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Metformin: Risk/Reward Profile (Tradeoff Considerations; Balancing of Factors; Cost-Benefit Analysis) [Author: Type-IIx]

Type-IIx

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Metformin: Risk vs. Reward Profile
Author: Type-IIx


Here are the basic contours of risks versus rewards for the practical use of Metformin, a biguanide, for bodybuilding, that I will build out with more depth and breadth if readers want to delve deeper:

Metformin: anti-hyperglycemic and an insulin-sensitizing agent.

The efficacy of metformin XR is about 12 h. IR 6 h.

Risks:
  1. Hypertrophy attenuation (↓ muscle growth in response to progressive resistance training [PRT])
    1. AMPK activation inhibits mTORC1/P70S6K1 phophorylation [1]
    2. Abrogates (blocks) the adaptive preferential shift from type I to type IIA fibers (resulting in a tendency towards reduced strength gains) [1]
    3. Reduces testosterone (free & total) & increases SHBG in healthy men [2] (relevant for those who do not use exogenous androgens)
  2. Abrogates endurance training enhancement of insulin sensitivity (blocks cardio's effect to ↑insulin sensitivity) [1]
  3. No difference in fasting glucose, glucose response, insulin sensitivity versus progressive resistance training (PRT) alone [1]
  4. Attenuation of lipid oxidation from ET (↓ fat oxidation by cardio)
    1. Inhibition of mitochondrial complex I overrides AMPK activation (PRT/PRT+ET indicates against metformin) [1]
  5. Gastrointestinal dysregulation (bloating, diarrhea, nausea, abdominal distension)
  6. Vitamin B12 deficiency [4]
    1. Consequent increase in homocysteine levels (if B vitamins not supplemented) [3]
  7. Potential birth defects (data needed)

Rewards:

Principally applies to those who are on rhGH and/or aromatizing androgen:
  1. Insulin sensitizing properties attenuate the increase in blood glucose from rhGH [10]
  2. Improved glucose and fatty acid oxidation via AMPK activity [10]
  3. Likely improves symptoms of erectile dysfunction (ED) + PDE5 inhibitor vs. PDE5 inhibitor alone [5]
  4. Increases serum IGF-I in combination with rhGH [6]
  5. Likely improves palmitate-induced inflammation in skeletal muscle [2]
  6. Applies to those on testosterone:
    1. Likely attenuates BPH risk [7]
    2. May (highly speculative) ameliorate AAS-induced cardiac changes [9-10]

Conclusion:

Unless you're on rhGH or aromatizing androgen, or insulin resistant/prediabetic, weigh Metformin's risks (particularly acute in abating certain training adaptations) vs rewards.


References

[1] Walton, R. G., Dungan, C. M., Long, D. E., Tuggle, S. C., Kosmac, K., Peck, B. D., … Peterson, C. A. (2019). Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial. Aging Cell. doi:10.1111/acel.13039
[2] Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM. Effects of short term metformin administration on androgens in normal men. Saudi Med J. 2002 Aug;23(8):934-7. PMID: 12235466.
[3] Zhang, Q., Li, S., Li, L., Li, Q., Ren, K., Sun, X., & Li, J. (2016). Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients, 8(12), 798. doi:10.3390/nu8120798
[4] Roy RP, Ghosh K, Ghosh M, Acharyya A, Bhattacharya A, Pal M, Chakraborty S, Sengupta N, Mukhopadhyay S. Study of Vitamin B 12 deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus. Indian J Endocr Metab 2016; 20:631-7
[5] Rey-Valzacchi, G. J., Costanzo, P. R., Finger, L. A., Layus, A. O., Gueglio, G. M., Litwak, L. E., & Knoblovits, P. (2011). Addition of Metformin to Sildenafil Treatment for Erectile Dysfunction in Eugonadal Nondiabetic Men With Insulin Resistance. A Prospective, Randomized, Double-Blind Pilot Study. Journal of Andrology, 33(4), 608–614. doi:10.2164/jandrol.111.013714
[6] Type-IIx. hGH + Metformin: A Good Thing (Metformin does not lower, but rather increases IGF-1). 2021 Apr. Source: https://thinksteroids.com/community...t-lower-but-rather-increases-igf-1.134404953/
[7] Mosli HH, Esmat A, Atawia RT, Shoieb SM, Mosli HA, Abdel-Naim AB. Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective. Sci Rep. 2015;5:15639. Published 2015 Oct 23. doi:10.1038/srep15639
[8] Crocker CL, Baumgarner BL, Kinsey ST. β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil. 2020;41(2-3):221-237. doi:10.1007/s10974-019-09568-0
[9] Lv, L., Zheng, N., Zhang, L., Li, R., Li, Y., Yang, R., … Shan, H. (2020). Metformin ameliorates cardiac conduction delay by regulating microRNA-1 in mice. European Journal of Pharmacology, 881, 173131. doi:10.1016/j.ejphar.2020.173131
[10] Li, J., Minćzuk, K., Massey, J. C., Howell, N. L., Roy, R.J., Paul, S., … Kundu, B. K. (2020). Metformin Improves Cardiac Metabolism and Function, and Prevents Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats. Journal of the American Heart Association, 9(7). doi:10.1161/jaha.119.015154
[11] Kwon B, Querfurth HW. Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin. Biochimie. 2015 Nov;118:141-50. doi: 10.1016/j.biochi.2015.09.006. Epub 2015 Sep 5. PMID: 26344902.
 
