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Fatty liver the cause not the consequence of hyperinsulinemia
Insulin’s job is to PUT AWAY the groceries.
Now, with this kind of job description, one would expect insulin to ONLY be out and about, during the day, when eating happens.
And in healthy folks, this is pretty much the story.
Ready, set, go..
Insulin levels quickly rise in response to the arrival of a meal, both the presence of sugars and amino acids, spark a flurry of activity in the pancreas. The insulin that is released, quickly gets to work moving nutrients out of the blood and into tissues. Once all the sugar has been taken care of and the sugar levels are back IN RANGE, the cells responsible for insulin production, can take a break.
Until the next feeding occasion.
Now when you’re insulin resistant, the pancreas seems to be a little slow off the mark, when you eat something yummy. Unfortunately, this tiny delay, can mean that sugar levels rise a little higher than ideal, but when all is said and done, the sugar is handled.
We admonish the pancreas for being slow.
But what is not always appreciated, is one of the reasons for the dilly dallying, is the beta cells, are taking SERIOUS strain.
They’re being expected to produce insulin 24/7.
Instead of insulin levels, ebbing and flowing, across the day and flat lining, overnight, in the metabolically challenged insulin levels are high : morning, noon and NIGHT.
NOTE : People who are insulin resistant, wake up with high levels of insulin, despite not having eaten for hours.
The high insulin levels are not just stressful for beta cells, pretty much every body part SUFFERS. The lucky ones manage to…………. RESIST insulin !
Among the most vulnerable body parts, are blood vessels.
Since they are bearing the full brunt of the egomaniac whose mission it is, is to put away THE GROCERIES.
High insulin is not healthful for anyone.
Doctors call it metabolic syndrome – it’s the bad body chemistry behind, heart attacks, diabetes and many cancers. Eish ! Ironically, the way they often treat it, is to demand beta cells work harder. Eish !
Who is keeping beta cells awake all night ?
This is the big question……….
The first response might be, the elevated glucose levels are the problem. But, truth be told, it takes years of beta cell abuse, to get to the point, where they fail to deliver enough insulin, to keep the sugar levels IN RANGE.
Something or someone else, is keeping beta cells awake all night.
A team of researchers based in Tuscon, Arizona had a hunch, the someone was the liver.
A vagus powerplay
What clued them into this was the fact that the easiest way to stop excess insulin production, is to disconnect the liver from the parasympathetic network.
The procedure is called a hepatic vagotomy.
When the hepatic afferent nerve (HVAN) is snipped, it stops the liver from being able to send reports to the brain, but despite the missing data, the brain’s ability to run the show, is more or less intact.
More or less….. less insulin is produced overnight and there are no sugar spikes to worry about.
Now, before you book yourself in for a hepatic vagotomy, BE WARNED. It’s not a perfect solution. Mice fed a high fat diet become IMMUNE to the “bad’” diet i.e. they don’t pack on the pounds or develop metabolic complications.
But on the flip side, skinny mice become INSULIN RESISTANT !
NOTE : This happens because stimulating the nerve, prompts the liver to produce something that increases glucose uptake in the muscle. Click here to learn more.
HVAN fire power
Our team wanted to know why, severing the nerve, resulted in less insulin being secreted, despite an obesogenic diet. They theorized that if they could put the pieces of the puzzle together, they could SOLVE the hyperinsulinemia problem and reap some rewards.
But at first glance, this decrease in insulin secretion, didn’t make sense…….
Studies have shown, nerve firing dampens down insulin secretion !
Conversely, only when the nerve is NOT firing, is insulin secretion, amplified !
Eish ! Biology is complicated.
No fire power
There were two possible explanations for the increased insulin secretion, associated with obesity….
The liver is either firing up the nerve, by sending excitatory chemicals it’s way
It’s interfering with the signal, that should dampen down the response.
GABA is the signal
Using slices of liver from obese animals, the team pin pointed the signal….
Fatty livers were deliberately dampening down the nerves response, by releasing GABA, the quintessential inhibitory neurotransmitter.
The releasing of the GABA is not entirely voluntary.
It’s leaking out.
A positivity problem
Using a combination of mutant mice and pharmacologically, our team pieced together why and how fat livers, drive beta cells……………. CRAZY !
They’re full of positive ions.
In biological speak, the liver cells’ membranes are depolarized.
The reason for this unfortunate situation is despite being full of fat aka. fuel, the hepatocytes are short of energy, because accessing the fuel in those lipid droplets is not easy. The energy shortages, force them to cut back on some energy intensive processes, such as pumping sodium out, via the Na K ATPase pump.
This creates the positivity problem.
And contributes to there being a little more GABA than usual, thanks to GABA shunt.
Since GABA is ordinarily transported by ion dependent transporters, the enhanced positivity, sees more GABA moving out of the cells. Once it’s out of the cells, it is able to hook up with GABAA receptors on the hepatic afferent nerve, where it does what GABA does…it INHIBITS.
And nerve firing slows.
Insulin secretion increases, effectively cancelling beta cell tea breaks….
GABA the bad guy ?
Only on paper.
GABA is THE MAJOR inhibitory neurotransmitter – 60-75 % of all synapses in the brain are GABAergic and the pancreas, has it’s own GABAergic system in place, which keeps beta cells happy and healthy. So the option to exploit this biology, is more than likely a fantasy, but the research team are committed to give it a go.
The trouble is stopping, the production of this tiny amount of GABA, which is being produced locally, deep inside the liver, will potentially have a lot of negative consequences.
GABA is ESSENTIAL !
But all is NOT LOST…….
GABA levels track fat levels
The team found, the more fat stashed away in the liver, the more GABA was being leaked out.
Fatty liver goes hand in hand with metabolic syndrome.
It’s typically seen as a consequence of insulin resistance, but this research suggests, it might be a big contributor to the problem. And what needs to BE FIXED, in the metabolically challenged.
The fix for fatty liver
There are multiple points in the fat processing cycle of the liver, that can be leveraged.
One that might not be on your radar is to facilitate the assembly of VLDL particles. You can do this, by making sure your liver cells have an adequate supply of BUBBLE WRAP i.e. choline. Click here to learn more.
A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity. Cell Reports (2021) 35: 109301. Caroline E. Geisler, Susma Ghimire, Stephanie M. Bruggink, Kendra E. Miller, Savanna N. Weninger, Jason M. Kronenfeld, Jun Yoshino, Samuel Klein, Frank A. Duca, and Benjamin J. Renquist
SUGAR is the enemy and INSULIN is the saviour. The “success” of bariatric surgery, as a treatment for type 2 diabetes, is forcing a re-think of the story.
The story of diabetes is always written like this…. you put on weight, become insulin resistant, then eventually diabetic. But, this diabetes timeline is WRONG.
Normal mice, fed a normal diet but given, EXCESS insulin, develop type 2 diabetes. More insulin is NOT the cure for type 2 diabetes.