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Mitochondria in insulin resistance

Posted by Dr Sandy on in IR | 62 Views | Leave a response

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When you’re insulin resistant, that is, you’ve got  metabolic syndrome, pretty much every chemical in the body is NOT QUITE RIGHT.  Some are up.  Some are down.  Few are actually at physiologically NORMAL levels.

Traditionally the focus is on the big guns.

  • Sugar
  • Insulin
  • And cholesterol

In this series, we  take a look at some of the other players.

Who they are, what they’re up to and how they’re part of the state of insulin resistance.

This week, we contemplate  how well your cell furnaces (mitochondria) are working.

Now, when you’re insulin resistant,  you typically have decreased oxidative capacity, which is a fancy was of saying……… you’re not burning fuel, very well, part of the problem, is you have fewer mitochondria.

It’s a situation that leaves you low on energy.

mitochondrial dysfunction inside a cell

And, battling the accumulation of fuels, that have not been burned.

This happens INSIDE cells, as well as in the circulation.  Eish !

Exactly why, oxidative capacity is decreased is a matter of some controversy.  Some people think, it is the problem.  Others think, it is as a result of the problem.  I am not sure it matters all that much.

The point is, if you’re insulin resistant, turning up the furnace(s), is likely to be beneficial, which brings me to the star of this video,  PGC-1 alpha.

PGC-1 alpha to the rescue

Peroxisome proliferator–activated receptor-? coactivator-1? or  PGC-1 alpha for short – this little guy, turns up cell furnaces.  The more active PGC1 alpha is, the more insulin sensitive you are.

So what is PGC-1 alpha ?

PGC-1alpha, belongs to a family of chemicals called transcription co-activators and there are multiple forms of PGC-1 alpha.  It’s modus operandi, is to partner with specific transcription factors……………

pgc1 alpha turning on mitochondrial synthesis

PGC-1alpha,  hooks up with specific transcription factors and then helps them,  scan  through all the genes in the nucleus, and select the “RIGHT” genes, he then helps them lock onto the DNA, and get the gene, turned on. .

PGC-1alpha has a working relationship, with quite a few transcription factors.

pgc1 alpha interacting with transcription factors

Exactly who he hooks up with, depends on the cell type.

When it comes to furnaces – the parternership with NTF is most important. It’s a supervisory role, which results in the installation of more furnaces, in a whole host of cell types.

pgc1 alpha switching on mitochondrial biogenesis

For the most part, the additional fire power is beneficial.

This is especially so in the skeletal muscle, because there is lots of skeletal muscle, making it a power user of fuel, Particularly sugar.   80 % of the sugar that comes in with a meal, should end up in muscles.

So what get’s PGC1 alpha, out and about, in muscle cells ?

An energy crisis

If PGC1 alpha, perceives an energy crisis……………… he get’s on his bicycle and heads for the nucleus, with the explicit aim of cranking up energy production.  His first port of call is to increase the actual number of furnaces on the ground (mitochondrial biogenesis), but in addition to this, he’ll do what he can, to tweak the efficiency of the existing furnaces.

In his tool kit…….

  • Improving blood delivery, by the process of angiogenesis
  • Neuromuscular junction remodelling etc.
  • Muscle fibre type switching
  • ROS (reactive oxygen species) scavenging

So you want to create an energy crisis inside muscle cells !

Now this can be done pharmacologically or naturally…..

Creating an energy crisis, using drugs

There are quite a few pharmacological options, currently the option, all work indirectly, but this is an area of active research,  and drug companies are actively exploring ways to stimulate PGC-1 alpha, in specific cell types, DIRECTLY.

drugs that impact mitochondrial function

NOTE :  Several of the drugs, currently prescribed to treat type 2 diabetes, end up increasing PGC-1 alpha. Metformin does this, by sabotaging on of the pumps, inside the furnace.  The glitazones, mimic PGC-1 alpha.

Creating an energy crisis, naturally

The good news is………. there are at least two ways to this naturally.

natural ways to stimulate pgc1 alpha

NOTE :  Natural is always going to be, a better option, because these strategies ensure the expression of PGC-1 alpha, happens in the “right” place, at the “right” time.

