What I Learned from the Glucose Monitor

My fasting blood glucose has been creeping up over several years. (My fasting blood sugar is around 110, and HbA1c=5.7; fasting insulin=3.1, triglycerides=91.) Recently, I tried a continuous glucose monitor for the first time, to see what I could learn about eating and exercise habits that affect my blood glucose. The experiment led me to some reading and thinking that was worthwhile, but the results themselves were disappointing, limited (first) by flaws in the technology and (second) by wide variability that I could not trace to any of the usual behavioral correlates.


Why concern ourselves with blood sugar?

Insulin is generated in the pancreas after we eat, with a cascade of effects on the body. The primary short-term effect is to prevent glucose levels in the blood from getting too high, by notifying the liver of the need to pull glucose out of the blood and store energy as fat.

Loss of insulin sensitivity is a primary hallmark of human aging. Most of the known life extension strategies in lab animals have to do with insulin in one way or another. For example, the worm gene daf-2 is the worm’s only insulin receptor, and mutating (weakening) the daf-2 gene doubles the worm’s lifespan. Life extension benefits of exercise and caloric restriction are thought to work, at least in part, through the insulin metabolism.

But glucose is also dangerous, and as we get older we are poisoned by excess sugar in the blood. High blood sugar leads to [list from Mayo Clinic]

  • Cardiovascular disease
  • Nerve damage (neuropathy)
  • Kidney damage (diabetic nephropathy) or kidney failure
  • Damage to the blood vessels of the retina (diabetic retinopathy), potentially leading to blindness
  • Clouding of the lens of your eye (cataract)
  • Feet problems caused by damaged nerves or poor blood flow that can lead to serious skin infections, ulcerations, and in some severe cases, amputation
  • Bone and joint problems
  • Teeth and gum infections

So for long-term health, the name of the game is to keep blood sugar down with as little insulin as possible, hence preservation of insulin sensitivity is the target. Metformin is a well-studied drug for keeping blood sugar down without insulin. I have been taking it (irregularly) for the last several years, intermixed with berberine and Gynostemma (Chinese name: jiaogulan = 绞股蓝).

This reasoning plus direct evidence for life extension in rodents and indirect evidence of life extension in humans has led me to take metformin, though it is not without side-effects.

Long-term effects of metformin 

Metformin is a credible longevity drug, statistically associated with lower risk of cancer, heart disease and especially dementia in humans. Six years ago, this study laid the foundation for metformin as a longevity drug with the claim that people taking metformin had lower all-cause mortality, despite the fact that a population of type-2 diabetics was being compared to a healthier population. This finding inspired Nir Barzilai to raise support for the TAME study.

But metformin has its risks. A long-time contributor to this site, Dr Paul Rivas pointed me to evidence that metformin can interfere with exercise metabolism. Paul notes his personal experience with loss of peak performance while taking metformin. My own experience is consistent with this, though I have never done a rigorous A/B comparison. This study, demonstrating a small but consistent decrease in peak performance, appears to me to be well-designed and analyzed. A plausible mechanism is the interference of metformin with mitochondrial function [refref].  This article claims that metformin suppresses synthesis of ATP, which is the reservoir of energy for immediate use in all cell types. Ben Miller has done the most direct and most recently relevant human experiments in this area and his findings suggest the intriguing possibility that metformin blocks exercise adaptations almost completely in about half of individuals, but not at all in the other half. (If you want to know which half you’re in, you’ll have to wait for next year’s study.)

For the majority of Westerners who exercise little or not at all, metformin may show reduction in long-term risk of age-related disease; but there is no data I know of on the subset of people who do vigorous exercise, comparing metformin to no metformin. Does metformin block the health effects of exercise? Rhonda Patrick cites credible references on this subject as fast as she can get the words out, and her conclusion is that exercise is a better anti-aging program than metformin, and you really can’t have both.

Do glucose-control herbs also blunt the benefits of exercise?

I wrote a few years ago listing botanical alternatives to metformin. Much less research has gone into these herbs, so we must think theoretically about interference with benefits of exercise.Branch of ripe red barberry after a rain with drops of water

Berberine works by a mechanism of action that overlaps metformin. Both metformin and berberine promote AMPK (which in turn promotes sugar burning). Both metformin and berberine inhibit mitochondrial Complex I (slowing the conversion of sugar to usable energy). There is tentative experimental evidence that (unlike metformin) berberine does not inhibit adaptations to exercise [refrefref].

Gynostemma is a Chinese herb popularized by Life Extension Foundation in their proprietary compound called AMPK Activator. In animal models and in humans, Gynostemma suppresses blood sugar and blood cholesterol. Like metformin and berberine, it works through AMPK, which appears to be a good thing.  It is anti-inflammatory, and has a history in China as cancer therapy, supported by mouse and in vitro studies. In rodent studies, Gynostemma has a beneficial effect on strength and endurance [refrefref]. The one study I’ve found on human diabetes shows modest benefits after 12 weeks. The only counter-indication that I have seen is that it increases insulin release (in vitro), which I believe to be pro-aging.

Is it more important to suppress postprandial spikes or to depress fasting glucose levels? 

HbA1c is a standard blood test for diabetes. It is related to average blood glucose levels over the previous 90 days (= the half-life of hemoglobin in the blood). But the glycation of hemoglobin (as measured by A1c) happens predominantly during the brief glucose spikes, rather than the much longer periods of average glucose levels. So it might be fairer to say that A1c summarizes peak glucose events over a 90-day period. And we might guess that the long-term health risks of high blood sugar are similarly more sensitive to the peaks than to the average.

I believe that apoptosis is on a hair trigger as we age, and part of the reason for this is too much p53. This study links P53 activation to postprandial glucose spikes, rather than to high average glucose levels.  This study links deterioration in endothelial function (related to arterial disease) with glucose spikes. The same paper lists ROS and oxidative stress as additional risks.

For a long while, it has been established that high fasting blood sugar is associated with cardiovascular risk. Of course, there is also association with obesity and T2 diabetes, but for these, it is natural to think of fasting blood sugar as the result, rather than the cause.

