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Is metformin optimal for health in this video we’ll have a look at data from three studies that suggest that maybe metformin is not optimal for health in the first we’ll see that metformin induces muscle atrophy and mice and then in two randomized controlled trials in older adults we’ll see that metformin blunts muscle hypertrophy in response to progressive resistance
Exercise training and in the second we’ll see that metformin affects insulin sensitivity and potentially vo2 max in older adults that underwent aerobic exercise training for 12 weeks so when considering these data in terms of skeletal muscle and exercise training related health and functional improvements metformin may not be optimal for health so first let’s take
A look at the data in cells so in there we’ll see that metformin increases myostatin gene expression and myostatin protein levels so the obvious question should be why is myostatin important so here we’re looking at muscle mass in normal mice the upper arm in the left picture and the lower leg in the right picture so what happens when you knock out myostatin so you
Delete the gene from myostatin and then the animals don’t have detectable levels of myostatin so here we can see dramatically increased muscle mass so when the animals don’t have myostatin there’s dramatically increased muscle mass in the both upper arm as you can see on the left bottom bottom panel and in the leg in the right corner so does metformin affect levels
Of myostatin and as as i mentioned i’m going to start with the data in cells we’ll go over to mice and then we’ll go into the human data so here we’re looking at relative myostatin gene expression so this is mrna expression for myostatin in the presence or absence of metformin so the absence of metformin uh with the minus sign and in the presence of metformin with
The plus sign and again these are in c2 c12 muscle cells this is an in vitro acid that’s performed outside of the body in cell cells uh in cells in muscle cells so in the presence of metformin we can see dramatically increased myostatin expression myostatin gene expression almost 150 fold so although gene expression is important that doesn’t mean that the gene
Is going to be translated into protein so to assess that the authors of this study then looked at myostatin protein levels in these muscle cells and as you can see as the metformin levels ink were increased up to two millimolar myostatin protein levels correspondingly increased so these data suggest that myostatin is maybe sorry metformin may be bad for muscle
In part by increasing levels of myostatin now note that these data are in muscle cells what about metformin’s effects in mice so to test that the authors of that same study then uh supplemented seven week old male c-57 black 6j mice so note that a seven week old mouse is the equivalent of about a five-year-old in human years uh when considering about a 40-month
Maximum lifespan so these week old mice these very young mice were injected with metformin or saline as controls three times a week for for four weeks so what was the effect of myostatin uh sorry metformin treatment on myostatin so that’s we can see here again we’re looking at myostatin gene expression on the y-axis and controls and in the metformin treated mice
And what we can see is that metformin treatment treatment significantly increased myostatin expression about 50 percent about a 50 increase for myostatin gene expression in the animals that were supplemented with metformin so then the big question is did metformin treatment affect muscle mass in these mice so to assess that the authors of this study looked at
Average muscle fiber cross-sectional area so csa when comparing the controls with the metformin supplemented mice and as you can see there was significantly smaller muscle cross-sectional area in the metformin treated mice so what about effects on muscle function so did metformin treatment affect muscle strength so to assess that they looked at grip strength and
Remember this was a four-week study so at the end of the four-week study uh you know whether being supplemented with metformin or controls or sorry injected with metformin or saline as a control we can see that the metformin injected mice or mice that were injected with metformin had significantly reduced grip strength at the end of the four week study so the dashed
Lines when compared with the saline injected animals with the solid lines so from this we can conclude there’s reduced not only muscle cross-sectional area but also reduced muscle strength in the metformin treated mice so to sum these data up in the mice metformin induces myostatin gene expression decreases muscle cross-sectional area and reduces grip strength
In young mice so then the next question should obviously be does metformin impact muscle related measures in people so this is the first randomized controlled trial of metformin supplementation in older adults and in this study uh the metformin dose was 1700 milligrams per day and just to define the subject population a little bit more these were overweight so
Uh the average bmi for both groups the controls and the metformin supplemented group was a greater than 25 kilograms per meter squared and then in terms of their age the average age was 69 and there were 94 total subjects in the study and these older adults were at risk for mobility disability so first when looking at the change in lean mass as a result of the 14
Week strength training program we can see that the placebo had significantly significant increases for whole body lean mass whereas the metformin group increased less and the difference between the improvement in whole body lean mass was greater for the placebo group when compared with the metformin supplemented group as you can see by the statistically significant
P value of 0.03 now note that this lean mass was measured with dexa so dexa measured lean mass doesn’t only include muscle mass but it also includes the organ masses so to account for that the authors of this study also looked at thigh muscle mass and as we can see there placebo supplemented older adults had a far greater improvement for thigh muscle mass or the
Percentage of thigh muscle mass when compared with metformin supplemented older adults and again these these two groups of data are statistically significant so a greater increase for thigh muscle mass percentage in the placebo treated when compared with the metformin treated so what about metformin supplementation and how it affects muscle function and that’s what
