose levels can be “normal” and a person can feel fine, inside the body can be insulin resistant and very, very unhappy.
Comparing glucose spikes of a standard diet to a ketogenic diet. The flatter the line, the happier the body. Incorporating intermittent fasting (eliminating one or two meals) in addition to a ketogenic diet will flatten those upticks even more. Source: Slide taken from presentation by Miriam Kalamian, EdM, MS, CNS, at Low Carb USA in San Diego, July 2017.
Insulin resistance doesn’t need to progress to Type 2 diabetes to damage the body and manifest in the form of a chronic disease, such as Alzheimer’s. See Insulin Resistance.

This is also one of the justifications for ApoEε4s to follow a ketogenic diet, in addition to providing ketones for fuel to an insulin resistant energy starved brain, a ketogenic diet flattens glucose spikes, placing less demand on insulin thus facilitating the reversal of insulin resistance. See Ketosis and Ketogenic Diet and Insulin Resistance in the brain.

High blood glucose, hyperglycemia, turns blood from a life sustaining fluid into a slow, silent, destructive force. According to WebMD High Blood Sugar and Diabetes (accessed Feb 27, 2019) ongoing high blood sugar may cause:

  • Vaginal and skin infections
  • Slow-healing cuts and sores
  • Worse vision
  • Nerve damage causing painful cold or insensitive feet, loss of hair on the lower extremities, or erectile dysfunction
  • Stomach and intestinal problems such as chronic constipation or diarrhea
  • Damage to your eyes, blood vessels, or kidneys
Too much blood glucose is neurotoxic

High blood glucose is also damaging to the brain, it is toxic to neurons in a variety of different ways. Glucose Neurotoxicity (DR Tomlinson and NJ Gardiner, 2008)

  • Depletes natural antioxidant reserves, glutathione, the body’s own antioxidant
  • Promotes damaging free radical formation, these are violent molecules that create collateral damage, wrecking havoc with your DNA and more
  • Generates Advanced Glycation End Products (AGEs), sticky dysfunctional proteins
  • Slows nerve cell conduction speed
  • Reduces growth factor activity, growth factor keeps cells healthy and robust and thriving

Low Blood Sugar

What is low blood sugar? The American Diabetes Association says anything below 70 is low blood sugar, hypoglycemia. But if not diabetic, and especially if maintaining a ketogenic diet, don’t freak out if the glucose meter reflects something below 70. We have ketogenic ApoEε4 members who have undertaken multi-day fasts and experienced blood glucose levels in the 30s yet felt fine: no feelings of energy deprivation, full mental clarity, and they maintained normal daily routines including muscle-demanding workouts. This is because they met the necessary energy demands with ketone production. Ketones rose significantly in the initial first days of the multi-day fast in reciprocal relationship to the blood glucose level which went down. Later in the fast, the body turned to gluconeogenesis to meet its glucose needs. It should be noted electrolyte supplementation (sodium, potassium and magnesium) was included with the fast, lackluster energy can be the result of low electrolytes, not necessarily low blood sugar.

Can blood sugar be too low for the brain? Because of the brain’s constant demand for energy, a healthy body does everything it can to provide enough glucose for the brain. During periods of extended severe caloric restriction, like how our ancestors experienced in the wintertime or during droughts, the human body will even breakdown its own muscles in order to produce glucose for the brain and will compensate for the rest of the brain’s energy needs by producing ketones. So it’s very hard to have blood sugar so low that the brain can’t function.

However, the brain can experience slow glucose processing known as cerebral glucose hypometabolism. The brain can be surrounded by plenty of glucose yet not be able to use it as a result of insulin resistance. This is found universally in Alzheimer’s patients, which is why Alzheimer’s is often referred to colloquially as Type 3 Diabetes. This situation is like the Samuel Taylor Coleridge quote, “Water, water everywhere but not a drop to drink” only we’re talking glucose being everywhere and not only is the brain unable to use it, but the excess glucose is damaging the brain. See Insulin Resistance in the brain

Blood Sugar Measurement - common tests including “new normals”

It is critical for overall health to keep blood sugar levels under control, especially for the brain. The higher your blood sugar levels, the higher your brain sugar. Sixty percent of blood sugar is brain sugar. So for example, if a blood glucose level is 100, brain glucose is 60.

