Can metformin reverse Inflammatory Hysteresis? My 105-day trial..

Metformin: A longevity drug?

The following is based not only on my own general research and drug trial, but also on nearly 2 years’ of client biometric & performance data gathered through Ultimate Fitness, with some clients taking metformin themselves in order to manage their blood sugars prior to and during training with UF. Admittedly the data set is relatively small but some trends regarding inflammation and inflammatory hysteresis are becoming clear, as I have described below. I hope that this provides inspiration and further discussion for others involved with high intensity strength training as well as health care professionals to consider the long-term effects of a poor diet on chronic systemic inflammation, physical performance in the gym, insulin resistance in general and the various methods by which reversal of inflammatory hysteresis may be achieved in order to maintain optimal health-span for their clients and or patients.

What is Inflammation?

“What is Inflammation? Frankly, it might be easier to explain the meaning of life”. This quote comes from Phinney & Volek’s book, “The Art & Science of Low Carb Living”. For me, a non-specialist in the field, I see inflammation somewhat more fundamentally. I see the human body as a living, thermodynamic engine, one that operates in a similar fashion to that of the internal combustion engine. The only difference between a human and a car engine is that the human is a living organism and the car is not. More critically, you, or any other living organism for that matter have the ability to repair yourself, something a car engine can’t do. Apart from that, respiration [living organisms] is the equivalent of combustion [car engines, etc] – “fuel in” gives you “performance out”, plus combustion by-products such as CO2 & water. We all know that you need to put the correct fuel in the tank of your car; you can’t run a diesel engine on petrol or vice versa and this also applies to humans. If you eat the wrong food you’re going to damage “the engine” and the longer you continue to do so, the greater the damage will be. Hence, for me, systemic inflammation is a sign of incomplete combustion due to “incorrect fuel” input.

Delve into any biochemistry text book and if you look up the term “inflammation” you’re going to be deluged with a whole list of cellular and sub-cellular indicators such as macrophages, inflammogens, C-reactive proteins, peptides, interleukins, etc., etc. These are what I call “laboratory indicators”, offer way too much detail and don’t allow us to measure inflammation in simple, practical terms that we can all understand & relate to. Instead, I prefer to consider inflammation using 3 very simple and easy to obtain indicators.

The first is a straightforward waist circumference measurement, as measured around the navel. This allows us to calculate the waist/ height [w/h] ratio, a very easy and practical risk marker for all of the “Big 5” diseases of civilization [CVD, stroke, cancer, diabetes, dementia] behind which inflammation firmly sits. A w/h ratio greater than 0.5 tells us a person is potentially chronically inflamed, regardless of their weight. The second sign is performance in the gym. Through meticulous recording of performance data over time, it has become clear that a general plateau in performance is commonly associated with a plateau in weight loss AND w/h > 0.5. It takes more time and effort to break such plateaus, if they can be broken at all, with more intense training over a longer period of time compared to an “non-inflamed” person, plus there are “over-training” risks using this kind of approach. The third and final indirect measurement of inflammation is insulin resistance [IR]. One of the most important and earliest signs of systemic inflammation is your level of insulin resistance. Being IR, even mildly, is directly correlated to long-term chronic inflammation. The gold standard for measuring IR is via the euglycemic clamp method, where the subject’s plasma insulin concentration is acutely raised and maintained by a continuous infusion of insulin. This requires trained medical supervision and is not without risk due to the possibility of hypoglycaemia. The other method for measuring IR is via a calculation known as the Homeostatic Model Assessment of Insulin Resistance or HOMA-IR, easily determined via two simple blood tests. There are currently 2 models for HOMA-IR assessment, appropriately named HOMA1 & HOMA2, employing non-linear mathematical solutions. HOMA2 is considered to be superior to HOMA1 in terms of accuracy but requires software and a PC to run it on. HOMA1 is a more practical, back-of-the-envelope solution and is the one I prefer to use. Both require fasting insulin & blood sugar levels. Based on either of these models, a HOMA-IR score greater than 1.0 is an indication of IR. Depending on who you ask, anything above 3.0 is an indication of diabetes mellitus. In other words, if your HOMA-IR score is <1.0, you are considered to be insulin sensitive i.e. your body is highly efficient at managing blood glucose levels and only a small amount of insulin is required to keep them in check. I can find no reason, either physiologically or from an evolutionary perspective as to why it would be considered a “good thing” to be even slightly insulin resistant. Insulin is after all a hormone, just like any other. Would you consider it normal to be resistant to other hormones such as testosterone, adrenalin, thyroxine, etc? They are all there to do a vital job.

