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

[DragonBits]

Glycogenolysis and gluconeogenesis occur frequently in everyone in response to many common stimuli (awakening, exercise, adrenaline release, etc.). In those with truly normal blood sugars, the body's homeostasis mechanisms produce the correct release of endogenous insulin to precisely control serum glucose levels in response (and in response to ingestion of carbohydrates). That normal response is what's impaired in diabetes.

There are no magic answers. There are no OTC supplements proven effective at controlling abnormal blood sugars. Abnormally high blood sugar levels following meals are generally indicative of diabetes, at least the early stages of such, and should be treated accordingly.

If your liver releases glucose in response to a heavy meal, when it shouldn't do that, then seems like a different problem.

The constant spikes up might well lead to diabetes.

In any case, I am willing to give the supplement a try.

BTW, it's not magic, in my view some supplements are very similar to a prescription drug. If you need a supplement to have normal blood glucose, it isn't any different in principal from taking a drug like Metformin.

I know sometimes people go to great lengths to avoid prescription drugs, but if they need XYZ supplements is that really any different?

I always think the classic example is red yeast rice which contains compounds like monacolin K, the same ingredient that is in the prescription cholesterol-lowering drug lovastatin.

So if you take red yeast rice as a supplement, you can tell yourself you aren't taking a statin, but you really are.

 

[dnfuss]

If your liver releases glucose in response to a heavy meal, when it shouldn't do that, then seems like a different problem.

If your body is not compensating properly for that release, it's not a different problem, it's diabetes.

The constant spikes up might well lead to diabetes.

Constant spikes don't lead to diabetes, they are diabetes.

In any case, I am willing to give the supplement a try.

I would not be so quick to be a guinea pig. I reiterate, there are no supplements proven effective in controlling diabetes. And if they were, I would be extremely cautious about taking them. A supplement (drug) strong enough to control diabetes is exerting profound effects on body chemistry (downregulating certain liver functions, stimulating pancreatic beta cells, etc.). You want such compounds to undergo rigorous clinical testing to learn about safety, efficacy, side effects, etc. Their serious side effects may not become apparent for years or even decades later. I would not even want to take a prescription drug for diabetes before it had been prescribed for several years to evaluate side effects after widespread use (see, e.g., sulfonylurea drugs (increased likelihood of heart attack), the incretin drugs (can damage the pancreas), and Avandia and Actos (can cause severe osteoporosis)).

 

[DragonBits]

If any problems are 3 decades away, I am OK with that, likely be dead before that.

Like many supplements, this is CoffeeGenic® Green Coffee extract, derived from green coffee beans. Something people have been drinking for a very long time, so it is tested that way. Granted, that doesn't make it safe, people have chewed and smoked tobacco for 2000 years.

Moving on ...

One reason I suspended Metformin was to see if it affected my exercise. As it can limit V02 max, perception of exercise intensity, raise heart rate, and exercise can interfere with the glucose-lowering effect of metformin.

I have tried to get my max heart rate as high as I could by intermittently running sprints (8.5 mpg) for an hour. I got my heart rate to 151, covered about 4.5 miles on a 1% slope, last sprint I increase the slope to 2%.

According to the formula, 220-age, I should be able to peak out at 153. (I know max heart rate figured this way isn't super reliable, but it does seem to usually work)

When I go back on Metformin, it should be easy to compare exercise results. Not a big "trial" but close enough for government work.

 

[RoneTone]

Curious as to what are the benefits you are seeing at that dose. Is there a measurable reduction in your serum glucose levels? Most adult males see no significant reduction in blood sugar levels at metformin doses below 1,500 mg./day.

Yes, Met absolutely controls the level to which glucose rises if I take 500mg with a meal. I have a meter and can verify. Even at 500mg a day my blood sugar as far as I can tell doesn't go above 115 or so post meal and often not above 100. I've eaten meals with met and an hour later my BS is still at 90. It's a night and day difference.

I'm probably not 'most adult males' and don't need the typical high dosage. I'm very lean, athletic, and have been working out, playing sports, etc., my entire life. I also eat a very good diet these days.

I've found the ER version of met is too strong and gives me fatigue/muscle soreness. I like low doses of the immediate release after trying different combos over the last few months. I usually take 500mg with the last meal of the day and sometimes 125mg to 250mg with the first.

For other effects I see are - loss of belly fat, less bloating, much better erections (I'm guessing this is Met's effect on the endothelial function. Met has helped more in this area than any other drugs, including TRT.) less anxiety, and I feel more calm.