One way, you can create an energy crisis, inside your muscles, is to get on your bicycle and go for a LONG RIDE i.e. do a bout of vigorous exercise.  The other option, is  to skip eating for a couple of hours i.e. fast.  If you’re up to it, DO BOTH, at the same time.

It’s called fasted cardio.

In all these scenarios, you create an energy short fall, inside the muscle, getting PGC-1 alpha’s attention, so you end up,  commisioning a few more furnaces.

warm and toasty inside cell

BURN BABY BURN  !

Too warm and toasty ?

Hang on minute !   Won’t more furnaces, mean more fire and potentially,  more damage i.e. oxidative stress ?

Yes and No.

You’re “right”,  mitochondrial activity, does generate toxic products. This happens when a small percentage of electrons “leak” out and combine with oxygen, creating reactive oxygen species (ROS).

There are 11 spots in the electron transfer chain, where this happens.  Eish !

But NO WORRIES……

Mother Nature ALWAYS has a plan B.

The commissioning of anti-oxidant forces

Remember PGC1 alpha is a transcription CO-ACTIVATOR.   He works with quite a few transcription factors, among them, is NRF-2 (nuclear respiratory factor), whose claim to fame, is he turns on the anti-oxidant defence system.

pgcq alpha turning on oxidative defence systems

NOTE :  Which for the record, when you’re insulin resistance, is usually not pumping on all four cylinders either.

Complicating the story………….

Inflammasomes undermine PGC-1alpha

Any time there is inflammation, which there is, when you’re insulin resistant, the transcription factor in charge of inflammation, nicknamed, the INFLAMMASOME –  works hard to oppose PGC1 alpha.

It’s a job requirement.

Dealing with inflammatory forces, requires a supply of ROS tazzers.

This ALL adds up to, MORE  oxidative stress – and more metabolic troubles….

NOTE : Adding insult to injury, insulin also suppresses PGC-1 alpha activity…… it turns out, PGC-1alpha, cramps insulin’s style, as well.

The take home message, if you’re insulin resistant………

FIRE UP THOSE FURNACES  !  

You need to work at getting your insulin levels down, and work at creating an energy crisis, every now and again – so you stoke up your furnaces.  It will help you burn up all that fuel, which is accumulating and tame some of that oxidative stress, contributing to metabolic havoc.

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Here are a few of the journal articles I’ve used to tell the mitochondrial dysfunction story.

Intercellular: local and systemic actions of skeletal muscle PGC-1s. Trends in Endocrinology and Metabolism (2015) 26(6):305-14. Jorge C. Correia, Duarte M.S. Ferreira, and Jorge L. Ruas

PGC-1?, Inflammation, and Oxidative Stress: An Integrative View in Metabolism. Oxidative Medicine and Cellular Longevity  (2020)  Article ID 1452696. Sergio Rius-Pérez, Isabel Torres-Cuevas, Iván Millán, Ángel L. Ortega and Salvador Pérez

Insulin Resistance and Mitochondrial Dysfunction.  Advances in Experimental Medicine and Biology (2017) 982:465-520. Alba Gonzalez-Franquesa and Mary-Elizabeth Patti

Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance? Int. J. Mol. Sci.(2020) 21 : 6948. Amanda J. Genders, Graham P. Holloway and David J. Bishop

Targeting Mitochondrial Biogenesis to Treat Insulin Resistance.  Curr Pharm Des (2014) 20(35):5527-57. Mònica Zamora and Josep A. Villena

Further reading

antioxidants with exercise

Combining an antioxidant with exercise is NOT a health move

Exercise improves insulin sensitivity, but the benefit requires a little oxidative stress. So if you combine an antioxidant with exercise, you lose the benefit

smoking hot mitochondria

Body power stations are not designed to run 24/7

If your body rhythms are off, there is a good chance your mitochondrial furnace never turns off. This means ROS 24/7 and oxidative stress is what kills.

green mitochondria

Mitochondria burn out brings fire to the feet

Moving mitochondria 90 + cm from the spine to the toes takes time. When the equipment arrives, its dysfunctional, making foot nerves vulnerable to break downs

Want to discover more ways to create BETTER BODY CHEMISTRY ?

Posted in IR | Tagged energy crisis, inflammation, insulin resistance, metabolic syndrome, mitochondria, muscles, oxidative stress, PGC-1 alpha, transcription co-activator, transcription factors, type 2 diabetes

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