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