It should be noted that while blood glucose typically becomes elevated from foods that are considered high glycemic, there are other non-food factors that can elevate blood glucose as well (discussed below).

Hemoglobin A1c

How to convert an HbA1c reading into average blood glucose levels

This test, conducted by a lab, reflects the average level of blood sugar over the past 2 to 3 months. It's also called HbA1c, or sometimes just A1c. According to the American Diabetes Association: A1c less than 5.7% is “normal”, A1c 5.7 to 6.4 is prediabetes, A1c 6.5 or higher is diabetes.

However, Dr Bredesen's protocol recommends an A1c of less than 5.6, see Fasting insulin less than 5; HgbA1c less than 5.6

Our PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies recommends keeping A1c to 5.5 or under (37 mmol/mol), preferably closer to 5% (32 mmol/mol).

There are those who say down to 5.2 there’s an increased risk for brain shrinkage. Studies that have additionally determined that HbA1c levels considered "normal", especially at the higher end of normal, are associated with increased risk for cardiovascular disease, and lowered mortality, see studies cited in the Deeper Dive section of Insulin Resistance

Fasting blood glucose (FBG)

This is determined from a blood sample after fasting (no food or caloric drinks) for at least 8 hours. Blood can be tested by a lab or at home with a glucose meter. Blood sugar that is higher than 130 mg/dl (milligrams per deciliter) is conventionally considered hyperglycemia (high blood glucose), but it can easily be argued that standard is too lenient.

Our PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies recommends a fasting glucose of under 99 mg/dl (5.5 mmol/l) to start, with aiming for 90mg/dl or less (5mmol/l) as one gets better at managing their diet and insulin resistance.

Postprandial blood glucose (PPBG)

Postprandial means after eating a meal. This test measures the blood glucose levels at exactly 2 hours after eating, with the timer starting at the beginning of the meal. It can be tested by a lab or with a home glucose meter. After two hours, in “healthy” people, blood sugar goes back down to normal levels. But remember the above discussion of how insulin works, if a person is on the path to Type 2 Diabetes, i.e. insulin resistant, they body can still produce enough insulin to maintain a “normal” level of glucose, so having a “normal “ postprandial blood glucose level can provide a false sense of security. Conventional wisdom cites Postprandial hyperglycemia at higher than 180 mg/dL.

Our PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies recommends postprandial glucose of no higher than 130-ish mg/dl (7.2mmol/l), and preferably lower.

Oral Glucose Tolerance Test (OGTT)

This is a common test used to diagnose diabetes and prediabetes by measuring the body's ability to use glucose. It involves fasting overnight, then measuring the fasting blood sugar level. That is followed by consuming a sugary liquid drink and testing blood sugar levels periodically for the next two hours. It tells the doctor how a body processes glucose. This test's efficacy has been debated within the ApoE4 forums as being an incomplete diagnostic tool since it does not include an insulin measurements.

Dr Joseph Kraft glucose test with insulin assay

As discussed above, BOTH glucose and insulin are important. Measuring only glucose presents an incomplete picture. Dr Kraft (passed away in 2017 at age 95) has been referred to numerous times within the ApoE4.info forums. Dr. Kraft’s test is similar to the oral glucose tolerance test (OGTT), but runs longer and adds insulin measurements. He looked at 14,308 individuals ages 8 to 88 and recorded the insulin response. He found that 80% of those who had normal glucose responses had abnormal insulin responses. In other words, subjects who would be classified as “normal” under Fasting Blood Glucose Tests, thereby not even progressing to an OGTT test, are not “normal” in their insulin response, but without measuring insulin this abnormal insulin response is unknown and unfortunately this means that 80% of the individuals who only have their glucose tested are progressing to Type 2 diabetes and/or other health concerns. For more info see Dr Joseph Kraft or read his book, Diabetes Epidemic & You. Dr Catherine Crofts has also been referred to within the forums. She used Dr. Kraft's database to determine a way of understanding the insulin response measure with a shorter test. Her Phd, “Understanding and Diagnosing Hyperinsulinaemia” can be found here Understanding and Diagnosing Hyperinsulinaemia