I had some fatty liver that came up on an ultrasound (yet normal liver enzymes) and always had somewhat high blood sugars post meals (probably years of eating poorly as a kid - like SAD bad - fried my liver). I'm also someone that could be considered norepinephrine dominate (wired, erections would come up fast but easily fade, some anxiety) and met seems to help in this area. norepinephrine blocking drugs worked but the side effects are awful. Met seems to address the core issues.

 

[DragonBits]

Yes, Met absolutely controls the level to which glucose rises if I take 500mg with a meal. I have a meter and can verify. Even at 500mg a day my blood sugar as far as I can tell doesn't go above 115 or so post meal and often not above 100. I've eaten meals with met and an hour later my BS is still at 90. It's a night and day difference.

I'm probably not 'most adult males' and don't need the typical high dosage. I'm very lean, athletic, and have been working out, playing sports, etc., my entire life. I also eat a very good diet these days.

I've found the ER version of met is too strong and gives me fatigue/muscle soreness. I like low doses of the immediate release after trying different combos over the last few months. I usually take 500mg with the last meal of the day and sometimes 125mg to 250mg with the first.

For other effects I see are - loss of belly fat, less bloating, much better erections (I'm guessing this is Met's effect on the endothelial function. Met has helped more in this area than any other drugs, including TRT.) less anxiety, and I feel more calm.

I had some fatty liver that came up on an ultrasound (yet normal liver enzymes) and always had somewhat high blood sugars post meals (probably years of eating poorly as a kid - like SAD bad - fried my liver). I'm also someone that could be considered norepinephrine dominate (wired, erections would come up fast but easily fade, some anxiety) and met seems to help in this area. norepinephrine blocking drugs worked but the side effects are awful. Met seems to address the core issues.

I have metformin XR, I wanted to try IR.

I bet if I crushed a 500 mg XR, it would turn it into IR, immediate release. (I have never had any gastric problems on any drug.)

I was curious if I took either 250 mg or 500 mg right before eating, would it impede the absorption of carbs?

 

[dnfuss]

If any problems are 3 decades away, I am OK with that, likely be dead before that.

When I said serious side effects might not be apparent for some time, I meant a connection between the drug and the side effect might not be realized by the medical community for some time. The serious damage to the individual could occur quite quickly.

Like many supplements, this is CoffeeGenic® Green Coffee extract, derived from green coffee beans. Something people have been drinking for a very long time, so it is tested that way.

Coffee has been drunk in our society for hundreds of years. The long-term effects of green coffee extract in vivo to my knowledge have never been studied.

 

[dnfuss]

I have metformin XR, I wanted to try IR.

I bet if I crushed a 500 mg XR, it would turn it into IR, immediate release. (I have never had any gastric problems on any drug.)

It wasn't designed to be taken that way, and it might be safe and effective or it might not. But why do so? Metformin is a very cheap drug. I would just purchase some of the instant-release form.

I was curious if I took either 250 mg or 500 mg right before eating, would it impede the absorption of carbs?

Its mechanism of action is only generally understood, but metformin does not block the absorption of carbs (there are such drugs, e.g., Acarbose, but they block only complex carbs, not simple sugars). Metformin is generally most effective in conjunction with a low-carb diet. In fact, taking it when on a high-carb diet tends to cause gastric distress (diarrhea, indigestion, nausea, etc.).

 

[testiculus]

Just read the full study text. Unfortunately it is difficult to draw any conclusions due to the study design. It wasn't conducted as a cross-over trial. There is a huge amount of variability in individual response to aerobic exercise. Some people are non-responders and others are hyper-responders. No attempt was made to account for this and therefore it completely invalidates the randomization of the trial. In addition to that, they made another bad decision in how they conducted the exercise. The VO2max testing was done on a stationary bike, but the study participants were allow to select the type of exercise they performed over the course of the study (treadmill, stationary bike, or elliptical). Since VO2max testing is specific to the type of exercise performed, any participant that did their exercise on the stationary bike would have seen more improvement in the subsequent VO2max test than those if they had used the other modalities. The paper did not report the breakdown of exercise modality between the two groups. More participants choosing the stationary bike in one group would also invalidate the results. So the only conclusion is that for some people metformin may not work well when combined with exercise, while for others it will work just fine when combined with exercise.