Chris Kresser says the best indicator of metabolic health is blood glucose levels 2 hours after a meal. If you can bring your blood glucose down to normal within 2 hours after eating your insulin sensitivity is good. For me, unmedicated, it was 3 hours after dinner, but less than 2 hours after breakfast. Either berberine or metformin tamed the after dinner spikes within 2 hours.

Marker Normal Pre-diabetes Diabetes
Fasting blood glucose (mg/dL) <99 100-125 >126
OGGT / post-meal (mg/dL after 2 hours) <140 140-199 >200
Hemoglobin A1c (%) <6 6-6.4 >6.4

Kresser claims that these guidelines from the American Diabetes Association are not strict enough, and that statistics show increased future risk of diabetes even for people in the ADA “normal” range. But he cites Petro Dobromylskyj, who makes an exception for anyone on a low-carb diet (how low isn’t specified). Paradoxically, low-carb diets are claimed to be healthy, even though they decrease insulin sensitivity. I have been unable to make sense of this.

Kresser emphasizes that all numbers should be interpreted in the context of a person’s other lifestyle and health indicators. In people who are active and not overweight, he is not inclined to worry about statistics in the “prediabetic” range. (I take comfort in this personally, and who can say if I’m fooling myself?) But I can learn something from the way my glucose stats respond to medications, eating and exercising, whether or not I believe the absolute levels are concerning.

Writing in Science Magazine last year, Charles Piller reviewed the ADA guidelines and found a consensus in the opposite direction — that they were probably too strict, and unnecessarily worrisome to a great many people. By ADA’s definition, 80 million Americans are “pre-diabetic”, which is 40% of the adult population. The conflict really is not over the statistics but the interpretation. You can say either “People with A1c levels above 6 are at increased risk of progressing to diabetes” or equally well, “Most people with A1c levels less than 6.4 will never develop diabetes.” Both statements are true.

As promised: my experience

The Freestyle Libre was very easy to use and set up. I followed the instructions and used a spring-loaded device to insert the monitor behind my biceps. It was painless. There’s a tiny wire that goes a few millimeters into the skin and an adhesive covering with a button containing the electronics.

The wearable button stores data for up to 8 hours. The other part of the kit is a reader that downloads data every time you bring the reader within an inch or two of the button. As long as you take a reading every 8 hours or less, you won’t lose any data. And you can do it as often as you like, to get real time feedback on your glucose state.

The wearable button ($45) is meant to last two weeks, and then it must be discarded. My insurance (Blue Cross Medicare Advantage) wouldn’t pay for it because I didn’t have a diagnosis of diabetes. I found this out only after several trips to the drug store, interspersed with phone calls to Blue Cross, where I got repeated assurances that it would be covered. The reader ($85) can be reused. Apparently, it doesn’t do anything that a cell phone app couldn’t do, but Abbott (parent company of Freestyle) has arranged it so that you can only use the cell phone app if you purchase the reader.

To analyze historic data, you can use capabilities built into the phone app, or plug the reader or cell phone into a computer, using a USB cable. The data is uploaded to a web site containing analysis tools and an option for creating a CSV file for more detailed manipulation in a spreadsheet. (The download button is not so easy to find, but I called Abbott’s tech support number, and connected without excessive wait time to a friendly and knowledgeable technician.)

My intention was to vary the glycemic content of my meals, my exercise schedule, eating and fasting schedule, and the medications I was taking (metformin and berberine) to learn what I could about glucose management. The first day I fasted, and I was concerned to see that all day my fasting glucose ranged between 110 and 120. (For reference: the standard healthy range for fasting glucose is 70-100. Below 70 is “hypoglycemia”. Above 100 is “pre-diabetes” and above 125 is “type 2 diabetes”.)

I ate a meal, and glucose shot up to 179 before bedtime, only gradually coming back down during the night. As it turned out, 179 was my high for the week.

The data is cut off after 10 days, though the monitor is supposed to have a lifetime of 14, because it fell off my arm. I looked for patterns in my data, and was able to learn only four things:

  • Glucose rose after a meal. (I didn’t get as far as being able to distinguish a meal with more carbs from a meal with more fiber or protein.)
  • Glucose also rose, to a lesser extent, when I exercised.
  • Taking metformin with a meal substantially reduced the glucose spike after the meal, and raising the glucose trough a few hours later. The range (stdev) but not the average glucose was affected.
  • Taking berberine did not have this immediate effect.
  • There was a strong downward trend over the 10 days. I interpreted this to mean that the monitor was gradually loosening in my skin, probably because I am a long-distance swimmer.

(In a long phone support session with an Abbott representative, they acknowledged the reality of my experience: that the monitor can loosen over time, resulting in readings that are anomalously low. They were happy to replace the monitor, and advised me against long periods of swimming. )

Unresolved

I was left wondering all the things I wanted to discover at the beginning of my experiment.

  • What kinds of meals minimize the glucose spike? High fat? High fiber? High protein?
  • Could exercise before or after the meal help tame the spike?
  • Could I detect short- and long-term effects of metformin, berberine, and jiaogulan?

The thing that impressed me most was the natural variability of blood sugar, changing from hour to hour, uncorrelated with either food or exercise. I trust the body knows what it’s doing. “Le corps a ses raisons que la raison ne connait pas.”*

I hope to try the monitor for 2 weeks again when swimming season is over.

In the meantime, I am taking a modest, common-sense approach. I am going to leave out metformin but continue daily exercise and low doses of berberine and Gynostemma, lightening my evening meal and ending the day’s food 3 hours before bedtime.

Walking burns calories (pulls sugar from the blood) 3 to 5 times as fast as sitting, and walking after a meal feels like a natural and pleasant thing to do. My doctor recommends it. I’m going to try walking half an hour after breakfast and dinner, pending my next experiment with the CGM.

70 thoughts on “What I Learned from the Glucose Monitor

  1. What means something is insulin sensitivity.
    To measure insulin sensitivity need to measure fasting insulin and fasting glucose same blood sample.
    HgA1c means something as reflects average glucose.

    Measurements of blood glucose without insulin and calculating insulin resistance is essentially nonsense. If fasting glucose over 125 defined as diabetes.

    This focus on glucose without measurement of insulin is the very definition of no idea of what somebody is talking about.

