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Mitochondria and Insulin Resistance

Mitochondria and Insulin Resistance

Do mitochondria play a role in insulin resistance?

Do you think having mitochondrial dysfunction might play a role in metabolism of glucose? Maybe…

The name “insulin resistance” should be somewhat self-explanatory. It is a chronic condition where your body does not respond to insulin like it should. That then translates to poor glucose metabolism. Thus, diabetes and insulin resistance are tied closely together. One could even argue they are the same disease state.

Hyperinsulinemia & insulin resistance are bad - Do mitochondria play a role in this?

Having impaired glucose metabolism leads to high blood sugar and, consequently, hyperinsulinemia (which has it’s own problems – check out our previous blog post to find out more). This is a cycle scientists don’t understand quite yet. Which one precedes which? Does insulin resistance lead to hyperinsulinemia, or does hyperinsulinemia lead to insulin resistance? The scientific community just doesn’t know right now. There are arguments on both sides.

But we have already tackled that bear in our previous blog post (linked here). Let’s switch gears a little bit to talk more about the role of the mitochondria in all of this. If insulin resistance leads to a problem with glucose metabolism, then the mitochondria are sure to play a part, right? After all, the mitochondria are the metabolism center pieces – the place where all broken down food ends up to create ATP, the energy of life.

We analyze an article in Endocrine Connections that hails from Australia to explain where the science stands in regards to how mitochondrial dysfunction and insulin resistance are related [click the title below for the file]:

Montgomery MK, Turner N. (2015). Mitochondrial dysfunction and insulin resistance: an update. Mitochondrial dysfunction and insulin resistance: an update. Endocrine Connections 4: R1-R15.

Summary

  • The scientific community (pretty much) has no idea what is going on with insulin resistance.
    • Comforting, we know…
    • There might be some genetic predisposition at play with insulin resistance.
  • Mitochondrial dysfunction may lead to insulin resistance – or – insulin resistance might lead to mitochondrial dysfunction.
    • (Most likely, it is a little of both – creating a vicious cycle like we saw with hyperinsulinemia and insulin resistance.)
  • Overloading on food (carbs or fat) leads to mitochondrial dysfunction and insulin resistance.
  • When the stress on a mitochondrion is too great (creating problematic metabolism), your body rids itself of it. This process is called “mitophagy.”
    • It appears as though your body is a well-oiled machine, able to take care of the problematic gears that disrupt the motor.
    • It is very similar to autophagy, which is the process by which your body cleanses itself of whole cells, leading to a longer life.

Introduction

This week’s research article attempts to summarize the link between insulin resistance and mitochondrial dysfunction. To be honest, this article put more questions in my head rather than clearing anything up. We think this quote from the journal summarizes our findings nicely:

“The relationship between mitochondria and insulin action is highly complex and there is still much to learn in this area.”[1]

Scientists don't know what is really going on

That is exactly right. The researchers bring up evidence on all sides of this issue: mitochondrial dysfunction induces insulin resistance; insulin resistance induces mitochondrial dysfunction; and there is no link between being insulin resistant and having dysfunctional mitochondria.

Damn, that isn’t super helpful. But it is still good to understand the mechanisms at play. Because they are so complex, we are going to leave the technicalities out. We are only going to focus on the conclusions and implications of each possible way misbehaving mitochondria and insulin resistance are tied.

This article is a review article, so it takes findings from tons of other researchers to come to come to conclusions. These kinds of research journals are awesome because they boil down so much of the experiments actually run on these topics. It’s an excellent summary, but it is still so dense with the information and technicalities that it takes a few times to read it.

Read along!

But anyway, we encourage you to take a look at the article and follow along if you wish to learn more about how these scientists actually work. We like breaking the barrier between doctors (and researchers) and the average person. This blog post is a little different from the previous ones – because no striking conclusions were made. I apologize if the post seems kind of jumbled. It was the nature of the article, and I will do my best to boil it down for you. It will mostly be commentary as opposed to heavy technicalities and follow-up research. So, let’s jump in!