We can see here so we’re looking at three relatively similar measures of strength testing and to assess strength they looked at knee extension so i should say they measured it with three various measures of knee extension so in the first it was the knee extension one repetition maximum one rm and then they looked at the maximum voluntary isometric contraction
For in the extension and then they looked at knee extension power and then we’re comparing the placebo group on the left so the base their baseline data 14 weeks after the progressive resistance training uh program and then the percent change for the placebo group when compared with you know the metformin group so you’ve got the baseline 14 week 14 weeks after
Baseline and then the percent change so first when looking at the knee extension one rep max we can see that the metformin group uh improved about eight percent less than the placebo group and this data was very close to us sorry statistical significance where a statistical significant uh p-value of less than 0.05 that’s statistically significant so this is very
Close 0.055 so similar data was also identified for the maximum voluntary isometric contraction where the metformin group improved about 5 percent less than the placebo group and then also that data also is close to statistical significance with a p-value of 0.08 and then last but not least in terms of knee extension power the metformin group improved about half as
Much as the placebo treated group and again that data was also very close to statistical significance 0.064 so from this we can conclude that there were trends for less muscle strength and power improvements in the metformin treated older adults that underwent progressive progressive resistance exercise training when compared with placebo now as a caveat to this
Data note the superscripts there the little b’s for each of those three measures and what that indicates is that uh for baseline levels of the strength and power measurements in the metformin treater group they were statistically significantly higher than the baseline values for these three measures in the placebo group which then raises the question were these
Strength and power measures did they improve less in the metformin treated group because they started at a higher strength and power baseline data you know so it’s harder to improve if you’re already at a relatively higher strength and power level when compared with the placebo group so that question gets raised with these data all right so metformin is well known
To reduce circulating levels of glucose so did metformin improve glucose levels and or insulin sensitivity in combination with this uh strength training program so that’s what we’re looking at here plus theta four placebo on the left and four metformin on the right and we’ve got data for fasting glucose on the top and an insulin sensitivity index on the bottom
So this is an oral glucose tolerance test ogt ogt participants were given 75 grams of sugar a sugar solution and then the blood levels of glucose and insulin were then measured at defined time periods after consumption of the sugar solution and the insulin sensitivity index was um calculated based on that data so first when both groups improved their fasting
Glucose levels as a result of the strength training program but note that the metformin treated group did not have a further improved fasting glucose level when compared with placebo similarly uh fat uh the insulin sensitivity index improved in both groups so placebo and metformin treated but again the metformin treaty group did not have a further improvement in
In insulin for insulin sensitivity when compared with placebo so from this we can conclude that glucose and insulin sensitivity were not further improved for the group that was supplemented with metformin and that underwent this strength training program when compared with placebo so in the last paper in this in the second randomized control trial which included
Obese subjects so their average bmi of the subject in this study was greater than 30 kilograms per meter squared these were older adults that were between 62 and 63 years old with a relatively smaller sample size 53 subjects and these people underwent 12 weeks of aerobic exercise training now in in terms of how much metformin they were taking a ramp protocol was
Used 500 milligrams per day during week one a thousand a week two fifteen hundred milligrams per day in week three and 2 000 milligrams in week 4 that continued until the 12-week study was concluded now for people that weighed less than 75 kilograms they were ramped to 1500 milligrams of metformin a day and then they stayed there at that dose for the remainder of
The you know the 12-week study so first in terms of uh improvements for whole body insulin sensitivity as a result of the 12-week aerobic exercise training program we can see that people in the placebo group improved their whole body sense insulin sensitivity significantly more than the metformin treated group so this data suggests that metformin impairs aerobic
Exercise induced improvements for insulin sensitivity and then in similar data to the physical function data of the last study when looking at vo2 max here on the y-axis for the placebo treated versus the metformin treated older adults we can see a close to statistically significant trend for the metformin group improving their vo2 vo2 max less as a result of
The aerobic exercise training when compared with the placebo treated so that p value is very close it’s 0.08 so again a trend for a lesser vo2 max improvement in the metformin supplemented subjects which which kind of agrees which with the data from the last study with very close uh two statistical significant uh decreases for uh strengthened power gains in the
Metformin treaty group only in this study it’s lesser improvements for vo2 max so at best when considering these two studies these two randomized controlled trials of metformin supplementation in older adults at best metformin does not further improve insulin sensitivity or physical function in exercise trained older adults but at worst metformin impairs insulin
Sensitivity reduces muscle mass and physical function gains in exercise trained older adults all right that’s all for now if you’re interested in more about my attempts to biohack aging come check us out and maybe even join us on patreon thanks for watching i hope you enjoyed the video have a great day
Transcribed from video
Metformin Impairs Exercise Training-Related Improvements In Older Adults By Conquer Aging Or Die Trying!liveBroadcastDetails{isLiveNowfalsestartTimestamp2021-11-13T120011+0000endTimestamp2021-11-13T121434+0000}