  2. Looking at Josh glucose numbers he could be healthy or unhealthy.
    He might have some degree of insulin resistance with high insulin.
    More likely Josh is insulin sensitive, healthy and has glucose intolerance due to low fasting insulin.

    Since Josh is active and thin and not fat and sedentary, more likely healthy.

    Throw away the glucose monitor and measure fasting insulin, fasting glucose and then go to HOMA-IR website, plug in numbers and get insulin resistance HOMA-IR score.

    • Hi, Dr. Green:
      I have read that rapamycin increases the “fasting glucose levels”.
      Does your experience with your patients confirm that?
      If so, what would be the average increase (approximately)?

  3. Good insight. I have found the #1 thing that lower glycemic variability and can suppress blood glucose based on CGM data for up to 8 hours is morning cold exposure (e.g. cold shower, cold bath, cold soak, etc.) for 5-10 minutes. Game-changer.

  4. I also tried the libre for a couple of weeks when I was 46. I noticed that my blood sugar would spike after eating or during exercise up to 13 mmol/L. I cut out carbs, alcohol and skipped breakfast. By day 4 I was back to good levels of control and even my nighttime sugar dropped to 4.0 mmol/L. Previously they were somewhat higher.

  5. Josh:

    If you want to control your blood sugar, here’s some information you should be aware of:

    In healthy people, the primary location for glucose storage is in skeletal muscle cells. Insulin’s primary role is to facilitate the transfer of glucose into muscle cells, where it is stored as muscle glycogen.

    Human muscle cells have finite capacity for glycogen storage. Since most people do little or no exercise that requires the use of glycogen, most humans are generally at the limits of their storage capacity.

    Think of a completely full subway car. It stops at the station and the doors open (that’s the role of insulin). But if no one gets off, then no one can get on. It’s not that the insulin is “insensitive” – the doors are opened – it’s just that the glucose can’t go where it’s supposed to. So some ends up as liver glycogen and the rest is ultimately stored as adipose tissue (fat).

    Here’s why diabetes medication can result in hypoglycemia. In order to ensure that the brain has an adequate supply of blood sugar, insulin is released (the doors are opened) only when there are more than enough people in the subway car. But if one does does burn his or her glycogen (through overexertion) while on insulin medication, the doors will stay open even after too many people have disembarked, and blood sugar levels can get dangerously low.

    Burning calories is not the same as pulling sugar from the blood. When you walk, the primary source of fuel is fat in the form of blood lipids. “Fat burning” physical activity is better than being completely sedentary, but it won’t help with blood sugar levels. You need to do more intense exercise, where the primary source of fuel is muscle glycogen (which then makes room for blood glucose to be converted into more glycogen).

    The incidence of high blood sugar among people who regularly engage in intense physical activity is zero, or very close to it.

      • Ashkay:

        Thanks for your positive feedback.

        Another commenter mentioned exposure to cold as being a means of lowering blood sugar quickly. That’s because shivering is a form of muscular activity that is intense enough to involve glycolysis (the breakdown of muscle glycogen and use of that fuel).

        In addition to disagreeing about the role played by insulin, I also take issue with the assertion that excess blood sugar “poisons” us. There is an association between chronic high blood sugar and the symptoms Josh mentions. Association does not prove causation. An equally valid explanation for the association is that people who have chronic high blood sugar almost never engage in physical activity that requires glycolysis.

        One specific example of why moderate to intense physical activity is essential to long-term health – there is a strong association between glycolysis and mitochondrial biogenesis. In adults, mitochondrial biogenesis is triggered by moderate to intense physical activity and exposure to cold — the same environmental stimuli that have been shown to lower blood sugar levels.

        One obvious fact supporting the hypothesis that long-term damage is caused by the absence of physical activity rather than blood poisoning: Other commenters who religiously monitor their blood glucose levels observe that they fluctuate greatly. If there were something inherently dangerous about high blood sugar, natural selection would have eliminated that trait eons ago.

        • @Mark,

          what’s the lowest amount and type of exercise to get glycolysis?. I love walking, but I hate to death running, weight lift,… and I console myself saying that exercise is overrated, and nutrition is orders of magnitude more important.

          As for base insuline measurements, in my experience from many years taking metformin and controling foods, the key is to avoid high glicemic foods.

          • Santiago:

            Sorry, but I don’t have a very precise answer for you. I’m a philosopher, not a scientist. Scientists love making incredibly precise measurements of irrelevant metrics. I try to see the big picture.

            Also, I view the world very differently than most people on this site. I don’t do gadgets; I don’t take supplements or drugs (unless you consider alcohol a drug; I do overdo that); I have never eaten anything because it’s “good” for me; and, other than trying not to eat unless I’m somewhat hungry (unless it’s really good), I completely ignore my diet. I have no idea what my glucose or insulin numbers might be.

            I believe in evolution. The human machine is miraculous, but it needs to be operated in the way it was intended. Scientists look at modern humans and forget that we are animals. Animals are defined by the fact that they can move. And if you consider the evolutionary environment (millions of years) that means periodically engaging in all out physical activity. For the last 10,000 or so years, humans have had the option of not acting like animals. And, as you say, most humans won’t engage in all-out physical activity because it’s unpleasant. Anyway, as I said above, type 2 diabetes is not a disorder in its own right; it’s just an indicator that we haven’t been operating the machine properly.

            Now, to your question: I used to be a runner, but I think you get better results with less time and effort (and less likelihood of injury) from doing resistance work (pushups) or plyometrics (jumping rope/burpees).

            It’s difficult doing this stuff on your own. I used to do Cross-Fit, which was fun, but Cross Fit is worse than running when it comes to causing injuries. And if you’re doing this for health benefits, the important thing is to keep doing it. So I joined a fun HIIT class called “Training Mate” (Aussie themed) with my 66-year old wife. And that worked great — you just do what they tell you to do to loud music and bad jokes, and you end up with a great workout. Unfortunately, the pandemic shut that down for the foreseeable future. Because I completely believe in this, and have done it for many years, I can construct my own at home workouts, but it’s not easy.

            If you can find any type of class that will make you put in some intensive effort while having fun, that’s what I would recommend. The critical metric is to exercise with enough intensity that you hyperventilate (but don’t overdo it). It’s easier than you might think. For example, try carrying some luggage up a couple flights of stairs.