Home glucose testing

Example of a home glucose meter

An “over the counter” glucose meter, also known as a glucometer, is an easy way to monitor blood sugar levels and very handy tool for those trying to control glucose (and depending on the meter – ketones). These meters provide immediate, individualized feedback.

Be aware, getting the cheapest meter may not be a good idea. The US Food and Drug Administration (FDA) only requires such meters to register within 20% of the true value (a lab measurement) 99% of the time. In other words, the acceptable manufacturer’s tolerance for a home glucose meter is plus or minus 20%, so a true glucose measure of 100 can read as low as 80 or as high 120, and 1% of the time, it can be even greater, that’s significant. But just because that’s what the FDA allows, doesn’t mean all meters are that loose with their tolerances, some are very accurate, an internet research is highly recommended before purchase.

Because of the emphasis many ApoE4s place on ketosis, some have purchased dual purpose glucose meters which test both blood glucose and ketones, such as the Keto-Mojo or the Precision Xtra.

A home blood glucose test is performed by first washing hands with warm water, this performs a dual function of warming the hands and removing any contaminants, then shaking one hand to get blood to accumulate near the end of the finger. Pierce the side of the fingertip (less painful and irritating than the top of the fingertip) with a device called a lancet. A lancet is spring loaded, so it quickly propels a thin pin into the skin, much easier than trying to prick oneself. The pins come in different thicknesses and most lancet have settings to adjust the depth that the pin enters the skin, especially helpful for those with calloused fingers. A small drop of blood is produced by gently squeezing below the fingertip. Then the disposable “test strip” which has been inserted in the meter is applied to the drop of blood where the small amount of blood is drawn into the strip and the glucose measurement is then quickly reflected on the meter.

Controlling insulin levels is also vitally important to the body, especially the brain, unfortunately there are no personal insulin meters, so glucose measurements are used as a proxy.

Causes of high glucose measurements

Diet

The most common factor for high glucose readings. Sugar and simple carbohydrates are the obvious drivers, but consuming more protein than the body needs can also raise glucose levels as the body will turn the protein into glucose in order to do something with the excess. Beware of “hidden” sugars in food. Sugar is not always labeled as such, other names include sucrose, glucose, fructose, maltose, dextrose, molasses, hydrolyzed starch, honey, invert sugar, cane sugar, glucose-fructose, high fructose corn syrup, brown sugar, corn sweetener, rice/ corn/ cane/ maple/ malt/ golden/ palm syrup, agave nectar, and evaporated cane juice. These aliases conceal the presence of large amounts of added sugars. Incorporating different sources of sugar into a product ingredient list allows the manufacturer to list something else as the first ingredient(s) even though in aggregate sugar is the overwhelming constituent. Check the carbohydrate content of packaged foods. Some seemingly non-sweet, “healthy” foods as spaghetti sauce, condiments, sauces, and salad dressings can be very high in sugar/carbohydrates. Better yet, stay away from packaged foods and eat real, whole foods instead.

Stress

Stress increases blood glucose levels. Stress can come from the job, food, illness, environment, beauty products, and more. Stressors come from many, some very surprising, sources. See Stress

Illness /disease/injury

Illnesses/injuries are stressful and that in turn raises blood glucose levels. See Stress

Non-alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic Fatty Liver Disease is a condition common with persistent insulin exposure. When the liver becomes fat it becomes insulin resistant, so it’s not regulated by insulin appropriately. As a result, throughout the night the liver secretes more and more glucose (gluconeogenesis) even though the body doesn’t need it. When people with a fatty liver wake up in the morning they will have high glucose levels even though they haven’t eaten for 8-10 hours.