Great post. What about the effects that only women get? Doesn’t it possibly reduce the risks of polycystic ovary syndrome? My girl is interested so I’ve been delving into it a little more.
 
Very well written. Pro’s/cons and suggested consensus. Love it and tend to agree as I’m not a big fan personally of metformin.

Would be curious to get your thoughts or have you do this for low dose Jardiance as I personally feel it’s a better choice for those hitting a wall with glucose issues. 😊
 
Really like the format this is written in. Obviously it's a well researched and thoughtful piece too but layout to help people digest, think about it and suggested conclusions is outstanding.
 
so with gh supplemented WITH metformin, it can boost IGF1 levels but without it can skew, correct?
 
Great post that summarizes all i have read about it and even more !
Still are the negative sides on cardio and strength relevant for enhanced bodybuilders on high test, androgens and l carnitine for instance ??
What about hydro berberine ??
 
Great post. What about the effects that only women get? Doesn’t it possibly reduce the risks of polycystic ovary syndrome? My girl is interested so I’ve been delving into it a little more.
I don't know right now. I did tailor this to men, but I shouldn't do that too much. I'll get back to this with a good section for women too.
 
Very well written. Pro’s/cons and suggested consensus. Love it and tend to agree as I’m not a big fan personally of metformin.

Would be curious to get your thoughts or have you do this for low dose Jardiance as I personally feel it’s a better choice for those hitting a wall with glucose issues. 😊
SGLT-2 inhibitors like Jardiance (empagliflozin) are indeed great GDAs.

Jardiance's mechanism to ameliorate hyperglycemia is more direct than Metformin's or others in its class like Berberine. The mechanism by which Jardiance works is that, where glucose from the blood is filtered for excretion and reabsorbed in the glomerulus such that (< 1% of) glucose is excreted in the urine, this reabsorption is mediated by the sodium-dependent glucose cotransporter (SGLT), mainly the type 2 which is responsible for 90% of the reabsorbed glucose. Jardiance is a small inhibitor of the SGLT2 and its activity increases glucose excretion, reducing hyperglycemia without the requirement of elevated insulin secretion.
 
so with gh supplemented WITH metformin, it can boost IGF1 levels but without it can skew, correct?
Correct!

I should add that the researchers, who conducted a meta-analysis (assessing a cohort of a bunch of studies directed at rhGH + Met measuring the outcome of changes to IGF-I), were horrified that this occurred, because the medical literature views IGF-I & mTOR activity as bad since their activities are mitogenic, meaning that they promote aging (via increased cell division). So, longevity folks want to crush IGF-I & mTOR, while we want to get them crunk so that we increase total-body size (mitogenesis) & muscle size (myogenesis).
 
Great post that summarizes all i have read about it and even more !
Still are the negative sides on cardio and strength relevant for enhanced bodybuilders on high test, androgens and l carnitine for instance ??
What about hydro berberine ??
Since the mechanisms by which Met:

A) Blunts hypertrophy (by inhibiting mTORC1/P70S6K1 phophorylation) are independent from the mechanisms by which AAS/T act (AR-mediated effects that do not implicate mTOR – see [link], with special reference to the section heading "✖ Translational efficiency")

&

B) Blunts fat oxidation via aerobic-endurance training (by inhibiting mitochondrial complex I) are independent from the mechanisms by which L-Carnitine (theoretically, but not demonstrated in humans) i. acts on fat oxidation by augmenting fatty-acid transport from the cytosol to the mitochondria for β-oxidation via the carnitine system due to malonyl CoA regulation in human skeletal muscle which acts as a feedback regultor to muscle carnitine, and/or ii. due to insufficient bioavailability in humans given exogenous L-Carnitine by any route

&

C) are different from those of hydroberberine, which blunts hypertrophy by two (2) novel mechanisms, including i. impairing mitochonidrial function stimulation of the expression of atrogin-1 expression without ii. affecting phosphorylation of forkhead (e.g., FOXO) transcription factors, which not only stimulates protein degradation (↑MPB) but also suppresses protein synthesis (↓MPS), causing muscle atrophy.