          • @Mark

            I like your view on evolution. I had the privilege to live off the grit and land for more than a decade in Yukon’s wilderness. Pretty much a hunter/gatherer lifestyle of our prehistoric ancestors. Today I still try to commit to this lifestyle as much as possible: resistance exercise, fasting, avoiding any modern Western-style food, spending lots of active time in nature. However, I admit I take supplements most noticeable NAD+ booster, Glutathione, Pterostilbene, Glucosamine among minerals and vitamins.

          • Josh:

            Glad I could provide you the opportunity to plug your book.

            The problem I have with debates about programmed v. non-programmed aging is that imprecise definitions of the term “aging” allows for an enormous amount of irrelevant evidence.

            Rather than use the term aging, let’s start with a particular set of symptoms associated with the passage of time – the progressive dysfunctionality suffered by most humans that results from the accumulation of damage at all levels of biological organization. I’ll call this set of symptoms functional decline syndrome (“FDS”). I select this particular set of symptoms because FDS is the one trait that is unambiguously inconsistent with the principles of natural selection. And none of the hypotheses that have been proposed over the years successfully explains how FDS can be a trait shared by typical 25 year old humans (although I confess that I haven’t yet read your book).

            Among the types of evidence that are irrelevant to a discussion about FDS are (i) observations relating to non-human animals; (ii) the fact that all humans eventually die; (iii) cancers; and (iv) the accumulation of damage that does not affect functionality (e.g., cosmetic changes such as graying and thinning hair).

            Your position is that FDS is not only genetically mandated but is part of a genetic aging program. The conventional contrary position is that FDS is genetically mandated, but not the result of an intentional genetic aging program.

            My position is that FDS is not genetically mandated at all, but instead results solely from environmental factors.

            Damage to biological components is inevitable. Over 50 billion cells die each day.
            But humans have been endowed by evolution with incredibly complex maintenance systems. Maintenance does not mean eliminating damage; maintenance involves identifying, removing and replacing damaged components. Well-known maintenance processes exist at all levels of human biological organization, from subcellular (e.g., mitochondrial turnover) to complete biological system (e.g., bone remodeling).

            We don’t typically observe how much maintenance is done on a routine basis. But when maintenance processes are interrupted by environmental factors, the results can be ugly. Deficiency diseases (e.g., scurvy, beriberi and rickets) are all examples of the absence of some critical substance interfering with the proper functioning of a routine maintenance process.

            FDS is the result of the human maintenance system functioning just slightly less effectively than it was designed to function over the course of decades. In contemporary humans, noticeable symptoms of FDS typically start appearing during the third decade of life.

            FDS is important because it is the cause of chronic degenerative diseases. The good news is that because FDS results from environmental factors, it can be prevented and reversed. All we need to do is make our maintenance systems work a little bit better.

            Several times a week, I take action that improves the performance of my maintenance system. Among the reasons that I don’t believe that FDS is genetically mandated is that I evidence no symptoms of FDS, and I’m about to complete my sixth decade on the planet. If FDS were genetically mandated, my experience would be impossible.

          • Hi Mark,
            Would you mind sharing in what precisely your action plan consists? It sounds interesting and I’m curious to hear what you are implementing that helped you to prevent signs of FDS!

          • Cynthia:

            My action plan is to engage in high intensity physical activity several times per week. For specifics, see my reply to Santiago above.

            FDS results from damage accumulation. Damage is inevitable, because all biological components have very short lifespans. Many types of cells only live for a few days before they must be replaced. Most healthy “lifestyle” changes are designed to eliminate environmental factors that increase the rate at which damage is inflicted. Examples include avoiding damage accelerants such as smoking, stress and obesity. But you can eliminate all of the accelerants and still suffer from FDS.

            I focus on the maintenance side of the equation. Damage accumulates only because our maintenance processes are not doing a good enough job of removing and replacing the damaged and dead components.

            Exercise would appear to pose a conundrum. It is a damage accelerant, but has a net beneficial effect. That’s because physical activity is necessary for all maintenance processes. And the benefit to the maintenance side of the equation outweighs the detriment to the damage side of the equation.

            My research shows that, in terms of benefits conferred to the maintenance system, there is a qualitative difference between low, medium and high level intensity physical activity. Because some physical activity is necessary for routine maintenance processes, even low intensity activity (e.g., walking or gardening) is better than nothing. I focus on the high intensity level, because it confers all of the benefits of all three levels of activity. Moreover, I have identified a particular maintenance process that is activated only when one engages in intense physical activity.

            I believe that failure to activate that process on a regular basis is the primary cause of FDS.

          • It certainly might be possible to go through a long life without significant functional decline, although I’ve yet to see someone do it. This is making healthspan equal lifespan. You’d still die on schedule, I suspect, only with a rapid rather than long painful decline.

          • Mark W.

            Personally, I think “making healthspan equal lifespan” is the ideal outcome. If I’m fated to die at a date certain, then so be it. But I’ve seen friends and relatives suffer through the infirmities associated with aging, and I do not what to experience that. For now I take comfort in the knowledge that at the age of almost 67, I’ll be stronger and healthier next year than I am now.

            The bigger picture is that making healthspan equal lifespan on a widespread basis would have enormous implications for societal costs. Using estimates from a few years ago, about two thirds of annual U.S. medical expenditures ($2 trillion out of $3 trillion) were spent on treating chronic degenerative diseases. Making healthspan approximately equal lifespan would greatly reduce those expenditures.

            What remains unknown is whether we will die “on schedule.” Animals such as lab rats do have genetically mandated lifespan limitations. Lifespan is determined by the effectiveness of the maintenance system (just as intelligence is determined by the effectiveness of the brain and central nervous system). In the evolutionary environment, over 95% of lab rats die in their first year. Only an infinitesimal number survive past year 2. So there was no evolutionary advantage to allocating finite resources to traits that would allow a rat’s maintenance system to extend its potential lifespan beyond a few years. As a result, even in a perfect environment, a lab rat will not survive for more than a few years.

