Five weeks ago when Dr. Alice Talks got a Facebook presence, I started a whole new episode of learning about drug side effects. Until then I was used to reading about a few reports here and there and then wait decades to have enough cases to draw a conclusion. Facebook is different: I encounter dozens of reports every day as I get online. If I ask for clarification the reply comes right away with plenty of details and often pictures too! 

The power of your voice

Each drug side effect means something important. It has a story, a reason, and a consequence. It tells us specific information about one individual. Changing the drug does not change the cause for which a patient responded in a given way to a drug treatment (i.e. experienced a side effect). It is like looking in the mirror and pretending it never happened! Sometimes that very same cause may trigger future events of dramatic importance in one’s life. I mean this in both the very good and the very bad way. Understanding that reason could get us so much closer to the Holy Grail of how our body works…

Being the pharmacist that I am, when 10 people taking metformin share detailed information about one given side effect in one single day I can’t just keep doing what I was doing. Naturally, I stop and switch gears to figure what in the world that meant. As we speak, more than a few individuals experience muscle pain and weakness after taking metformin. Others notice a urine color change to dark orange. What does this mean?

From the pill to the effect

Metformin is a simple salt before it gets in the body but shifts into a water-loving positively charged particle once the tablet dissolves. This makes it completely insoluble in fat which makes the ability of this particle to diffuse through cell membranes basically impossible. Simply said: metformin can’t just get into a cell because it happens to be next to it. In fact, it’s even easier to penetrate through space in between the cells (paracellular diffusion), than getting into a cell. That is one of the reasons for which metformin’s bioavailability (what actually gets in the body) is roughly 50% of the taken dose, the rest ending up in the poop. There are, however, many cells that can uptake metformin – such as the cells in the wall of the small intestine – but this is another story for another time.

In the case of immediate-release tablets, the absorption in the stomach or the large intestine is negligible.  The already low bioavailability of metformin is further reduced by the gastric motility and there is evidence that meals – especially high-fat meals – further reduce its absorption to half. Thus an overall of only 25% of the dose gets absorbed into the body. The rest is just explosive diarrhea caused by the fat and the gut bugs’ response to the environment created by the drug that did not get absorbed. Nevertheless, back to the muscle pain and the dark orange urine!

Based on what I just told you above, two aspects seem self-explanatory: the drug itself wouldn’t be able to get into the muscle fiber to cause pain and neither would be enough of it in the blood to get into the urine to make it change its color! On a side note: metformin is a white compound that doesn’t get metabolized; it cannot change a body fluid to orange not even if we swallow a ton of it. So, one thing is sure: the drug couldn’t have reached toxic levels in any of the individuals reporting these symptoms. Still, how did that happen?

The intricated pathways of our genetic polymorphism

Picture this: the body responds very well to a certain dose of metformin that reaches the blood. As a consequence, the skeletal muscle can take in more glucose but this happens so fast that the muscle doesn’t catch up burning it (that’s why we should exercise!). The glucose that will normally burn to CO2 and water into the muscle, ends-up being converted instead into pyruvate and lactate. Don’t rush into thinking that this is how lactic acidosis occurs – far from it. For today’s story, the more effective metformin is and the less muscle mass one has, the more lactate is going to accumulate into the muscle fibers and they will hurt, feel weak and prematurely tired.

For the vast majority of us, the lactate transporter located on the membrane of the muscle fiber will quickly remove the lactate from inside the fiber and push it outside. It will then travel to the liver and be converted there into glycogen – a form of long-term stored sugar, similar to cotton candy but at the molecular level. In other individuals, however, the removal of lactate from the muscle fiber is far less efficient. This is due to inherited genetic variants of the lactate transporter gene (mct-1). This gene holds the DNA information for the body to make what scientists call the monocarboxylate transporter 1 (i.e. MCT-1). Like with other genes, every now and then a mutation may occur. Should we be lucky enough, that may occur in a “noncoding” portion of a gene, but at times it may happen in the coding zone and translate into a protein that will look slightly different than others like it. Please notice that I did not say different from normal neither did I say different from the ideal. That’s because there isn’t such thing! We are all different and our proteins are different too. That’s because Mother Nature wants to give humans the best possible chance to adapt to anything that comes their way. We may simply not know yet, but these variants may provide an advantage for the host!

Individuals having a lactate transporter that isn’t very efficient to take the lactate out of the muscle fiber are perfectly healthy otherwise. They may never find out about carrying a genetic variant unless they undergo a full genetic sequence of their genome. These individuals are perfectly ok except with performing extreme physical endurance in running, hiking, swimming, or gymnastics. Not having a very efficient lactate transporter doesn’t mean the absence of one. The lactate removal takes place anyway but is slower. So, after taking metformin the sugar enters the muscle, undergoes incomplete burning, and increases the amount of lactate. In consequence, the muscles will hurt and feel fatigued as after an intense workout. If this has occurred suddenly and persisted for a while, myoglobin – a protein specific to the muscle fiber – may begin to break down. It is this event that leads to the color change of the urine to dark orange.

How do you deal with a less efficient MCT-1 transporter?

Any of the above signs and symptoms indicate 1) little muscle mass and 2) very effective response to metformin. The best solution is to get more muscle mass. Developing more muscle mass should be the goal of anyone that was prescribed metformin anyway. Why? Because the muscle fiber is the main tissue that can burn the glucose, which is what we are trying to get rid off in the first place. With appropriate muscle fiber formation, one-day in the future metformin won’t be needed any longer. Moreover, the effectiveness of the MCT-1 transporter will be irrelevant as there will be dramatically more muscle fibers to burn the same amount of glucose. So, the lactate formed per muscle fiber will be much lower – hence no pain.

• Would metformin become toxic in meantime?

That is highly unlikely. In fact, if one would measure the metformin blood levels in patients experiencing these symptoms will rather find normal or low levels of metformin. Check with a licensed provider to be on the safe side and always ask questions, but remember the context explained above.

• How should one deal with the symptoms while working on to develop muscle mass?

Oxygen is key. Bring fresh air into the space where you live, take long walks outside, and move as much as possible. The more oxygen is available to the skeletal muscle, the more complete the burning of glucose and the less lactate is formed in the muscle. Hence, the less work for the lactate transporter. Make sure that your blood has a maximum capacity to carry oxygen. Check your hemoglobin (not only A1c, but the actual hemoglobin) and ensure that is within normal ranges. Check out all my posts on anemia and understand what are the risks of not carrying sufficient oxygen to the tissues. Ensure that B12, folate, and iron are all at goal. If they are suboptimal, learn how to correct them by diet or supplementation. Exercise a bit more every week and drink plenty of water. Remember that muscle mass isn’t light, so as you build more muscle mass be prepared not to see a drop in weight on the scale. Lastly, avoid carbs as they are directly responsible for increasing the circulating glucose that gets converted to lactate.

• Can lactate transporter deficiency become serios?

I am aware of one single case report of complete MCT-1 deficiency, but I learned that this doesn’t mean much as it may have gone unreported in many others. In such case of extreme deficiency, symptoms may unveil far before a diabetes diagnosis and long before the first dose of metformin. Complications may occur in individuals with a history of ketoacidosis or having relatives that have a history of ketoacidosis as such history may indicate the presence of a moderately impaired lactate transporter which may further worsen metformin side effects if metformin is prescribed. Should you be aware of ketoacidosis history in a family member, do reach out to at least one clinician and discuss your risk.

I hope that you found this information helpful. Feel free to share your thoughts and ask more questions or let me know in the comments what you want to learn next! Click like below if you found this useful 😀 and stay healthy until next time.

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