I’m not going to speculate in this post what the “correct diet” for any individual should be in terms of actual macros and food types best suited to systemic low inflammation, I did that here, but I will say this: If your diet is correct for you, then from an inflammatory perspective, you should be showing no outward or inward signs of systemic inflammation [incomplete combustion], principally elevated HOMA-IR & waist/ height ratio . If your car wasn’t running properly you’d probably do something about it pretty quickly. You should treat your body in the same way.

This leads us to the next question: Is it possible to have a w/h ratio greater than 0.50 yet have a HOMA-IR score less than 1.0? What about the opposite situation; is it possible to have a thin waist but still be IR with HOMA-IR > 1.0? In both cases the answer is probably yes. Just consider the case of the powerlifter, famed for their thick waists, for the former, and the Indian “skinny” diabetic for the latter. Who has the greatest systemic inflammation? If we consider w/h or HOMA-IR individually we may be fooled into getting the wrong answer! In order to overcome this it is essential that we take both into consideration by what I propose as the inflammatory index, or simply the product of w/h & HOMA-IR. For the non-inflamed individual this would be [w/h = 0.5] x [HOMA-IR = 1.0] = 0.5 or less. Anything above this value would be an indicator of systemic inflammation. Using our prior examples, the powerlifter would have a w/h of, say, 0.56 and a HOMA-IR of 0.90 = 0.50 inflammatory index. The skinny diabetic on the other hand has a w/h of 0.45 but a HOMA-IR of 3.8 = 1.71 inflammatory index! Our instincts tell us that it is the seemingly bigger [fatter?] person who should be carrying the greater systemic inflammation when in fact the opposite is true.

What is Inflammatory Hysteresis?

Dietary Model of Inflammatory Hysteresis

Consider the above graphic, the “Dietary Model of Inflammatory Hysteresis”. The x-axis is labelled “diet type” and refers to diet in terms of its systemic inflammatory effects on the body, with a High Inflammation [HI] diet to the left, reducing to a Low Inflammation [LI] diet on the right. The y-axis is labelled “Systemic Inflammation” as measured by the inflammatory index [II], introduced earlier.

Let us say that a person starts out on a HI Diet at point A on the graph and, as time goes by, assuming all other things remain equal, their II will start to increase upwards towards point B. At this point they decide they’ve had enough of being constantly sick & inflamed and decide to go onto a LI Diet. What happens to their Inflammatory Index? Of course it starts to fall over time but it is the manner in which it falls which decides where they will finally end up on the chart. For the person who can completely reverse their elevated II score they will proceed from B down the inflammation curve to D, the point at which II = 0.50 or below, back to where they should always have been with little or no permanent damage done. However, for the person who is unable to completely reverse their II, their path down the inflammation curve is different i.e. point B to point C where they get stuck! Some temporary or permanent damage to the endocrine system has occurred. This is known as inflammatory hysteresis or metabolic memory. This same effect applies to any other diet in-between HI & LI on the x-axis e.g. point X to point Y. With no hysteresis, the person moves from Y to D on the graph when they change to a LI diet. For the person with temporary or permanent hysteresis they get stuck at point C again, just like in our previous example.

Inflammatory Hysteresis Risk Groups

The following questions now arise. What kind of people get stuck at point C on the above graph? What is it about their physiology and genetics that keeps them there when others are able to quickly and easily revert to a normalized level of systemic inflammation? Further, is this a permanent or temporary situation and can it be fully reversed given more time, selective combinations of further training, dietary modifications, or even medical intervention using drugs?