            Humans are different. With increasing brainpower over the millions of years of human evolution, humans learned how to avoid death from causes other than aging. Thus traits that would improve the maintenance system did confer an evolutionary advantage. Those traits were selected and, as a result, humans have remarkably elaborate maintenance systems. It’s remarkable to me that although many gerontologists have acknowledged that aging is caused by damage overwhelming maintenance processes, gerontologists focus almost exclusively on the damage side of the equation.

            Like lab rats, humans may have a genetically mandated lifespan limitation (i.e., a chronological limitation on the effectiveness of the maintenance system). But if there is one, I haven’t reached it yet. Which to me argues that the FDS suffered by much younger people is not the same phenomenon as the aging observed in animals taken out of their evolutionary environment.

          • Josh, your motivations and proven aptitudes are much appreciated here.

            Cellular glucose homeostasis is largely misunderstood. T2 diabetes (insulin resistance) is not a deficiency of glucose uptake into cells but rather a defective shunting of lactate-pyruvate into the mitochondria. The lactate end product of glycolysis in the cytosol is largely excreted from diabetic tissues into the blood and ultimately processed into more glucose via gluconeogenesis by the liver. It has been observed that glucose uptake in the T2 diabetics may actually exceed that of healthy normals by as much as 40%. Insulin resistance is still properly described in that the increased membrane cholesterol mediates insulin receptor dysfunction (phosphatase cleavage) and results in a dramatic extension of the duration required for a slower rate of equivalent glucose uptake. T2 diabetes is more properly defined as a defective shunting of lactate, fatty acids, amino acids, proteins and other substrates into the mitochondria for reduced oxidative phosphorylation, reduced protein synthesis and reduced ATP production.

          • @Mark
            “Moreover, I have identified a particular maintenance process that is activated only when one engages in intense physical activity.”

            Could you please elaborate on the maintenance process you have identified. Also, what is your definition of intense physical activity?

            I’m about your age and do resistance exercises in the gym 5 times a week for 75 min. Over the years I changed the way I fatigue my muscles. Instead of heavyweights I use medium weights and do 3 drop sets without breaks.

            Also, on average I hike (steep mountains), walk, paddle, snowshoe, ski 150 km per month.

            Would my physical activities activate the maintenance process you have identified?

          • Stephan:

            To activate the process, you need to exercise with sufficient intensity to exceed the lactate threshold. The best indicator of that is whether you are hyperventilating and have to take a break to “catch your breath.” Steady state exercise doesn’t do it.

            I used to be a runner, and, although I was healthier than most of my contemporaries, I was still experiencing the progressive physiological deterioration that is typical of most humans. Old runners look like old runners. Loss of muscle mass is one obvious example.

            But after doing HIIT for a few months (starting at about age 58), I noticed that I was adding muscle mass. So I started researching what made HIIT qualitatively different from steady state exercise. One big difference is the effect on the endocrine system. Multiple studies show that when your intensity level exceeds the lactate threshold, there is an increase in blood levels of HGH, steroids, and dozens of other substances that are necessary to build muscle.

            Conventional scientists dismiss this phenomenon as aberrational or counterproductive because it involves hyperventilating and radical deviations from homeostatic equilibrium. Also any particular scientists tends to specialize in only a single substance. I look for patterns. If all of these substances are being released simultaneously and in proportion to one another, it must be a process.

            Here’s an easy way for you to test my hypothesis. There are any number of substances that are associated with health or rejuvenation (e.g., BDNF, Klotho, stem cells, any growth hormone, etc.). Pick any such substance (you can either use my examples or ones that you’ve heard of that maybe I haven’t). Do a Google search using the name of that substance and “intense exercise.” You’ll find that someone has done a study that shows that when one engages in intense exercise, blood levels of that substance increase “in an intensity dependent manner.”

            Anyway, I’ve been doing this for about 8 years now and I do get stronger and healthier every year.

          • @Stephan – Exercise is very individual. Some of us love to hike, and some of us love to swim, and some only get our heart rates up when we’re competing on the squash court and others have no stomach for competition but practice yoga every morning without fail.

            For sure, experiment with new forms of physical activity and see what sticks. See what can become a habit. But if you set up rules for yourself about what you have to do, you’re setting yourself up for failure and a downward spiral.

            Do the exercise that feels good to you, and feel good about the exercise you do. Keep experimenting, keep expanding, stay active because it brings joy and enthusiasm to your life, not because it’s a bitter medicine for long life.

          • @Mark

            Thanks for sharing your insides. Like you, I’m going about 8 years to the gym and get fitter and stronger every year. I actually can prove that we can build considerably lean muscle mass at old age without resorting to steroids and hormone enhancers.

            However, exercise has a drawback: It improves your robustness but shortens your lifespan by activating or accelerating the mTOR passway (Akshay and I and some others have discuss this topic on this blog some time ago).

            To balance this disadvantage out I fast for more than 16 hours before hitting the gym.
            (I have tried different regimes of fasting but settled for daily 18:6 time-restricted feeding). I break my fast after my workout with food high in protein and fat. I guess any fitness professional will tell you to have a pre-workout meal high in carbs, which the body can quickly utilize to produce the demand for energy. Why this might be true I think fasting is more efficient in energy production.

            Here are my thoughts although I’m just a layman: I think fasting is deeply rooted in our evolutionary history and survival circuits in our cells turn on and off certain genes to get the body in the most effective way through times of food deprivation. The body will reach a state of ketosis burning only fat to produce energy and to my knowledge burning fat produces about 60% more energy than burning carbs. That’s why I experience having more energy in the gym or hiking the mountains while fasting.

            While most people associate fasting with weight management I think the more important benefit is elevating autophagy and body homeostasis.

          • Stephan:

            Thanks for the info re the mTOR pathway. I’d never heard of it before. As I’ve said, I’m not a scientist.

            Having done some quick research, I agree with your assertion that exercise activates and/or accelerates the mTOR pathway, but disagree with the conclusion that that would necessarily shorten human lifespan.

            In my simplistic view of the world, there are two sides to the aging equation: the damage side and the maintenance side. The mTOR pathway relates to metabolic rates/rate at which damage is inflicted. For short-lived animals, the damage side is more significant, because they have limited maintenance systems. So, for example, CR, which slows metabolism, extends the lifespan of lab rats by slowing the rate at which damage is inflicted. It makes sense that accelerating the mTOR pathway shortens the lifespans of worms and rats.