Atrogin-1 & MuRF1 are downstream in the IL-6 (Inflammatory Signaling) & Myostatin (Negative Muscle Growth Regulation) signaling & secondary messenger pathways & Smad 2,3 (Myostatin) pathway is downstream of the latter (Myostatin) that is indeed acted upon by T/AAS (which inhibits it),

Since atrogin-1 is potently suppressed by Tren (> Test) & Test (i.e., AAS broadly), and Test attenuates proteolytic and inflammatory responses by reducing resting skeletal muscle expression of fibroblast growth factor-inducible 14 (Fn14), thereby exerting a protective effect against IL-6 signaling, & since Test negatively regulates Myostatin expression by cross-talk with it, it's hypothetically more likely that AAS/T can to some extent mechanistically claw back some lost anabolism from the use of hydroberberine, unlike Met. But this has not been demonstrated in any model (e.g., BBR + T measuring hypertrophy signaling and/or outcomes), it is merely theoretical.
 
Great post! Short, informative, and easy to read. My take away is if your using GH along with AAS then the pros of using Met out weigh the cons. I take Met daily at night to since I am also taking GH daily along with AAS and the combo has worked great. Keeps my blood glucose in check which allows me to push the GH and food.
 
SGLT-2 inhibitors like Jardiance (empagliflozin) are indeed great GDAs.

Jardiance's mechanism to ameliorate hyperglycemia is more direct than Metformin's or others in its class like Berberine. The mechanism by which Jardiance works is that, where glucose from the blood is filtered for excretion and reabsorbed in the glomerulus such that (< 1% of) glucose is excreted in the urine, this reabsorption is mediated by the sodium-dependent glucose cotransporter (SGLT), mainly the type 2 which is responsible for 90% of the reabsorbed glucose. Jardiance is a small inhibitor of the SGLT2 and its activity increases glucose excretion, reducing hyperglycemia without the requirement of elevated insulin secretion.
Very well written. Add to it the cardio protective benefits and it’s a solid edition for bodybuilders running high gear, using insulin and HGH.

Ironically enough my cardiologist was ahead of me on this one and actually suggested it to me knowing I body build a while back which prompted me to do a deep dive. Thats when you know you have a good cardiologist. This was with clean cardiac test and numbers.
 
Good stuff. If someone already has very good insulin sensitivity (fasting glucose always in low end of range, a1c constantly below range), is there any advantage to continuing to work to improve it?

For example is a guy at the 99th percentile any healthier, or have any advantage in body composition (response to diet, training, AAS) than someone at the 90th percentile? Or once we are very sensitive to insulin I assume there is a law of diminishing returns?
 
Good stuff. If someone already has very good insulin sensitivity (fasting glucose always in low end of range, a1c constantly below range), is there any advantage to continuing to work to improve it?

For example is a guy at the 99th percentile any healthier, or have any advantage in body composition (response to diet, training, AAS) than someone at the 90th percentile? Or once we are very sensitive to insulin I assume there is a law of diminishing returns?
There's very little to be gained by enhancing insulin sensitivity from the 99th to the 100th percentile to the point of it being a totally fruitless undertaking.

This risk/reward profile basically sums up the utility of Met in the third risk given: "No difference in fasting glucose, glucose response, insulin sensitivity versus progressive resistance training (PRT) alone." So, basically, initiating a progressive resistance training program alone is equally effective in enhancing insulin sensitivity for a type 2 diabetic (sedentary & fat) to the drug, but is free of any risk.

The shit healthy bodybuilders already do (maintain an active lifestyle with a progressive resistance training program & a low body fat level) blows any drug combo out of the water.
 
just to clarify because not everyone knows the importance and differences off the bat:

  1. High Insulin Sensitivity (Desirable):
    • Efficient glucose uptake by cells.
    • Lower risk of type 2 diabetes.
    • Better control of blood sugar levels.
    • Associated with good metabolic health.
  2. Insulin Resistance (Undesirable):
    • Reduced effectiveness of insulin.
    • Higher levels of insulin are needed to manage blood sugar.
    • Increased risk of type 2 diabetes, cardiovascular disease, and other metabolic disorders.
 
Great post. What about the effects that only women get? Doesn’t it possibly reduce the risks of polycystic ovary syndrome? My girl is interested so I’ve been delving into it a little more.
I don't know right now. I did tailor this to men, but I shouldn't do that too much. I'll get back to this with a good section for women too.
I dated a girl for five years who had severe endometriosis and had surgery with Dr. Ken Sinervo at the Center for Endometriosis Care. In the post-op consultation he recommended metformin and said they often give it to women with PCOS and other hormonal issues because, in his words, 'metformin tends to make everything work better'.
 
@Type-IIx what are your thoughts on Acarbose for bodybuilders?
 

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