My Client A story is typical of someone who is stuck at point C and I have witnessed others. When she started LIHF & strength training, her weight rapidly fell. Within 6-8 months she had lost around 23 kg and there she has remained ever since, despite nearly 18 months of highly intense strength training using various protocols & strategies, plus a strict LIHF diet, in this case mainly meat & water. Critically, her HOMA-IR score has come down from 3.4 to 1.4, this despite having a “normal” long-term blood sugar reading [HbA1c] of 5.8%. I am not a doctor but given her elevated HOMA-IR score plus the various symptoms she was experiencing on a conventional, western HI diet, such as fatigue, swollen ankles, elbow and upper joint pain [including severely restricted movement], GERD, morning coughs and high blood pressure, it’s hard not to imagine that she wasn’t already diabetic! The only thing missing from this picture was a HbA1c reading of over 6.0 mmol/L, the common cut-off for suspecting a patient has diabetes. [With the exception of some slight movement restriction in the right elbow, all of these symptoms have now resolved nicely thanks to an LI diet and a structured strength training program]. Also her w/h ratio has come down from 0.65 to 0.51 and, like her weight, has remained there ever since. This gives her an II of 0.51 x 1.4 = 0.71, not quite where she should be. Her II “delta” [0.71 – 0.50] of 0.21 is her level of inflammatory hysteresis [IH], the difference between point C where she is now, and point D where she ideally should be. We both know that she needs to lose another 5-6kg in weight for this to happen. The only question that remains is how?

It is my belief that Client A falls into all of the epigenetic high risk groups susceptible to IH, listed below:-

  • Nordic/ Celtic genealogy
  • Peri/ post-menopausal
  • Long-term HI diet imparting permanent endocrine system damage

Note that this list is by no means exhaustive and only addresses epigenetic risk factors. It forms part of my research and personal client heuristics so far. No doubt there are other high risk groups around the world. These just happen to be the ones I have come into contact with through my work at Ultimate Fitness. With the exception of menopausal risk, I believe these apply equally to men.

Other IH risk groups related to lifestyle rather than epigenetics, assuming LI diet already in place:-

  • Previous history of long-term calorific restriction with low nutrient density, plus aggressive high to low cycling thereof e.g. Indian “skinny” diabetics
  • Over-training or insufficient recovery
  • Over 40, with lifetime HI diet
  • Shift working and frequent time-zone shifts
  • Stress

Reversing Inflammatory Hysteresis

Client A is no stranger to exercise or working with a personal trainer, PT. She worked with a “traditional” PT several years ago, working out for several hours a week in the gym. It did produce results; she lost weight and gained fitness but she found this intense level of exercise unsustainable and gave up. Within a year or so she had regained all her weight and more! Interestingly, when she lost weight, it came down to exactly where it is now. However, the crucial difference between then and now is that client A has a much better understanding of what is going on. She now realizes that diet is the primary driver in moving down the inflammation curve and not exercise. She realizes that the type of exercise you undertake is also critical – it needs to be intense yet enjoyable and, crucially, sustainable over the long term. Having read Body by Science, she also understands that strength training [emptying muscle glycogen, thereby increasing insulin sensitivity, IS] is superior to traditional “aerobic” activity [cycling liver glycogen with little or no increase in IS, at least not for an equivalent amount of time spent in the gym]. Knowing that she has IH has kept her motivated to keep going and to try new protocols and training schedules, whilst keeping a strict eye on maintaining a LI diet and without giving in to the temptation to over-train again! Critically, unlike the last time she employed a PT, she has not gained any of the weight back that she has already lost.

For me as her PT, there are only 2 questions left to answer for client A: Is her IH permanent or temporary [remission] and, if temporary, what can be done to reverse it completely [cure]?

I believe there are only 4 things a person who has IH can do do reverse it, namely:

  • Some form of intermittent fasting
  • Moving to a strict, ultra-low inflammation diet, if not already there e.g. meat & water.
  • Short-term, high-intensity training cycle “compression” & “expansion” employing various training protocols.
  • Drug therapy using metformin.

The use of metformin should be considered as an absolute last resort, only when the first three have failed. There is also the question of whether or not training whilst taking metformin may be counter productive [discussed below].

What is metformin & can it reverse Inflammatory Hysteresis?