            My counter is that humans have very sophisticated maintenance systems, so the maintenance side of the equation is the more important variable. When we exercise, we do accelerate the rate at which cells and other biological components are damaged and die. However, by activating various maintenance processes that remove and replace the damaged components, exercise more than compensates for the damage it inflicts.

            I may be wrong, but fasting has never been my thing.

          • @Josh

            I totally agree with you, everyone is special and different. When not on a trip as an adventure guide, I work occasionally as a fitness trainer. Unlike younger trainers, I’m not pushing clients through a set exercise program. I provide people with different routines they can try out to see what works best for them. If they have this freedom, they are more likely to start enjoying their workout, stay committed, and experience results.

            However, at our age, I highly recommend resistance exercise to build more lean muscle mass and strength, to enhance bone density to prevent frailty and falls.

            In my case, being strong and fit helps me to maintain my new lifestyle as a wilderness guide. My original trade was software engineering, and today I feel I wasted have of my life on a computer desk. I try to have another 70 years of good healthy life to correct the mistakes I made in the past.

          • @Mark

            Well, as you said:
            “I believe in evolution. The human machine is miraculous, but it needs to be operated in the way it was intended. Scientists look at modern humans and forget that we are animals. Animals are defined by the fact that they can move. And if you consider the evolutionary environment (millions of years) that means periodically engaging in all out physical activity.”

            Our prehistoric ancestors didn’t have food to eat every day, there were periods of famine and periods of feasts. That’s how our species has evolved, it’s all in our DNA. For me, fasting is a game-changer. I use to say:

            “Exercise is second only to starvation as the healthiest poison known to man”

        • It’s not about shivering, in my experience. Short exposures to cold are intensely stimulating to the skin, and (subjectively) raise my metabolic rate. But they don’t affect my core temperature, which would induce shivering.

  6. Another great article, thank you, Josh. If you’re eating your last meal at least three hours before bedtime for the plausible but hypothetical circadian rhythm considerations, and not just to prevent gastric reflux or sleep difficulties, I trust that you’ll agree that the evidence for earlier feeding is preliminary at best. Both the Jones, et al and Sutton, et al studies of early time restricted feeding suffered from having their experimental and control groups differ by not only the times of day that feeding was allowed, but also by the confounding variable of the total number of hours that feeding was allowed. Of course, cramming more feeding into a shorter feeding period could theoretically exacerbate the serum glucose spikes that we’re concerned about.

  7. Did you do any experimentation with tease meals which I have seen recommended?

    As for 40% the pre-diabetic, I actually wonder how many are actual valid test results? I know my wife had the usual battery of tests done with no instructions to fast, the glucose came in the pre-diabetic range (after breakfast) and the doctor announced she was pre-diabetic.

    One other note, I think there is an association of melatonin with higher levels of blood sugar in some people.

    • Diagnosis of “pre-diabetes” on non-fasting glucose is Quack medicine.

      Pre-diabetes is INSULIN RESISTANCE. Only way to determine insulin resistance is to measure level of fasting insulin and fasting glucose on same blood sample. Then calculate HOMA-IR score.
      1.0 is healthy, 2.0 is early insulin resistance, 3.0 is severe insulin resistance.
      Glucose intolerance is fairly benign condition frequent in thin people.
      Insulin resistance is serious condition, very common in over weight people; but entirely reversible.

      The topic of insulin resistance and pre-diabetes is very screwed up by most physicians so essential people understand the subject.

      Insulin sensitivity most important part of good metabolic health. You determine insulin sensitivity by measurement of insulin.

      • I very much agree Alan. The problem is that doctors have largely bought in without examining the evidence and that forms a standard of care. Violating such a standard is grounds for a medical board investigation. This lays the groundwork for the dozen or so drugs that are pending fda approval . The rich will get richer.

      • I think this is where the confusion is over DAF worm mutants. The benefit to lifespan is not because this mutation decreases blood glucose; it actually increases it via decreasing the uptake of excessive glucose into cells (which can drive them to senescence).

    • I once fasted my dog prior to bringing him to the veterinarian for glucose blood test.

      I had fasted the dog from midnight.

      In the office the veterinarian, immediately feeds the dog a handful of dog biscuits, Leaves the room for about ten minutes, than returns to take blood work.

      Of course, it came back with high blood sugar.

      I changed veterinarians, after that incident.

      The dog was not determined to have diabetes or pre-diabetes.

  8. The designation of diabetes is a bit arbitrary. It used to be 140 and then was changed to 120, and then a whole new “ disease” was created, “ prediabetes”, which enveloped 70 million people and is a huge boon to big pharma even though there is scant evidence that a mild elevation of FBS leads to clinically significant end organ damage. Here’s the science magazine https://www.sciencemag.org/news/2019/03/war-prediabetes-could-be-boon-pharma-it-good-medicine# .
    Well worth reading.

  9. Hey Josh,
    We have been using metformin fairly regularly in our medical practice to keep A1c at 5.3 or less. Now we are all about performance and we truly monitor every parameter possible including weekly monitoring of clients Garmin fitness data. We do this as part of a comprehensive program that includes optimizing fitness and frequently use hormone replacement. Having used the metformin in several hundred clients over the past 10 years and monitoring their fitness parameters and performance, I can say anecdotally we have only seen improvements in muscle mass, performance metrics, as well as reduction of A1c, fasting glucose, and fasting insulin.
    I think it is difficult to take a single intervention and extrapolate that to a full system response that applies across individuals. In addition, ongoing monitoring is imperative as there is adaptation with emergence of new traits and that requires dynamic thinking.