What is mitochondrial dysfunction?

The mitochondrion is the “powerhouse” of the cell. It is where you generate energy to supply to every part of your body. Needless to say, it is very important. It is also the main place where oxygen consumption takes place – cellular respiration.

Let’s start with how they define “mitochondrial dysfunction” because it actually varies depending on what researchers you read. This article has it in the context of reduced metabolic capacity – meaning, the mitochondria have a lower rate of breaking down compounds (reduced electron flow at the ETC) to generate ATP. So the mitochondria are analyzed based on whether there is sufficient substrate oxidation (metabolism).

Rather than your mitochondria actually turning food into usable energy, they get clogged up or they “refuse” to metabolize anything. Insulin resistance is a key part of this problem, because your body might “refuse” to use glucose because it is not receptive to insulin! Insulin is the key that unlocks your cells to be able to take glucose in. If there is no signaling by your insulin to the other parts of the cell, you can bet there is not going to be any metabolism taking place.

The researchers break down the reduction of food metabolism into 3 main pathways: a decrease in the number mitochondria; a decrease in the creation of mitochondria; or a decrease in the protein action/number along the electron transport chain. Check out part A of the simplified figure below.

How do we get mitochondrial dysfunction?

 

What does it lead to that is problematic?

One major problem of decreased substrate oxidation is that there is an accumulation of lipids that hang outside the mitochondria and cell. They don’t end up being used like they normally would. They usually go through beta-oxidation for energy production, and you can review how that normally happens here. According to this article, when lipids accumulate, they cause reduced insulin signaling. This is one possible connection.

Another possible mechanism is that lower metabolism leads to higher electron leakage. When you leak electrons backwards through the electron transport chain, you generate oxidative species. Because oxygen is a key player in metabolism, you create “reactive oxygen species” (ROS) that go around and damage everything. We have done several blog posts on why ROS are bad, you can check out a starting point here.

Spilling electrons backwards only causes more insulin resistance

The kind of oxidative stress that ROS puts on mitochondria can lead to several problems (directly or indirectly) with insulin signaling. This stress is not good on mitochondria, and your body might decide to get rid of them (mitophagy). This will lead to a lower number of mitochondria, which means there is less of it around to signal with insulin. Thus, we have another possible mechanism for why mitochondrial dysfunction can lead to impaired insulin function.

The main point here is: having mitochondria that can’t metabolize food as well leads to lowered insulin action. Having a lower metabolic rate through this pathway is not favorable for insulin activity.

[However, having a lower metabolic rate might be beneficial, but we will save that topic for another time… Admittedly, I have not done enough research on it to know exactly. But for right now, let’s just consider that lower metabolism of substrates leads to insulin resistance.]

How do we decrease our substrate oxidation?

That is a great question, and this is the part where you’ll see the vicious cycle coming to play. We saw above that ROS creation leads to a smaller number of mitochondria That is a possible way you have lower insulin capabilities. But then having less mitochondria will lead to less substrate oxidation. The less substrate oxidation will lead to more ROS generation. And the cycle continues!

Also, they suggest that overeating on fats will lead to insulin resistance. There will be an increase in lipid oxidation, but a decrease in insulin sensitivity. I would be curious to know if these “high fat diets” were also low in carbohydrate. If not, then it is pretty useless information. Anyway, overeating on fats will lead to the accumulation of lipids on the outside of mitochondria that we talked about before. This will lead to insulin resistance. They did also find research that suggested eating fat actually improved insulin resistance. We theorize that eating fat helps, as long as you do not overeat!

 

Caloric restriction helps with mitochondrial dysfunction

 

How the keto lifestyle fits in

When you are insulin resistant, the best therapy for you is to eat more fat. Follow the ketogenic lifestyle. But be careful! If you overeat on the fat, then you can actually be causing more insulin resistance. But, in our eyes, it doesn’t matter that much because you won’t be eating as many carbohydrates – you’ll need less insulin. That is yet another topic for another time. The point is: don’t overeat… on anything! Carbohydrate or fat.