Sleep

Impaired sleep will raise glucose levels. A comprehensive discussion can be found here Metabolic consequences of sleep and sleep loss. Sleeping less than seven hours a night has been associated with diabetes or eventually developing the condition. Also see Sleep

Impairing the body’s natural circadian rhythm by going to bed too late (or early) or exposing the eyes to too much artificial light, especially the blue light from electronic devices such as phones and computers disrupt circadian rhythm and sleep quality which in turn effects glucose levels. There’s a discussion of circadian rhythm in our wiki article Stress.

Dawn Phenomenon aka Dawn Effect

In the early morning hours, before waking up, a surge of hormones is produced in the body including the rise of cortisol which is associated with higher glucose levels. An elevated early morning glucose measurement could simply reflect that the the body is making less insulin and more glucagon (a hormone that increases blood glucose) at that time. This is know as the Dawn Phenomenon or Dawn Effect. Try a little later in the morning for a more reflective glucose measure which should be easy if following Dr Bredesen’s recommendation of overnight fasting for at least 12 hours, preferably 14-16 hours for ApoEε4s. See Dr Bredesen’s protocol on Enhance autophagy, ketogenesis

Physiological Insulin Resistance aka Adaptive Glucose Sparing

This is a benign condition when fasting glucose levels are high (> 90 mg/dL) despite strict adherence to a low carbohydrate or ketogenic diet. This phenomenon occurs after the muscles have gotten good at fatty acid oxidation as a result of metabolic adaptation so it’s not pulling glucose into the muscles so the muscle tissue becomes "insulin resistant" in order to preserve (spare) serum glucose availability for the brain. This condition is very different from the insulin resistance associated with Type 2 Diabetes, which is why many are now referring to this as Adaptive Glucose Sparing instead. Just as with dawn effect, try a little later in the morning for a more reflective glucose measure which should be easy if following Dr Bredesen’s recommendation of overnight fasting for at least 12 hours, preferably 14-16 hours for ApoEε4s. See Dr Bredesen’s protocol on Enhance autophagy, ketogenesis

Regardless of what it's called, this situation can result in a failed glucose tolerance test. If maintaining a low carbohydrate or ketogenic with high fasting glucose readings and directed to take an oral glucose tolerance test, increase carbohydrate intake to ~150g for a few days and then take the test. The few days of increased carbohydrate intake will let the body adapt to increased carbohydrate availability and the physiological insulin resistance will go away.

Medications and supplements

Prescription drugs, over the counter drugs, even supplements and natural botanicals can raise glucose levels.

According to Non-Diabetes Drugs and Supplements That Affect Glucose Levels some common medications that can increase glucose levels:

  • Valium and Ativan (benzodiazepines)
  • Thiazide diuretics, which are taken as blood pressure medicine
  • The steroids cortisone, prednisone, and hydrocortisone
  • Birth control pills
  • Progesterone
  • Catecholamines, which include the EpiPen and asthma inhalers
  • Decongestants that contain pseudoephedrine
  • Niacin
  • Zyprexa and many other antipsychotic medications

A more comprehensive list can be found at Drugs that can affect Blood Glucose Levels

Statins are notable for increasing blood sugar, Hb1AC, insulin, and new diabetes diagnoses. Is Atorvastatin Associated with New Onset Diabetes or Deterioration of Glycemic Control? Systematic Review Using Data from 1.9 Million Patients and Statins are effective at lowering cholesterol and protecting against a heart attack and stroke, although they may lead to side effects for some people.

High dose niacin can raise glucose levels. Effects of niacin on glucose control in patients with dyslipidemia (RB Goldberg and TA Jacobson, 2018).

Intravenous vitamin C. This should only an issue for cancer patients receiving intravenous Vitamin C treatments, not for those taking Vitamin C supplements. But for such cancer patients, glucose meters will reflect an alarmingly high glucose measurement. But this is not glucose, the Vitamin C molecule looks like glucose to the meter thus giving a false high measurement of glucose levels.

