#1

I frequently see fasting blood glucose (FBG) of between 140-180 (average would be ~136). This means I’m diabetic. However, my last A1C was 5.6 (normal). Two years ago, it was 6.2 (pre-diabetic). Last year, due to low back issue I was on narcotic pain meds round-the-clock and could not stand long enough to wash my dishes.

Last July I had a hip replacement. Obesity is a risk factor so I lost 25lbs, had my hip replaced and w/in a month, all low back pain was gone. Was it the hip replacement, the weight loss, both or neither, who knows?

Over the past 4 years I had visibly and palpably lost about ½ of my thigh quadriceps. My PT person commented: You’ve a lot of fat in your muscle.

Over 6 months, doing keto, OMAD and forty days of 1-3-day fasts, I dropped another 24lbs, for total of 54 and reached “normal,” BMI. Sadly, though I expected otherwise, my FBG and my blood pressure did not change—even though all the talking heads say that keto + weight loss will reverse even diabetes and normalize my BP. Well, it did not even reverse my FBG which stubbornly stays elevated and my BP stays at 120/70 (with 3 meds!).

6 weeks ago, I started back at the gym and I am so thrilled to experience DOMS (delayed onset muscle soreness) from lifting. I want desperately to get back what I had just 5-years ago (I’m now 74).
Here is the quandary: Metformin will drop my A1C and keep me solidly in the “normal BG range.” But metformin really blunts both muscle-building and cardio improvements. I work out about 5 days a week, 45 minutes cardio + 45 minutes weight, lower body one day, upper body the next.

So, I can take metformin to good advantage in some respects, but to dis-advantage in getting my body back in shape. Or I can continue to not take metformin and hopefully gain back the fitness/muscle that I’ve lost.

Any thoughts as I’m not the only one here “on the edge,” of diabetes. Thanks.

Have any of you experience about gaining muscle while on metformin?

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#2

I wonder if the other medications for high BG might be workable (like acarbose or canagliflozin, etc.) rather than metformin, in that they don’t seem to have the same impact on muscle growth (and Vo2Max improvement), that meformin offers.

The recent talk by Adam Konopka really drove home the issues associated with metformin and exercise… and they are definitely not good: Dr. Adam Konopka, from UW-Madison, "Can rapamycin potentiate the health benefits of exercise in aged subjects?"

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#3

Thanks admin. All these (acarbose, canagliflozion) are new and unknown to me. I’ll look into them.

#4

You might also want to look at adding galantamine, as is described in this new research: Rejuvenate Biomed 的药物组合（二甲双胍和加兰他敏）在 1b 期试验中显示出治疗肌肉减少症的前景

We’ve discussed acarbose and canagliflozin (SGLT2 inhibitors) a lot here. See these threads:

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#5

*“Acarbose (and canagliflozin) are working by eliminating the huge peak of glucose you get after you eat a meal with a lot of starch in it.”

Darn, I don’t eat starch. I keep my net carbs down below 20g a day and have for the past 9 months. My A1c is on the border (but still in the normal range). If I were to eat any starches such as wheat/sugar I’d throw peaks. Using a CGM my BG is flat as a pancake, with two exceptions over the past 9 months. One was a chocolate covered marshmallow Easter egg that popped me to 200 and I can’t remember the other but it popped me to about 160. (I did both just to see how carbs effected me)

Btw, I’m extremely insulin sensitive–having reversed from insulin resistant to very sensitive over 7 months.

Metformin will work, perhaps I’ll just work on muscle-cardio improvement for 16 weeks then go on Metformin. Metformin blunts the improvment but I don’t think it reverses muscle/cardio response.

Since I live so keto’ish it seems that neither would help me a lot…?

#6

Yes - you are right there. Perhaps the galantamine / metformin approach would be better for you?

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#7

@Justin, I started talking some classes through Optimizing Nutrition last year that have been very helpful for fine tuning things towards building muscle and getting a handle on my borderline FBG levels. I just felt my BG was often a bit higher than it should be considering I was eating keto. The Data Driven Fasting challenge/class was particularly eye opening and reasonably priced. I’m not affiliated with them other than being a happy customer. I learned in the course that although fat doesn’t spike glucose the way carbs do it can still keep glucose levels elevated for longer and that’s what was happening to me. There’s also the possibility that you are simply eating too late and you have excess fuel circulating when you wake up. Here’s the article that got me interested in the classes.