We did a whole blog post on the topic of caloric restriction. Check it out here. It is very beneficial for your body. A great point about a keto diet is that you will naturally eat less anyway! So “overeating” becomes much harder. If you eat less carbohydrate and replace it with fat (but not too much), you will see increased lipid metabolism, and you won’t get the accumulation that occurs on the outside. You will become metabolically healthy.

Genetic predisposition for insulin resistance

This section could be really long if we wanted to go through each mechanism to see which exact genes lead to mitochondrial dysfunction and insulin resistance. But we won’t do that here because there is really only one main takeaway. Genes play a major role in your ability to metabolize substrates and respond to insulin. Shocker…

This may seem obvious at first – it was for me. Genetics always play a role in our body’s ability to do stuff. But what was new to us was the order in which this happens. Some studies suggest that having dysfunctional mitochondria might lead to genes that are “messed up.” Or, you might have genes that are messed up, and that leads to problematic mitochondria. Again, it is probably a little of both.

Genetic makeup plays a part in mitochondrial dysfunction and insulin resistance

The researchers looked at other experiments that dealt with all of this stuff. These experiments involved removing some gene to see what happens. They found a few that relate directly to insulin signaling and substrate oxidation through the electron transport chain. This implies that you can alter your genetics based on what you put into your body! That is so cool.

Conclusion

According to the article, the best way to fight insulin resistance is to keep up light exercise and to decrease the amount you’re eating. We would suggest the very same thing. They also mention some pharmaceutical approaches to this as well. They suggest that drugs that cause mitochondrial uncoupling will help with insulin resistance. This is something I remain skeptical of.

Uncoupling is where your mitochondria are going though the motions to create ATP, but the ATP never comes. Pretty much, you are wasting energy by getting everything set up, and then… it all falls through. Apparently this kind of process helps with insulin resistance. But is this really how we want to improve insulin sensitivity?? Proton leak (in excess) is not good, so why we would want to induce it is beyond me.

I would avoid mitochondrial uncoupling if I was you. Not that you’ll ever run into someone who asks, “Hey! Would you like some uncoupling in your body?” – but just beware of this kind of therapy.

Okay. In summary, scientists still have no idea what is going on with the order of insulin resistance and mitochdrial dysfunction. But we are at least on our way! One major problem they saw with the experiments as that they were done in lab dishes rather than the actual body. So, we need to study what happens in the actual body if we want to fully understand what is going on. More research is needed – classic.

Summary

This week, we did not do as much outside research on the topic because this summarized it really well. Also, there is no point to doing outside research when we would come to the same conclusion they did: we are only on the surface of understanding what’s going on. Anyway, I hoped you learned something new today – and leave a comment below if you have something to add or have any questions!

  • The scientific community (pretty much) has no idea what is going on with insulin resistance.
    • Comforting, we know…
    • There might be some genetic predisposition at play with insulin resistance.
  • Mitochondrial dysfunction may lead to insulin resistance – or – insulin resistance might lead to mitochondrial dysfunction.
    • (Most likely, it is a little of both – creating a vicious cycle like we saw with hyperinsulinemia and insulin resistance.)
  • Overloading on food (carbs or fat) leads to mitochondrial dysfunction and insulin resistance.
  • When the stress on a mitochondrion is too great (creating problematic metabolism), your body rids itself of it. This process is called “mitophagy.”
    • It appears as though your body is a well-oiled machine, able to take care of the problematic gears that disrupt the motor.
    • It is very similar to autophagy, which is the process by which your body cleanses itself of whole cells, leading to a longer life.

References:

[1] Montgomery MK, Turner N. (2015). Mitochondrial dysfunction and insulin resistance: an update. Mitochondrial dysfunction and insulin resistance: an update. Endocrine Connections 4: R1-R15.

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