Low Hematocrit

Can raise glucose measures, see Hematocrit Interference of Blood Glucose Meters for Patient Self-Measurement

Hormones

Especially female hormones the week before a menstrual cycle can produce elevated glucose measures.

Meal timing

Snacking, even heathy snacks should be avoided. Also, it is best to go to bed at least 3 hours after the last meal, with NO snacking/evening wine, etc. For older adults this should progress to 4 hours before bedtime

Age

Older adults, 60+, generally have higher glucose levels

Alcohol

Will raise blood glucose.

Caffeine

Caffeine can raise glucose in some people. Use a glucometer to determine your individual response. “Bulletproof” coffee, i.e. coffee that adds healthy fat to it, tends to dampen the glucose response.

Physical Activity

Taking blood glucose measurement shortly after a workout will likely reflect elevated glucose, wait until the body “settles down” before pulling a glucose measurement. Overall, physical activity is a good thing, especially moderate exercise (not intense which will raise oxidation and stress in the body) and especially resistance training which make muscles more insulin sensitive. See Exercise - Types, Lengths, and Benefits

Meter Error

Sooner or later there’s going to be a reading that seems incongruent, wash your hands and try again. A meter can be inaccurate on rare occasion. The disposable strips could be expired or have been mishandled (keep them in their protective contain and handle as little as possible). Also, the finger could have been contaminated with a foreign, sugary substance.

Normal Variation

Individuals are different. Take two healthy, insulin sensitive people – same age, weight and gender, feed them the exact same meal and chances are their glucose measurements will be different.


Why it is important for ApoE4s

1) "Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6)." [1]

2) In contrast, the Kungsholmen project ([2]) reported no interaction between diabetes and the APOE ε4 genotype, as described in [3]. These authors stated that “These differences could be due to chance or differences in ethnicity and sex distribution in the populations.”

3) “Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory.” [4]. However, a 2013 study showed that the response might be dose related. [5]

4) "Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4." [6]


Strategies for controlling blood sugar

Doctors tend to overlook testing for blood glucose levels in Alzheimer's patients. When recruiting people for a resveratrol study to study glucose effects in patients with Alzheimer’s, a Georgetown neurologist was “shocked” by how many had pre-diabetes. [7]

For strategies, check out the Insulin Resistance page.


The Science

- Epidemiological studies.

  • Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. (2002, full text) PubMed ID:11916953
  • Increased Alzheimer's disease neuropathology is associated with type 2 diabetes and ApoE ε.4 carrier status. (2013) PubMed ID:23627755


- Other studies/Papers.

Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence (2013, full text) PubMed ID:23719722


- Animal studies.

  • Increased Susceptibility to Amyloid-β Toxicity in Rat Brain Microvascular Endothelial Cells under Hyperglycemic Conditions. (2013) PubMed ID:23948922
  • Amyloid-β and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. (2012) PubMed ID:22785400
  • Epigenetic mechanisms linking diabetes and synaptic impairments. (2013) PubMed ID:24154559


Proposed mechanism(s)

1) Insulin plays an important role in the formation of memories. Abnormal insulin and insulin receptor levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients. ([8]) Increased blood glucose increases amyloid beta “oligomer” assemblies in the brain, which bind to hippocampal neurons and cause insulin receptors to be eliminated from the surface membranes, contributing to insulin resistance in the brain. ([9])

2) Diabetes may induce epigenetic modifications in the brain. Elevation of HDAC IIa in the brains of diabetics coincide with altered expression of synaptic proteins. [10]

Source: Glycemic Variability and Acute Ischemic Stroke: The Missing Link?, (Gonzalez-Moreno, et al, 2014) https://www.researchgate.net/publication/264431084_Glycemic_Variability_and_Acute_Ischemic_Stroke_The_Missing_Link



Related SNPs

SNPs associated with Type II Diabetes: List

SNPs associated with HbA1c levels : Article