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#8

Hello Mr RapAdmin,
It seems you know a lot about this topic and I’m just learning about what is out there… I’m not at the point of putting the pieces together though. This post has me thinking… so, my deal is I live a very healthy lifestyle (wfpb and rarely cheat with something yummy, I don’t have enough muscle, tiny bones, am slim, I have a super high heart calcium score so i am at high risk for CVD… you get the picture… in wearing a cgm, even though my bloodwork is great, i saw that even with my uber good diet, i get huge spikes. Justin mentioned 200 with an Easter treat… i get that with a bowl of berries and unsweetened vegan yogurt!! And because i think I’ve learned (from podcasts!) that high spikes might contribute to heart disease, I’m not on metformin so i can spike like ‘normal’ people… it’s working for me, but i see you all mentioning alternatives to metformin… based on what you are hearing, should i be considering something else?? THANK YOU!

#9

Apparently, you can reduce the adverse exercise response to metformin. I have never had a significant issue with metformin reducing my exercise benefits, but if that worries someone they can just add galantamine to their stack.
Too bad galantamine is now a prescription medicine in the U.S. I used to get it from Amazon. I just quizzed Jagdish and he won’t supply it because it is considered an anti-depressant drug that is forbidden to export from India without a prescription.
I got the same response from Jagdish when I asked about trazodone.
However, I found several other shippers that would seemingly ignore the restriction and was able to get trazodone, which I was using to reduce sleep onset time.
The prices quoted for galantamine are higher than I expected and are not much cheaper than I previously paid on Amazon ~28 cents/4mg/tablet.

As I said before I do like the “Dream Weaver” qualities of galatamine.
“The combination drug metformin and galantamine (RJx-01) is under development for the treatment of sarcopenia, disuse-induced muscle atrophy and unspecified indications”

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#10

Much of what you say makes sense, and so to does much of what all the talking heads that promote keto, carnivore, fasting and so on.

However, it’s not my eating late, as not eating for 4 days only drops my BG to about 90, no lower and that’s a ketone level at 6! (Using a ketone device, not urine). It’s definitely the “dawn phenomenon,” because I can pull a BG at 11am, see 160, eat three eggs, and three sausages and poof, two hours later I’m down to 122.

Optimizing nutrition seems to point solidly at insulin resistance, therefore high basal insulin, but get this, I do NOT have high basal insulin, in fact I have very low:

I was actually shocked to see such sensitivity to insulin but then I had pretty much ignored that for 8 months I’ve lived on zero to 12 net carbs per day and did clean water fasting of a total of 40-days (mostly 2-day fasts, w/ some 1, 3 &4-day fasts). I was actually doing the fasting more for autophagy than weight loss but I did go from obese to normal, from 42” Levis to 34”.

And all the way down, my morning, 12-hour FBG did not budge, nor did my BP.
Back when I was age 50 I started working at a hospital as adult ICU nurse, as horrid and stressful job as exists. I gained 35lbs and my BP went through the roof, so I quit and moved into Occupational Health (factory nursing) and loved it. I lost the weight over 3 months and my BP plummeted. This time I lost almost 2x and my BP did not move a bit. Plus, I now do 270 minutes of cardio at 70% w/ excursions to 85% and do 5 hours of lifting. And, no change in morning BG (still usually 135-170 allowing 12-hours from prior meal). My theory is that it’s my age = 73, about to turn 74.

I did become somewhat cachectic and I’m hoping that when I get back the 20lbs of lost muscle that may lower BG and BP.

I did use a CGM and metformin did help, but metformin devastates both aerobic gains and physical muscle gains. RapAdmin’s galantamine/metformin might be the way to go. Canagliflozin or Acarbose is not the way for me because I rarely eat any starch or sugars.

I have come across others who have proven sensitive to insulin, who have low basal insulin and yet who have high to very high (150-180, high for a non-diabetic) morning BG.