 

[DragonBits]

It wasn't designed to be taken that way, and it might be safe and effective or it might not. But why do so? Metformin is a very cheap drug. I would just purchase some of the instant-release form.

It's more logistics than cost.

You do need a prescription to order Metformin, I already have 3 months supply, I would need to get a doctor to order it, which maybe time consuming or more expensive, insurance wouldn't pay since I already have it, and I don't know if it is something I really want. If I get a prescription for IR it will be for 3 months, it's not like I can get 20 pills just to experiment.

I could find somewhere to order it without a prescription, that has it's own set of negatives.

Its mechanism of action is only generally understood, but metformin does not block the absorption of carbs (there are such drugs, e.g., Acarbose, but they block only complex carbs, not simple sugars). Metformin is generally most effective in conjunction with a low-carb diet. In fact, taking it when on a high-carb diet tends to cause gastric distress (diarrhea, indigestion, nausea, etc.).

Low carb works best to lower BG, with or without Metformin.

That said, everything I read says different about what metformin does. Maybe we disagree about "block" Vs "delay"?

Metformin:

It increases the sensitivity of muscle cells to insulin.

Secondly, it reduces the amount of sugar produced by cells in the liver.

It delays the absorption of sugar from the intestines into the bloodstream after eating so that there is less of a spike in blood sugar levels after meals.

I just want to delay the absorption of sugar to mitigate the spike in blood sugar levels after a big meal and reduce sugar produced in the liver.

It's mainly an experiment by me, it seemed to work on 1 meal, but let's see how it works more than just once.

Maybe I will have a pizza for lunch, that is sure to cause a spike if I am not taking metformin.

 

[dnfuss]

I could find somewhere to order it without a prescription, that has it's own set of negatives.

It can be ordered through All Day Chemist or Reliable Rx Pharmacy in India (some say without prescription). It's a perfectly good generic. Very cheap.

Low carb works best to lower BG, with or without Metformin.

That was not the question. The statement was that metformin is most effective when combined with a low-carb diet. That is, it generally won't bring the blood sugars of someone who is pre-diabetic or diabetic into the completely normal range if they continue on the Standard American Diet.

That said, everything I read says different about what metformin does. Maybe we disagree about "block" Vs "delay"?

They are different. There are oral agents, such as Acarbose, that actually block (prevent the digestion of) a (limited) amount of complex carbs when taken correctly. But (1) they don't have the same effect on simple sugars, (2) they are quite difficult to time and dose correctly and (3) they have their own side effects. Such blocking of carbohydrate digestion is not a known mechanism of action of metformin.

Metformin:

It increases the sensitivity of muscle cells to insulin.

Secondly, it reduces the amount of sugar produced by cells in the liver.

It delays the absorption of sugar from the intestines into the bloodstream after eating so that there is less of a spike in blood sugar levels after meals.

Metformin much more profoundly affects the first two pathways than the third. That's why it is so much more effective in conjunction with a low-carbohydrate diet.

Maybe I will have a pizza for lunch, that is sure to cause a spike if I am not taking metformin.

It wouldn't be surprising if blood sugar spikes after a high-carb meal when on metformin were lower than they might be without metformin but still higher than normal levels (and therefore still damaging). But good luck.

 

[DragonBits]

It wouldn't be surprising if blood sugar spikes after a high-carb meal when on metformin were lower than they might be without metformin but still higher than normal levels (and therefore still damaging). But good luck.

The pizza got me to 161 BG tested after 45 min, an 1 hour 20 min after that my BG was 112.

A higher spike up than I am comfortable with.

Next I will try the green coffee extract to see what it does.

 

[DragonBits]

LEF coffeeGenic Green Coffee extract seems to work.

My blood glucose before eating was 80, after 45 min it was 125, 20 mins after that it was 108.

The same size pizza as before.

Yesterday before eating pizza BG was 93, 45 mins after eating 161, after another hour 112.

Of course, I will have to repeat a couple of times to see if it is consistent.

125 BG after pizza is OK.

The ultimate BG challenge, Olive Garden's Never Ending Stuffed Pasta (just kidding).

 

[DragonBits]

I had to do it. For science.

On Saturday we went to Olive Garden's never ending stuffed pasta dinner.

I had a salad, 1 breadstick and Chicken & Gnocchi soup.

Three and 1/2 dishes of pasta each covered with With Sautéed Shrimp & Scallops and Marinara sauce.