  10. Hi Josh,
    That is a really interesting story. About 2 years ago, when I was still in dental school I got myself a glucometer because I needed to take the glucose levels of my patients before minor surgeries like tooth extractions. Of course I was curious about my own levels – especially because I have several relatives with type 2 diabetes. At that time, because of all the stress related to university I would rarely have breakfast. I just had not enough time and at about 4am in the morning I just wasn’t hungry. But often times I would go without food until 2 or 3 pm. Therefore, my surprise was even bigger when I took the test and it showed me fasting glucose levels around 100 . I was worried and consulted with an endocrinologist. He ordered a an analysis of my insulin levels and a glucose challenge test. It came out that my fasting insulin levels in the morning where lower than normal, but the weirdest thing was the glucose challenge test. Before the ingestion of 70g pure sugar solution my blood sugar was about 99. Then, two hours later it was 87 – even lower than in the fasted state. My endocrinologist was surprised but told my I was healthy but that the prolonged period without having breakfast had conditioned my body to suppress my morning insulin levels and to rely more on gluconeogenesis to get through the day until afternoon. He told me that results of the glucose challenge were compatible with a protective phenotype and that I was not in danger to develop diabetes in the near future. Nonetheless I wanted to find out if a keto diet would have some effects on my blood glucose levels. So I fasted one day and then implemented a strict keto diet. After about 3 days my blood glucose levels would never climb higher than 90 and most of the time (even immediately after a meal) they would be between 70 and 80. Of course, this is only my experience, but I thought that you might find my observations helpful.

    Thank you for always posting such interesting topics!

    Best regards,
    Cynthia

  11. Hi Josh,

    regarding low carb and insulin sensitivity:

    If someone on a very low carb diet takes a glucose tolerance test the result is very likely that blood glucose spikes dramatically and falls slowly as if that person is insulin resistant and diabetic. But if the same person ramps up dietary carbohydrates a couple of days before the GTT the result will likely be OK. This is a well known phenomenon. LC proponents distinguish between “pathological insulin resistance” (as in T2D) and “physiological insulin resistance” (when eating LC). Another way to put it is to describe the situation in a LC state as “glucose sparing”.
    So what is going on here?
    Most of our cells are perfectly fine using glucose or fatty acids as energy source except neurons and specialized cells like red blood cells which rely on glucose. If someone eats a high carb/low fat diet all cells are using predominantly glucose as energy source.
    Now our storage capacity for glucose (in form of glycogen) is limited: Muscles have some capacity (but never give back to the circulation) and of course the liver whose most important function is to guarantee a steady supply of glucose in the blood if no new dietary carbs are consumed. Else we would be brain dead in a couple of minutes.
    What happens if someone goes into a prolonged very low carb diet (or zero carb diet or complete fast)?
    Liver glycogen stores will be depleted in a matter of days. To hold up the glucose supply needed for our brain the liver will use protein to produce glucose via gluconeogenesis, and start to produce ketones from fat which the brain happily accepts as an additional energy source (and which spares precious protein).
    All cells which do not rely on glucose will switch to fat as primary energy source (coming from the diet or from our adipose tissue). And it makes perfectly sense that all our cells which can burn fat reject glucose if dietary glucose is low/not existent to spare glucose for the brain.

    Best,
    Johannes

  12. tried benfotiamine josh? i take 150 mg daily. seems to help but have not monitored Began taking based on research i saw years ago. No known side effects at 150 mg, long half life. Thoughts?

  13. Peripheral Insulin Resistance is what ketogenic diet followers and long term fasters have.

    This is the theory. You go so long with such a very low levels of ingested glucose and blood sugar spikes. As your body gets fat adapted your body isn’t going to prepare itself for carbohydrates that are not incoming. so it has no need to be ready for insulin on a high level if you know what I mean.

    I remember a time I did high intensity interval training and checked my blood sugar and ketones. Before hiit 85mg, 1.2 ketones. End of hiit, 180mg, no ketones. One hour later, 90 mg 1.1 ketones.

    180 freaked me out a little bit but I realized it’s just because I’ve gone so long with such little carbs that my body doesn’t need to be ready to produce that much insulin that quickly.

    I don’t think my words and explanation is the best but I’m saying the concept that is believed to be true.

    • Gerald:

      Berberine and Metformin are both shown to be mitochondrial inhibitors.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660979/

      From the link:

      “Mitochondrial dysfunction is not likely a risk factor for insulin resistance in type 2 diabetes. Instead, over activation of mitochondria is a potential risk for insulin resistance. A growing body of evidence has revealed the importance of mitochondrial over activation in the pathogenesis of insulin resistance.”

      • TY. Key for me is to keep the dose Low. Benf. is fat sol. I do 100-150 mgs day [has a long shelf life] then take a week off every month or so.. LEF is no better than a pharmaceutical co. Willing to suggest way high amounts of supplements and cherry picked research: literally little better than the unethical pharm. co’s. I would take care. At the very least take off 7 days for every 3 weeks or so, your body will get lazy producing on”it’s own, imo and based on-wise consul. Co’s like LEF make me angry with their willingness to promote such that is harmful over time imo. Take care all.

        • Hi Jeffrey:

          I rarely take the recommended dose on the label of a nutrient being taken as a maintenance dosage.

          I take most of them daily with occasional breaks, checking for a cumulative health effect.

          With a multi-nutrient I split the dosage, I do take, into an am/pm dose.

          Sometimes I do temporarily take therapeutic dose of a nutrient, to influence a particular health issue.

          Temporary therapeutic dosing is typically larger than the maintenance dosage.

  14. Why does it get more complicated. At 78 years young I’m deliberately attempting to simplify my life as I don’t believe I’ll live past 10 more years. My process for diabetes II hasn’t changed for 10 years. On insulin for 12 years, every day I increase the amount I take (according to the dr. chart). Why the confusion, why no solution yet?? I’ve had every major joint procedure, breast cancer, and yet this disease is a phantom. I do believe the medical community is in total chaos and will not improve as we move forward. The changes between the ages of 35 & 65 are startling. Yesteryear doctors listened to the patient, were kind, were patient and were not intimidated by information via the web. Today, the visit better not go beyond 15 minutes and the doctor is not a happy person.
    Everyone BE well as we move forward. good trouble…..

  15. “Paradoxically, low-carb diets are claimed to be healthy, even though they decrease insulin sensitivity. I have been unable to make sense of this.”

    Perhaps it’s because too many sources fail to distinguish between long-term/chronic insulin resistance (which is pathological) and short-term insulin resistance (which is often good and appropriate)?

    Insulin resistance (the non-chronic kind) is beneficial when less glucose is available and the body needs to conserve it for the tissues that need it (e.g., brain, red blood cells). On a low-carb diet, you’re getting lots of fat for fuel but only a little glucose, so your body needs to signal your muscles to prefer fat over glucose so your neurons can have the glucose.