The fix for me lately is keep my BG flat as a pancake and even w/ high morning BG, later in the day it’ll drop to 110 giving me an A1C that is normal, so ~122 average. Acceptable, but not ideal.

I think in the meantime I’ll forgo the metformin as being 74 does not make me a fast muscle builder as it is. We’ll see what happens in a few months.

I may start doing metformin for a few days, then off for a day. Then do heavy workouts, perhaps that is an option.

I just wonder if I’m some sort of subset, perhaps “older,” who knows?

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#11

A “normal” 2-hour postprandial BG level is 145 or less. When I was 25 my father died of diabetes and I played w/ his BG meter. It made do difference as to what I ate, cake, sugar cookies… my BG would rise to 110 - 120 then drop back to 85. That is normal. My shooting to 200

It would seem that either your cells have become very resistant to insulin uptake, or that you (as am I) are moving to that line which is called diabetes. If I eat 6-ounces of red raspberries I get less than a 20-point bounce, so if I was at 110, it’ll rise to 130 and then an hour later drop back.

Consider doing a dexascan to quantify your bone density + your lean tissue mass. You may just be lean and slim, or you may be losing muscle mass–it would be nice to know.

And possibly consider doing the insulin sensitivity test that I did shown above, it cost me $70 and I think was worth it.

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#12

Thanks for the reply!

My doc has done the typical blood work and says I’m fine. He doesn’t feel I’m pre diabetes… but, that also doesn’t mean he’s right! I’ll check out the one you mentioned.

Argh, I’ve had a dexa and I’m skinny fat :). I’m 5’5” and 109 pounds (that sounds way too thin, but i have a tiny frame and don’t look scary, i promise :).

I have osteopenia (see: tiny bones) and am aprox 29-30% fat. My gyn put me on hrt almost a year ago because her opinion was there is no way I’m going to build muscle and bone if I’m not on anything. Again, no idea if she is right either :).

On metformin, if i eat carefully, i usually stay below 150 (lentil pasta, no rice, etc). Having said that, I’m going to nyc next week and I will be eating plenty of sugar and will not be wearing a cgm!!!

It does stink when you are doing most everything right but your genes have other plans! (I should do more exercise, so I’m definitely not doing everything right)

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#13

There’s so much benefit to exercise, losing weight, and adding muscle mass. Get to the gym and explore different medications for your diabetes/pre-diabetes.

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#14

You may want to switch from Metformin to a flozin like dapagliflozin or acarbose. Or both.

They’re also both synergistic with Metformin btw.

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#15

Very intersting findings comparing metformins mod of action for decreased muscle mass vs berberine. When it comes to liver pancreas gut microbes they seem to be very similar in end results. They get there thru slightly different pathways but they both lower gluconegenesis protect pancreatic beta cell function etc yada yada…

But in looking at the effects on skeletal muscle tissue research indicates that metformin increaees muscle cell myostatin sensitivity thru transcriptional regulation of myostatin via HDAC6 and FoxO3a making it’s effects more potent. Myostatin puts the breaks on muscle tissue growth and causes reduction if out of balance. Numerous studies find in metformin use decreased number of myofibers in the muscle. i.e decreased muscle mass.

Berberine on the otherhand actually downregulates the myostatin expression and the study I read showed a increaee in muscle myofiber and overall muscle mass in the muscle examined.

My thought for myself is lowering the dose of metaformin and using both with the idea (speculation) they will counter at least partially each other in effect on myostatin. Personally I take 850mg metformin QD 30min before my meal and phytosome berberine 500mg BID (1000mg total). I eat 1x per day.