First discovered in 1922, the drug metformin has been used as an oral anti-diabetic treatment for over 60 yrs and has become the world’s most widely prescribed antidiabetic medication. It is also one of the world’s cheapest drugs. In 1950, Filipino physician Eusebio Y. Garcia used metformin to treat influenza. He noted that the medication “lowered blood sugar to the minimum physiological limit” and that it was not toxic. In recent years, attention has turned to the use of metformin in further, so called “off-label” uses such as polycystic ovary syndrome [PCOS], non-alcoholic fatty liver disease [NAFLD], premature puberty and cancer. Interest has now also spread from the treatment of disease to the use of metformin as a “longevity drug”; metformin may influence metabolic and cellular processes associated with the development of age-related conditions, such as inflammation, oxidative damage, diminished autophagy, cell senescence and apoptosis. One ongoing study, the Metformin in Longevity Study [MILES], has as its declared aim to see whether “metformin will restore the gene expression profile of older adults with impaired glucose tolerance [IGT] to that of young healthy subjects” [reversal of inflammatory hysteresis].

Metformin & Exercise

There is some evidence to suggest that administering metformin during exercise may be counterproductive due to the fact it inhibits skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). This may or may not be the case and I suspect that individual responses will vary considerably. However, does it really matter if gym performance goes down slightly if all the time IH is being reversed? If the combination is working from an IH perspective then who cares? Once IH has been reversed and metformin dosing is over, strength performance should return at least to where it was before, if not better. Besides, if there’s any doubt, then training could even be suspended for a while in order to allow the metformin to take full effect. This is such a new concept that it is impossible to say at this stage what the best approach should be, at least until further trials and testing have taken place.

The Trial

I decided that only way to test my hypotheses concerning metformin and its effects on on inflammatory hysteresis would be to try it out on myself first before recommending it to any of my clients.

How and where did I get metformin?

Metformin, in this part of the world at least, remains a prescription drug. My prescription was for limited trial purposes only and I was able to collect it from my local pharmacy.

Risks

Like any drug, metformin carries potential side-effects but these are now well-known. Metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs with the most common adverse effects being diarrhea, cramps, nausea, vomiting and increased flatulence. The most serious potential side effect of metformin use is lactic acidosis. However, this complication is very rare, and the vast majority of these cases seem to be related to co-morbid conditions such as impaired liver or kidney function rather than to the metformin itself. Another potential side effect is a lowering of Vitamin B12 levels. These were all listed and discussed at length in a pamphlet that came with the prescription.

Trial Protocol & Preliminaries

The trial lasted 105 days from 18/072018 to 31/10/2018 with a 30 day follow-up assessment. My metformin prescription came in 500mg tablets and I decided to start off by taking 2x tablets/ day, just to see if there would be any adverse effects on my digestive system. Within the first two weeks it was obvious that there were no issues and so I decided to increase to “full dose” for the rest of the trial i.e. 3x 500mg/ day, taken at 08:00, 14:00 & 20:00 each day. A full set of bloods was taken immediately prior to the start of the trial and again every 30 days during the course of the trial itself. In addition, a final set of bloods was taken 30 days after the end of the trial; “30 day, trial follow-up”, see below. I also measured fasting blood sugars and weight almost on a daily basis throughout, the results of which are also presented below. I kept extensive notes about diet and general well-being. My diet was almost exclusively meat & water except for the last 30 days or so when I started to incorporate some berries. Drinks were restricted to water & coffee only, no alcohol. I maintained my training program throughout, namely body-weight callisthenics, no more than 15-30 mins/ week. Around the middle of the trial, I spent a short hiking holiday in Lapland, surviving on pemmican, water, some dark chocolate and foraged berries.

Results

The trial results are given below. The laboratory blood test biometrics I measured were the same as those that I have always done throughout this blog with the addition of vitamin B12.

Biometrics

Remarks

As soon as I started taking metformin, it was obvious that something was going on. Almost immediately I experienced a feeling of complete calm and loss of anxiety. I’m certain this wasn’t psychosomatic either. I felt very relaxed. At various times during the course of the trial, I experienced many of the side effects listed above, including bedtime cramps and strong feelings of nausea & heartburn, but they were relatively rare and short in duration. They almost always occurred at night, just before going to bed and after taking the 20:00 tablet.