Asiago Tortelloni
Stuffed Ziti Fritta
Mushroom Ravioli
1/2 Asiago Tortelloni with meat sauce and meatballs.

Got to be at least 200 grams of carbs.

Took one LEF Green Coffee extract (coffeeGenic) about 10 min before eating. Blood glucose and times.

17:37 89
14:43 110
9:41 107
1:35 104 Next day
22:41 113
21:00 120
19:44 129 (54 min after the meal.
18:50 112 (10 min after end of meal)
8:17 88 Fasting BG, started dinner at 17:20

Supplement definitely had an effect, really surprised BG only went as high as 129, but it didn't come down below 100 till 5 PM the next day. But I didn't do a lot of exercise either, my watch tells me I walked 2.2 miles that day and no gym time.

Probably 2000 calories in this one meal, this is the most food I have eaten in a single meal in 6 months, probably the most calories in a whole day.

Oh well, back on the wagon again. Salad and cod for dinner, weightlifting and walked 6.5 miles.

I am sold that LEF Green Coffee extract (coffeeGenic) works, though like most things it isn't a substitute for a good diet. But good to know.

 

[DragonBits]

I added R-lipoic acid to my supplements, it's suppose to lower blood sugar levels, reduced inflammation, slow skin aging and improved nerve function, maybe help with weight loss, studies show that ALA increases Glut-4 transporters on the outside of muscle cells. This means more glucose can be shuttled into muscle cells and away from fat cells. Lipoic acid is often taken with L-Carnitine.

I will have to see how 2 weeks of liopoic acid works out.

 

[DragonBits]

Not in and of itself, if that is close to one's average fasting level. But this is far below the other fasting levels, which are generally well into the 90s (concerning in and of itself), and only appeared after a huge upward spike. It's what is referred to as "reactive hypoglycemia" and is often seen in Type 2 diabetics who have an impaired first-phase insulin response. The underperforming pancreatic beta cells then try their best to address this with an over-compensating second-phase response.

Post-prandial response is not the same thing as the response to OGTT. Good possibility there would be a much stronger response to an actual OGTT. And the numbers cited for OGTT are what the ADA uses as diagnostic criteria. They also say fasting glucose levels of 100-124 are not diabetic. Many knowledgeable clinicians would say those guidelines wildly underdiagnose diabetes.

In someone with truly normal blood sugars the highest reading after meals is generally not much over 100 mg/dl and almost never over 120.

Now I have no doubt I have "reactive hypoglycemia" just not sure why and what if anything to do about it.

Probably I can prevent it by not fasting then eating a crap load of sugar/carbs. Maybe eat a small amount before a big meal. I used to get very sleepy in that situation, now I don't seem to, but who knows.

Reason I am more sure about it because a recent blood test after a glucose challenge at 3 hours I had a blood glucose reading of 40 mg/dl, which is really low. This is from a serum blood test. I didn't feel anything(dizzy, sweating, etc), and using a meter 25 min later my BG was 80 without taking any carbs, so it corrected itself but that was surprisingly low.

I don't have a lot of time this weekend, but when I do I will post the full set of labs, it was both interesting and a little confusing.

 

[Tad1979]

Now I have no doubt I have "reactive hypoglycemia" just not sure why and what if anything to do about it.

Probably I can prevent it by not fasting then eating a crap load of sugar/carbs. Maybe eat a small amount before a big meal. I used to get very sleepy in that situation, now I don't seem to, but who knows.

Reason I am more sure about it because a recent blood test after a glucose challenge at 3 hours I had a blood glucose reading of 40 mg/dl, which is really low. This is from a serum blood test. I didn't feel anything(dizzy, sweating, etc), and using a meter 25 min later my BG was 80 without taking any carbs, so it corrected itself but that was surprisingly low.

I don't have a lot of time this weekend, but when I do I will post the full set of labs, it was both interesting and a little confusing.

When you talk about reactive hypoglycemia you’re talking about a prolonged or overactive insulin response - large amounts of carbs will cause MORE insulin to be released, not less. Same with eating more frequently. Lower carb (not necessarily keto) and possibly intermittent fasting would most likely help, with additional (15 grams) of carbohydrate intake when you get symptoms of hypoglycemia.

 

[DragonBits]

When you talk about reactive hypoglycemia you’re talking about a prolonged or overactive insulin response - large amounts of carbs will cause MORE insulin to be released, not less. Same with eating more frequently. Lower carb (not necessarily keto) and possibly intermittent fasting would most likely help, with additional (15 grams) of carbohydrate intake when you get symptoms of hypoglycemia.