But understanding the pathway used by metformin helps as you then have a target. Things that decrease or inhibut myostatin. Testosterone is the major one along with all anabolic steriods. In fact a significant amount of the positive effect it has on increaeed muscle mass comes from inhibiting myostatin as well as the upregulati9n of follistatin expression which negatively regulates myostatin (double whammy) Thisis especially true with supraphysiological concentrations/doseing. Beyond that it gives a baseline for others to research. As we age especially as we approach 50 (usually early 40s) T takes a serious nose dive along with the rest of the hormonal cocktail that starts in our hypothalmus (GH IGF and the various signaling proteins and hormones)

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a

Berberine Down-Regulated Myostatin Expression and Facilitated Metabolism via Smad Pathway in Insulin Resistant Mice

Myostatin and its Regulation: A Comprehensive Review of Myostatin Inhibiting Strategies

Its intersting that myostatin works differently in the heart muscle vs skeletal. In the former it inhibits AMPK thus preventing glucose uptake and glycolysis which is a good thing. But in the later it activates AMPK which increases glucose uptake and sensitivity.

Rapamycin also effects myostatin upgragulating it. This is notva bad thing as we want it to modulate. But it is one of the reasons I prefer and have choosen every 2wk dosing… aMPK myostatin ect need to have periods of quiet just as we treat insulin.

I think especially for those of low bodyweight and muscle mass or are concerned about keeping or increasing muscle mass it would be a good idea to once or twice a year temporarily discontinuing rapa for around 8 wks or so and do a focused high freq mtorc1 pulse specifically targeting skelatal muscle hypertrophy. I do think the rapa use along with the various other protocols we use to activate AMPK it primes/sensitizes the body making mtorc1 activation to maximize skeletal hypertrophy. We have seen this same effect in the weightlifting sports atheltic world. The best way to prime the body for best muscle gains is to first go thru a long period of fat loss low cal high output. Then follow that with a hypertrophy focused period. 8-12 wk periods work well for reasons that would drag this more off topic.

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#16

@Justin, I’ve had similar sounding high stress ICU jobs and they definitely take a toll on the body and aren’t worth it at the end of the day (or night) hahaha! I’m glad you took care of yourself got out of that type of work.
From your explanation it does sound like you would benefit from medication. I’ve had very low fasting insulin before when I was basically eating zero carb but my FBG was still technically normal even though it was higher than I thought it should be. My lipids were my main concern so it seems our situations were a bit different. You’ve also done quite a bit of fasting and I have personally never been able to fast much. Your fuel tanks are probably not overflowing as mine were. Sorry the Optimizing Nutrition suggestion wasn’t relevant to your situation. That said as a menopausal female in my 50’s I’ve found higher protein (with attention to leucine) especially at my first meal of the day and strategically timed around weight training helpful for overcoming anabolic resistance and building muscle. I’m just trying to find a balance between my longevity goals and staying strong. Best wishes and please let us know how things go for you.

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#17

I think the negative effects of metformin on muscle hypertrophy have been overstated.
I have been taking metformin for decades and I am ~83 years old.
It’s easy for me to see that I have more muscles than 90% or more of people my age.
It is even easy to see this at the gym I go to, and I don’t even work out that hard. It surprises me at the general frailty of people over the age of 70 that I see at the gym. My secret is consistency over the years.

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#18

I was surprised by how negative the results were that were presented on metformin last week by Adam Konopka. Metformin blocks not only muscle recovery, but also blocks increases in insulin sensitivity and VO2Max. See the presentation: Dr. Adam Konopka, from UW-Madison, "Can rapamycin potentiate the health benefits of exercise in aged subjects?" - #5 by RapAdmin

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#19

Another benefit of berberine is an upregulation of liver LDL receptors like pcsk9 inhibitors. Lower effect of course. I use berberine 10 days every 14 days with metformin only around my rapa dose. I don’t use berberine and metformin together.

I just learned this from Dr Twyman. Episode to come out eventually.

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#20

As an aside - the intramyocyte fat is a direct contributor to elevated blood sugar, as it blocks muscle from taking up glucose.

I’ve personally soured on Metformin, I think there are better choices to improve body composition and glycemic control. The main advantage of metformin is cost, and lots of published data around it.

It has come off my list of things I’d prescribe with a goal of longevity with no diabetes present. I’ll still use it for diabetes - but have a lot to consider as to whether to follow guidelines making it first choice, or if I deviate from these. More and more, I’m deviating from current guidelines.

It is a great drug - but the potential effect on muscle mass has to be considered. Especially in combination with Rapamycin … I just have some reservations.

Are other’s thinking similarly with their use?

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