Apart from that, life and my training carried on pretty much as normal. I noticed towards the middle of the trial that my appetite started to fall off, together with my weight. It seemed to me that my training performance was also dipping slightly. However, since all my training is based around bodyweight exercises, this is very hard to gauge accurately and is a highly subjective observation.

30 day follow-up

I took some blood tests at the end of the main trial, immediately prior to stopping the metformin altogether, and then continued with my notes and observations for another 30 days after that, before taking a final set of bloods to conclude the trial altogether. Weight remained exactly the same throughout the 30 days and there were no significant remarks concerning fs-Gluc other than the fact that all readings returned to their usual, pre-trial elevated values, see above.

Summary

With a HOMA-IR score of 0.80 and an II of 0.36 going into the trial, I was never going to be a prime candidate for IH reversal since I was already there, in fact well below “point D”! Nevertheless, it was interesting to see whether or not II could be safely driven lower still using metformin, as well as what the general effects of relatively high doses would be on an otherwise healthy individual. II did indeed fall steadily throughout the trial, returning to almost where it was at the start, after the 30 day follow-up. Weight also fell steadily. Some of it returned after the 30 day follow-up but even today, nearly 3 months after the end of the trial, I remain 3-4kg lighter than at the start. Note that the big fall in weight around the middle of the trial was due to my Lapland hiking trip, mentioned above. CRP also fell, to some of the lowest levels I’ve ever recorded, the lowest of all being at the end of the follow-up period. There were clearly no issues with vitamin B12 either which actually increased during the trial, remaining well within suggested limits. HbA1c also fell but lipids remained more or less unchanged.

Of particular interest to me were my daily fasting blood glucose readings. Ever since I started reading BG back in 2012, I have had high fasting levels, almost always greater than 6.0 mmol/L. However, since my HbA1c levels have always been normal, I’ve never really been concerned about it, putting it down to the well-known “dawn effect”. The above chart shows the seemingly random set of readings I took. The only noteworthy items for me are the facts that I saw some of the lowest fs-Gluc readings I have ever taken, the lowest of which was 4.8 mmol/L, and that towards the end of the trial, fs-Gluc readings returned to their higher pre-trial levels. Apart from that, there was a great deal of variation from which it is impossible to draw any further conclusions.

Did I reverse any IH, either temporarily or permanently?

I think so. Even though my II score is only marginally less than it was going into the trial it is still lower, plus my weight and waist came down significantly and show no signs of returning despite the fact that I have now started incorporating some carbs back into my diet in the form of blueberries. Is it temporary or permanent? Only time will tell but three months on from the trial and it’s looking pretty permanent to me.

Conclusions

Like any drug, long-term metformin use may reduce its efficacy. For those with stubborn, hard-to-shift IH there may be some merit in cycling both the period & the dose if a first attempt fails. More research and data are required in order to determine what the best approach would be but I suspect there will be large individual variations. It really is just a case of trying and seeing what works best. One of the trial objectives was to demonstrate that metformin is a perfectly safe drug, even for seemingly healthy individuals. Three months after the end of the trial and I have experienced no lasting side-effects whatsoever. The other objective was to send a message to those reading this post.

If you are a healthcare professional:

Take systemic inflammation, insulin resistance and their long-term effects seriously. Don’t be fooled by normal-looking HbA1c values. Consider whether or not your patient falls into one of the high risk groups listed above. Measuring HOMA-IR is quick, easy and cheap to do. Problems relating to IR can be spotted upstream, way before a formal diagnosis of diabetes mellitus, when permanent damage [IH] may have already occurred. Encourage your patients to undertake a formal course of high intensity strength training as well as making appropriate dietary changes in order to achieve a low inflammation diet. If all this fails then consider using metformin. Despite all of these measures, there will no doubt be individuals for whom this will not work completely. Like Client A, they will get stuck at “point C”, possibly forever. This is NOT a failure, it is simply remission rather than a cure. Remember that without dietary changes and strength training they wouldn’t be at point C in the first place and that going back up the inflammation curve, for whatever reason, is not an option! Patients like these should be encouraged to manage their condition as best they can through diet, lifestyle and lifelong strength training.

