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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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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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
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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@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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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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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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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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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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@DrFraser I agree. I only take it to combine with rapamycin. For blood sugar control and other benefits I rely on berberine and Akkermansia.
Metformin taken regularly make HIIT exercise much harder. It is probably interfering with mitochondria function and forcing my type 2 muscle fibers to burn glucose without oxygen resulting in higher lactate and hydrogen.
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For a person that does not have diabetes, I’ll agree.
For me who is teetering on the very edge of diabetes I was waiting until I start w/ rapamycin to combine with Metformin.
“Rapamycin and metformin combination treatment in a mouse model of type 2 diabetes, NONcNZO10/LtJ males, prevents hyperinsulinemia, normalizes insulin sensitivity, and reduces pathological complications of diabetes. When combined, each compound prevents the negative side effects of the other. These results are relevant for the treatment of diabetes, the optimization of current rapamycin‐based treatments, and the development of treatments for healthy aging.”
Thoughts or suggestions for someone who is clearly moving towards diabetes and doesn’t want to go there?
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Depends on other risks/conditions/contraindications - but Acarbose is one option. If you have no contraindication, an SGLT2-i is something to review with your physician (I know most people won’t get good feedback there) … but given the likelihood that these agents dually have neurocognitive decline benefit and other aging benefits … I’ve got a new appreciation for this class of medications. The more I read, the more I like what I see.
Working in the ER and having seen a couple of complications with the SGLT2-i’s (albeit only in diabetics with lots of other health issues)- I was initially not that eager to jump in - but looking at the actual numbers, and the risk/benefit … apart from cost if you are not sourcing them outside of a U.S. pharmacy - it is worthy of a review.
Again, no medical advice, just my general thoughts on things to consider.
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I am also questioning my use of metformin. After taking metformin for decades my body seems to be growing intolerant of it. I have cycled on and off of metformin in the last couple of years to see what the effects of metformin are. Now I have found that metformin consistently causes me to have a sour stomach. I have had to cut down my dose to once a day with my largest meal.
When I have cycled off I found that I could just as effectively control fasting glucose levels with a variety of other supplements such as berberine. I also take acarbose.
I have continued to take metformin because of its supposed synergistic effect when used for life extension. The evidence is weak, especially for older people.
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I am a huge fan of Akkermansia. It is the only thing that has gotten my HbA1c to normal levels (5.0). I was 5.5-5.8 for 20 years. Low carb, no sugar, berberine, metformin…nothing moved it my more than a couple tenths. Akkermansia does something amazing for my body.
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Have you tried the extended release vs the immediate release? Same acid stomach symptoms?
I’ve only perused acarbose a bit but it does seem impressive. Though, I can’t get the image of the side effects of Orlistat out of my mind.
On most days I keep below a net 20 grams carb. Since Acarbose works on carbs how effective will it be for a person on strict keto?
For a SAD eater ingesting 100-200 grams of carbs, when those carbs cannot get used, they become fodder for the bugs, which may be a good thing but I’m imagining +2 degrees to CO2 worldwide due to expressed gas… 
How are the side effects of Acarbose?
Certainly most of the effect of acarbose is simply as an agent that inhibits alpha-amylase and intestinal alpha-glucosidase. So the biggest effect is slowing carbohydrate absorption. So if you have very few, then the drug would be unlikely to generate much results or side effects. Even in high carb eaters - most start low dose and wean up and have tolerability - depending on diet/gut flora, etc.
You might want to take a look at the SGLT2-inhibitors and review some literature on those - as this can be a consideration if wanting to avoid metformin.
Again, have a chat with your doctor on this - but that would be one area to look into - but I suspect the acarbose would not have the same efficacy in you with a low carb diet.
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No, I haven’t tried it. Next time I see my doctor I will ask him about it.
Check out figure 4 in this:
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I could “take a look,” at the SGLT2 inhibitors but not much more at $400+/month.
It was pulling teeth to get my Practitioner (a PA) to prescribe extended-release metformin.
Just yesterday, I pulled a 12-hour overnight fasting BG of 149. Yet my last A1C was “in the green,” at 5.6, albeit at the upper end. I look at that as just awful, but he seems to look only at the A1C. I don’t want to do so many days of water fasting to keep that A1c down.
Being on Medicare, I suspect there would be no way that insurance would pay for it, and no way that my PA would prescribe it.
On the other hand, Jardiance through Indiamart comes in at about $0.60/tablet in either 10 or 25mg.
What a sick world America is, the same med, in America at $13-/tablet from India at $0.60 only a 22x difference!
With my A1C “in the green,” but morning FBGs of 130-160 I look at this is being horrid, and something to fix. My PA simply says: “Lose weight, work out…” My response: “I’ve lost 54lbs over the past year and do 150-200 mins/wk cardio + ~5 hours lifting and my BG has not changed a bit—nor has my BP, to my chagrin. My lack of improvement mystifies me.
Luckily, with a A1c of 5.6 I don’t feel too pressed for time. I’ll keep off the Metformin for the time being since I’m so happy building back after my “second chance,” due to successful surgery.
One step at a time, I think, start low, go slow. And I do not want to stay strict keto forever…
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Metformin extended release appears to have significantly fewer side effects and greater efficacy.
Maybe one of the doctors on the forum could answer why the extended-release is not more commonly prescribed than the immediate release.
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