  16. Dr. Unwin of the UK and Dr. Sarah Hallberg of the USA are leading experts in reversing type II diabetes, and very successful.
    Dr. Joseph Kraft developed methods to determine diabetes 10 years before elevated glucose means there is severe insulin resistance and the pancreas cannot keep up with enough insulin release. With elevated insulin levels we have things like diabetic retinopathy developing so 20% of newly diagnosed diabetics have DR.
    Two studies showed glucose levels over 85 are directly related to elevated risk of dementia.
    I used to be prediabetic, but my A1C is now 5.2 and my c-peptide 1,2.
    My fasting glucose is 92-102, Both 72 hour fasts got it down to 72 and 75.
    The work of Dr. Kraft is really valuable.
    https://thefastingmethod.com/understanding-joseph-kraft-diabetes-in-situ-t2d-24/

  17. I found an eating window with berberine (and an assortment of fasting-mimicking supps) to be tough to marry with resistance exercise. I’ve settled on a feast/fast regime over a 5-6 day cycle, with feasting on exercise days and the day after exercise. Works as far as appearances go, but I’m now questioning the peak-glucose effects of feasting (mostly tuna/eggs/fruit). I’m also wondering if berberine post-fast will stall repair and recovery?

  18. Muscle mass could also be an important factor. Low calorie and low protein is not conducive to adding or maintaining muscle mass no matter how much exercise is done. This could be a common factor between the skinny and the skinny fat who might have glucose metabolism problems.

  19. Diabetes is an underlying metabolic disorder characterized by hyperglycemia, impaired immunity, end organ damage, and chronic inflammation. Note that hyperglycemia does not cause diabetes, but is rather a symptom of it. If hyperglycemia alone was the major problem with the disease, then strict glycemic control would be of great benefit- but it is Not. In fact, a Cochrane meta analysis of 25 studies looking at the impact of strictly reducing HbA1C from 8 to 6.5 to 7 demonstrated no reduction in cardiovascular disease, end organ damage, or mortality rates. None. There was, however, an increase in life threatening hypoglycemia!

    Furthermore, there is such an intimate relationship between diabetes and obesity that many of us refer to it as diabesity. The vast majority of the time, weight loss will cure diabetes. It will resolve all of the complications of the disease itself, not just blood sugar levels ( like metformin does).

    Josh is not diabetic or obese. No reason to worry.

  20. Is the basic idea for optimized systemic health to keep blood glucose, insulin, leptin, and mTOR low? If so, that would seem to involve eating low sugar, low protein, and high fat (as per Valter Longo, Rosedale, and others). Also to pulse dose a rapalog such as rapamycin to target the growth/aging control mechanism. Is this the formula most of you would do? Thanks.

      • Yes that is a legitimate concern. Perhaps there is an adequate amount of protein to prevent muscle wasting without overly elevating TOR. One gram of protein per kg of ideal body weight may be a reasonable estimate.

        • I go with at least 1.2 grams of protein per kg of body weight, but I do resistance exercise. Also, I came across papers that suggested that people 65+ should take 30% more protein than the younger folks.

    • Interesting thoughts:

      I mentioned this in another comment thread but it is relevant to this article.

      ……….So, There is an African tribe known as the Maasai.

      They manage to stay slim and healthy despite a high fat diet. The article at the link below states that they drink a lot of milk, but walk a great deal.

      Even the few tribesman with a higher BMI do not become pre-diabetic.

      Here is a link to an article about the Maasai, and portions of the Article:

      https://sciencenordic.com/denmark-diseases-exercise/the-maasai-keep-healthy-despite-a-high-fat-diet/1376530

      “The Maasai in East Africa consume a high-fat diet, but they don’t seem to suffer from lifestyle diseases. Scientists have now discovered that the Maasai move with a surprisingly low intensity. ”

      More..

      “Surprisingly, the measurements show that the good health of the Maasai is not due to intense physical activity all day long. It seems that moderate but constant physical activity explains the health difference between them and Westerners.”

      More..

      “”A study of overweight Maasai (with a BMI over 25) showed that they had a normal, healthy level of insulin. Few overweight Maasai showed signs of having moved into the pre-diabetes stage.”

      • It’s not the exercise that makes the difference. It is the type of fat they consume. The Western world has fallen for the marketing hype that unsaturated fats are healthy. It is the opposite.

        • More likely the Masaai have developed a certain degree of genetic protection over the course of time. The Bamboo lemur’s daily intake of bamboo leaves contains enough cyanide to kill 5 adult men, yet the Bamboo lemur shows no signs of cyanide poisoning whatsoever.

          • Hi Ole:

            Yes, perhaps genetics is the cause.

            No studies investigating that connection have yet been conducted. The reason for the seeming paradox, has not yet been definitively determined.

            The article mentioned that future studies will be researching that connection, as well as other possibilities, in order to acquire more definitive information.

      • BMI is not a reliable indicator of metabolic health because it doesn’t distinguish between fat and muscle. The amount of visceral fat is far more reliable. Waist to hip ratio measures this.

    • Actually I think Longo recommends more protein for older people.

      One particular problem for older people who are too thin is there are not much reserves to draw on in case of illness. Perhaps there is some advantage to some modest weight gain – nothing like obesity – during aging. At any rate, probably a balanced approach is best. That is pretty much where I have settled at any rate.

  21. There is so much that is unknown and dare I say based on beliefs? The mice/rats always know what is expected and comply. Sorry, new-agey but i think true [and much of research-is not even double blind]
    Example, with a bit of meditation you will experience a secretion coming down from the roof of your mouth. Mildly sweet very pleasant tasting. Not a big deal, prob the next normal for humanity: currently a very well known phenomena in the East [amritha] Definitely linked to the endocrine system [pineal pituitary?: not sure no scientific research as been done—-other than locking a few folks that have that secretion in a room for weeks without eating and apparently it has nutritional qualities]. At any rate conventional science doesn’t even take such into their equation, So we end up with such limited views re supplements etc. And finances are so often at the bottom of most research/studies. Anyway fair to say….relax….re this ones and that ones views on what must be done re anti-aging. Find your way…enjoy :).

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