If you are involved in the fitness and PT industry:

Learn more about IR and weight-loss. Regularly test all your clients for IR using HOMA-IR, no matter how fit and healthy you think they are! Accept that a poor diet will produce poor results in the gym and that no amount of training of any kind will lead to permanent weight loss and low systemic inflammation. Don’t imply that your client is lazy or doing the wrong things in the gym when they clearly have “point C” IH. Focus on high intensity strength training rather than “aerobics” in order to increase insulin sensitivity. Work with your client and their doctor to produce an effective diet & training program that works for them and, most importantly, one that is fun and sustainable over the long-term. For people with stubborn IH, focus on undoing this first before concentrating on getting meaningful progress in the gym. If your client is on metformin, accept that there may be a dip in performance in the gym while they are taking it but that this should return, or even improve, once they are off it and full IH reversal has occurred.

To everyone else:

Find out your HOMA-IR score and II. Talk to your doctor if you have to, especially if you think you may be in one of the high risk groups mentioned above. If you don’t get a sympathetic ear then take matters into your own hands by going to your nearest lab and getting tested yourself. If you have a high II index then do something about it by making appropriate lifestyle & dietary changes. Don’t run your “car engine” on the wrong fuel! Start a structured strength training program and make it a full part of your life. If you are insulin resistant, even slightly, take it seriously, as seriously as you would any other disease and tell you friends and family about it. Explain to them the measures you are taking and why they will be a permanent feature of your life from now on. If going onto a LI diet and strength training fails to get you to “point D” then talk to your doctor about going onto metformin for a short while. If all this fails then you may have to accept and live with some IH for the rest of your life. This is NOT a failure, it’s just a form of remission that you will have to manage as best you can using all the knowledge and techniques described above and perhaps even some of your own!

Proposal for a follow-up “low-dose” trial

I have a small amount of unused metformin tablets left on my original prescription. Rather than going to waste, I’m proposing a 100 day, “low-dose” follow-up trial later this year.

References and further reading:

  • Use and Abuse of HOMA Modeling: http://care.diabetesjournals.org/content/27/6/1487
  • Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults: https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
  • HOMA-IR calculator: https://www.mdcalc.com/homa-ir-homeostatic-model-assessment-insulin-resistance
  • Metformin: An Old Drug with New Applications: https://www.mdpi.com/1422-0067/19/10/2863/htm
  • Menopause Modifies the Association of Leukocyte Telomere Length with Insulin Resistance and Inflammation: https://academic.oup.com/jcem/article/91/2/635/2843471
  • The “Metabolic Memory” Theory and the Early Treatment of Hyperglycemia in Prevention of Diabetic Complications: https://www.mdpi.com/2072-6643/9/5/437/htm
  • Waist-to-height ratio as an indicator of ‘early health risk’: https://bmjopen.bmj.com/content/6/3/e010159
  • “I’m slim so why am I at risk of diabetes?”- BBC: https://www.bbc.com/news/magazine-35280028
  • Metformin in Longevity Study (MILES): https://clinicaltrials.gov/ct2/show/NCT02432287
  • REDUCTION IN THE INCIDENCE OF TYPE 2 DIABETES WITH LIFESTYLE INTERVENTION OR METFORMIN: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1370926/
  • How an 1836 Famine Altered the Genes of Children Born Decades Later: https://io9.gizmodo.com/how-an-1836-famine-altered-the-genes-of-children-born-d-1200001177
  • Haemochromatosis ‘bigger threat than we thought’: https://www.bbc.com/news/uk-england-devon-46891782
  • Night-Shift Work May Impair Glucose Tolerance: https://www.diabetesselfmanagement.com/blog/night-shift-work-may-impair-glucose-tolerance/
  • Can stress cause type 2 diabetes? https://www.diabetesaustralia.com.au/news/13921?type=articles
  • Metformin and cancer: An existing drug for cancer prevention and therapy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772929/

2 thoughts on “Can metformin reverse Inflammatory Hysteresis? My 105-day trial..

  1. So you tested Metformin by changing your diet? Yeah, that’s not science. What else did you do differently?

  2. As somene who has elevated morning blood sugar readings and is trying t be ‘low carb” and having read about the Newcastle diet I wonder whether a short trial of Metformin with a low carb diet should be investigated as a way of accelerating newly diagnosed Type 2 diabetics into remission?

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