I don't get any noticeable symptoms of hypoglycemia, so I wouldn't know to eat 15 grams of carbs. Even when my BG was at 40, maybe I felt a little hungry, but that was subtle. I hadn't eaten for ~ 16-17 hours, I thought that was it. Or maybe my BG quickly recovered.

When you fast then eat a big meal, you get a larger spike up in insulin / glucose than you would eating the same meal and not fasting. Makes my wonder about intermittent fasting benefits, though I assume if you don't eat a big meal then you wouldn't get a problem.

As far as I can tell, my insulin levels were never really high, from 2 uIU/ml - 21uIU/ml. But since my BG went down to 40, maybe prolonged insulin release too long?

I will post the labs sometime next week, several things were unexpected.

 

[thirdstone]

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?

This is a bad thing.

Mitochondria are the organelles in your cells which convert glucose and oxygen to ATP. ATP is the actual molecule which cells, and especially in this case muscle cells, use directly for energy. Glucose goes into your muscle cells, mitochondria convert it to ATP, the ATP goes to the muscle fibers and that's what makes them go. This can occur aerobicly (with oxygen) or anaerobicly (without oxygen). Hence why exercise is either aerobic or not. The more aerobic exercise you do the mitochondria adapt by building more of the proteins and such that do the conversion, or in other words they become more efficient at converting glucose to ATP, which gives you greater endurance and you become more fit.

This is saying that metformin interferes with the adaptation or improvement in your aerobic ability on a cellular level. Sounds to me like it's not horrible, just that you would likely adapt more slowly or make slower progress in your fitness goals while taking it.

For me personally though, that's a deal breaker for metformin and I guess I'm going to stop taking it.

 

[captain]

I don't get any noticeable symptoms of hypoglycemia, so I wouldn't know to eat 15 grams of carbs. Even when my BG was at 40, maybe I felt a little hungry, but that was subtle. I hadn't eaten for ~ 16-17 hours, I thought that was it. Or maybe my BG quickly recovered.

When you fast then eat a big meal, you get a larger spike up in insulin / glucose than you would eating the same meal and not fasting. Makes my wonder about intermittent fasting benefits, though I assume if you don't eat a big meal then you wouldn't get a problem.

As far as I can tell, my insulin levels were never really high, from 2 uIU/ml - 21uIU/ml. But since my BG went down to 40, maybe prolonged insulin release too long?

I will post the labs sometime next week, several things were unexpected.

I would guess you deplete your glucose stores when fasting and then when you eat the insulin spike wouldn't have the same effect as it would if you was glucose saturated. I recall it takes 3 days to deplete stores of glucose. This I think is where diabetics get in trouble as what they eat can effect glucose storage over 3 days. I may be wrong but this it what I have read over the years.

 

[Tad1979]

When you fast then eat a big meal, you get a larger spike up in insulin / glucose than you would eating the same meal and not fasting. Makes my wonder about intermittent fasting benefits, though I assume if you don't eat a big meal then you wouldn't get a problem.

That’s not really how that works. Fasting and carb restriction help to REDUCE your insulin resistance, meaning your body doesn’t need to churn out as much for the same effect. Think of it like developing a tolerance to alcohol - if you chug constantly it takes more to feel drunk, but if you go a year without drinking you turn into a lightweight.

As for “prolonged insulin response” - with reactive hypoglycemia many people report becoming symptomatic about 2 hours after eating. It’s thought this is because their body doesn’t register to stop producing insulin and keeps producing a steady amount even though glucose levels have hit fasted levels.

I dealt with this a lot when I was younger. I was anorexic thin up until my mid 20s. The thickest part of my arms was my elbow and it was next to impossible for me to put on weight. Even after a meal, my glucose levels would sit around 60 mg/dL. This is low for someone in a fasted state, much less for someone with a recent meal. Most of the time the only thing I noticed were persistent headaches and minor tremors to my hands. But on the other hand, I needed to eat something small about every two hours or I got nauseaus, weak, clammy skin, and mental status changes that eventually would progress to loss of consciousness. It took quite a bit of time to figure out what was going on with me. I was eventually told that if I weren’t careful this would lead to type 2 diabetes because my body would develop insulin resistance. Dietary changes have allowed me to avoid that, but years later it’s really no surprise I’m having additional endocrine issues.