Metformin Blocks Benefits of Aerobic Exercise on Insulin Sensitivity and VO2 max

Nelson Vergel

Founder, ExcelMale.com
Thread starter #1
Oh oh

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults


Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
 
#2
Oh oh

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults


Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
Hey Nelson,

These are also my concerns are with metformin. Meformin inhibits complex I of the mitochondrial respiratory chain. The consequences of this action is a loss of ATP production, increases in ATP and AMP which further activates AMP kinase. These actions don’t appear to cause mitochondrial toxicity but more research is needed.

I’ve been on the fence on metformin for years. At this time I feel the risks outweigh the benefits but I can’t be sure.

I would love to hear your current option on taking metformin? Do you believe the benefits outweigh the risks? What are your thoughts on metformin and mitochondria?
 

dnfuss

Active Member
#3
Hey Nelson,

These are also my concerns are with metformin. Meformin inhibits complex I of the mitochondrial respiratory chain. The consequences of this action is a loss of ATP production, increases in ATP and AMP which further activates AMP kinase. These actions don’t appear to cause mitochondrial toxicity but more research is needed.

I’ve been on the fence on metformin for years. At this time I feel the risks outweigh the benefits but I can’t be sure.

I would love to hear your current option on taking metformin? Do you believe the benefits outweigh the risks? What are your thoughts on metformin and mitochondria?
I have the greatest respect for Nelson and hope to hear his views. If you will indulge me, my own view is: 1) metformin is a drug; 2) all drugs have side effects; and 3) a drug should only be taken if its therapeutic benefit outweighs the risk of its side effects. Metformin's primary benefit is in lowering serum glucose levels in diabetes mellitus. For that purpose, it can be very effective and therefore its side effects acceptable. Absent such purpose, the risk analysis may be different.
 
#4
if you could align these affects and timeframes with natural circadian patterns you could still have a winner ... but I am not sure if the half life would align to a 24 hour cycle.
 

DragonBits

Active Member
#6
Oh oh

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults


Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
Nelson, it's interesting, I think I could cut out metformin and maintain BG levels through diet and exercise. Not sure I want to, I do like to eat a wide variety of foods.

But what do you think about the benefits Vs negatives?

With metformin, I can eat quite a few carbs, can't go crazy on them, but not low carb by any means and still get low BG. Without Met, I may have to be more serious about low carb.

I have felt that maybe my cardio has suffered a little from something, I thought maybe not being consistent enough. But it could be the Met.

Has anyone else noticed their cardio not being as easy on Metformin?
 

Nelson Vergel

Founder, ExcelMale.com
Thread starter #7
I stopped Metformin after 4 months since I was getting really tired. My IBS was great, though. I lost 7 pounds as my hunger and sweet cravings decreased. I restarted it again two months ago for two weeks and got tired again. Now I am considering restarting it with this combo:

Weight Loss Combo: Effect of Leucine plus Metformin and Sildenafil Combination on Weight and Metabolic Parameters

Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. - PubMed - NCBI
 

DragonBits

Active Member
#9
I stopped Metformin after 4 months since I was getting really tired. My IBS was great, though. I lost 7 pounds as my hunger and sweet cravings decreased. I restarted it again two months ago for two weeks and got tired again. Now I am considering restarting it with this combo:

Weight Loss Combo: Effect of Leucine plus Metformin and Sildenafil Combination on Weight and Metabolic Parameters

Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. - PubMed - NCBI
I am on 2x 500 ER, are you on 1500? Maybe that makes a difference also.
 
#10
Nelson what is your combo and how do you take per day? Been on Metformin for years so if a combo would mean that I could reduce the dosage it would be welcome.
 
#11
Can someone help me with the math on this NIH example? It’s a typical way for them to express amounts, but I never really felt sure I understood it.

Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice.

The effects of Leu (24 g/kg diet)+Met (0.05-0.5 g/kg diet) combinations were compared to standard therapeutic Met (1.5 g/kg diet; ~300 mg/kg BW) on glycemic control in high fat diet induced insulin resistant mice for 6 weeks.


Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. - PubMed - NCBI

I am never sure I get the amounts that subjects are fed. (In this case, mice).

As I read this, the standard therapeutic Met 300mg/kg BW would mean for a human at 64kg, they would need 19.2 Grams of Met to equal this, which is way above the max dosage of 2250 mg of Met. BUT if I look at MET = 1.5 g/kg diet and assume humans eat ~2.5Kkgs day, then it’s more reasonable 3.75 grams. Still way higher than the max recommended dose of 2550 mg a day for humans, more reasonable yet not in agreement with 300 mg/Kg BW quoted.

And Leucine (Leu), it doesn’t say how much per BW, but humans typically eat ~2.5 kg of cooked food a day, which would translate to 60 grams of Leucine.

(It could be that mice need a lot higher dose of MET to be therapeutic, and that mice eat a lot more kg of food (5x)per kg of BW than a human. But is that a correct way to interpret this?)

It's typical for me in these type of abstracts, I get that adding Leucine to your diet enhances the effects of Metformin, but I never get the actual amounts used in the study.

Am I correct or can someone provide a way of how to convert this to how much for a human that weighs 64kg or make sense of it for me?
 

Nelson Vergel

Founder, ExcelMale.com
Thread starter #12
1200 mg Leucine + 500 mg twice per day Metformin + probably 5 -10 mg sildenafil

I was using 500 mg twice per day of Metformin. Ordered some 25 mg viagra tablets to split them in 3. That is why I have not started. I got Leucine capsules from Amazon.
 
#14
I just started metformin a couple weeks back and it certainly appears to lower my glucose levels when i check.

I do feel like i may have a couple sides from it, including a twitching eye, and my forearms are killing me with a doms muscle soreness feeling. And i havent changed anything as far as my workouts go. I cannot however confirm that either of these sides are from Metformin 100%
 
#15
Oh oh

Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults


Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Source: https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880

Can someone put this in layman's terms for me?
 
#16
I just started metformin a couple weeks back and it certainly appears to lower my glucose levels when i check.

I do feel like i may have a couple sides from it, including a twitching eye, and my forearms are killing me with a doms muscle soreness feeling. And i havent changed anything as far as my workouts go. I cannot however confirm that either of these sides are from Metformin 100%
I have tried turmeric/pepperdine (IE golden paste) as a remedy for DOMS, it seems to work as well as Ibuprofen and is suppose to have other benefits. Not 100% sure on how well it works, you know how DOMS is, you get conditioned and it's not as bad.

Also, think about your magnesium / hydration levels, those also can cause more severe DOMS.
 
#19
I have tried turmeric/pepperdine (IE golden paste) as a remedy for DOMS, it seems to work as well as Ibuprofen and is suppose to have other benefits. Not 100% sure on how well it works, you know how DOMS is, you get conditioned and it's not as bad.

Also, think about your magnesium / hydration levels, those also can cause more severe DOMS.
I really don't think it is doms as i havent done any forearm work and I've never had doms related forearm pain in the past. Just something new thats popped up the last couple weeks since beginning MeT.
 
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