Saturday, April 01, 2023

Metformin (14) Normals

One of the flakiest aspects of Protons is the concept that the glycerophosphate shuttle transforms cytoplasmic NADH in to a mitochondrial FADH2 input, altering the FADH2:NADH ratio in a direction which favours reverse electron transport through complex I, given a reduced CoQ couple, and this leads to a) continued ROS generation to maintain insulin signalling and b) easy achievement of high ROS once a cell is replete with calories, ie when it is then necessary to resist further insulin mediated calorie ingress.

So the glycerophosphate shuttle should mediate both insulin signalling and insulin resistance, essentially controlled by the redox state of the CoQ couple. If CoQH2:CoQ is moderate ROS are still adequate to activate insulin signalling, if CoQH2:CoQ ratio is high ROS will also be high and insulin signalling will be curtailed.

Metformin blunts insulin signalling, in addition to reducing hepatic glucose output, by blockade of the glycerophosphate shuttle at mtG3Pdh.

Finding evidence to confirm this bias is not easy. I hope we all recall the poor Polish girl with SHORT syndrome who fell in to the hands of the endocrinologists who "treated" her insulin "resistance" with metformin. That ended well...

Metformin (11) a SHORT paradox

However, I tripped over this next paper while looking for something else. Oddly enough when I saved it it turned out I had already got a copy and had put up a one liner post about it

Metformin (12) You don't need to be SHORT

but didn't explain its significance. Here's the paper:

and here we go as to why I like it.

These are the results of treating either DMT2 people or people with a family history of DMT2 using metformin. There is an almost infinite supply of such responses in Pubmed, metformin is clearly insulin sensitising. If you wanted to you could say that metformin reduces insulin resistance. And then blanche at the thought of trying to define exactly what you mean by "insulin resistance".

I guess the first small fly in the ointment is the fasting FFAs,  as I've highlighted here

It looks like the rise in FFAs was not statistically significant but it must have come damned close. Increased insulin sensitivity should suppress FFAs.

So if we consider the insulin and glucose responses to be a direct result of suppressed gluconeogenesis in the liver and subsequent decreased hepatic glucose output then the rise in FFAs becomes as simple as being a direct consequence of metformin decreasing insulin signalling in adipocytes via blockade of mtG3Pdh plus a decreased absolute level insulin per se due to reduced hepatic glucose output. From my point of view all the adipocytes "see" is less  absolute insulin plus less ROS generated via the glycerophosphate shuttle, so less insulin signalling. They release FFAs.

If we then look at an obese person who is still insulin sensitive they have no fasting hyperglycaemia and no fasting hyperinsulinaemia.

Giving metformin for 10 days has essentially no effect on fasting insulin or glucose. Gluconeogenesis will still be reduced by metformin but the accompanying blunting of hepatic insulin signalling (via blockade of mtG3Pdh) allows more glucose release, so the two roughly balance out. This may not be the case under peak metformin effect, diabetic rats do drop their blood glucose on an IV dose of metformin at a therapeutic level of hepatic glucose output suppression. This may well be dependent of how much metformin you give, by which route and at which time you measure. Fed vs fasted would matter as well.

On feeding 75g of glucose to normal people for an OGTT insulin signalling becomes important and the decreased insulin signalling intrinsic to metformin shows as mildly impaired glucose tolerance (statistically ns but clinically 130mg/dl vs 170mg/dl might be undesirable) but because of blunted insulin signalling a significant compensatory hyperinsulinaemia is needed to get even this rather impaired glucose response.

So. In insulin sensitive people metformin's easily comprehensible action to obtund insulin signalling shows, under high glucose and high insulin conditions, as an impaired glucose tolerance with compensatory hyperinsulinaemia.

With supra-maximal dietary glucose (the specific intention in an OGTT is maximal activation of the insulin system) suppression of hepatic glucose output becomes irrelevant and all we see is mtG3Pdh inhibition manifest as poor insulin signalling. As it did for the poor girl with SHORT syndrome.


I'm now wondering if there is any logical way of working out why people with DMT2 almost always (and clearly unexpectedly) benefit from metformin, while people with simple obesity behave exactly as you would expect them to do under an insulin signal blunting agent, especially during an OGTT.

It might be possible. I'm thinking about it.



ItsTheWooo said...

My name is NORA VELLI, i am a RN from BAYONNE NJ. I posted under the moniker ITSTHEWOO, twitter handles itsthewoo and its_tew. You can review for yourself, years of communication between myself and these individuals.
I was targeted by EMILY DEANS MD, of evolutionary psychiatry, using the twitter moniker evolutionarypsy, back in 2010-2011. She arranged for me to be followed by hackers, and sold to a gang.
She and hacker accomplices also set up influencer JIMMY MOORE to go to prison 20 years for fake charges of pedophilia.

There are many, many people involved. They established fake influencers like TED NAIMAN, DR TRO for this project, the latter of which is a cash only MD conceirge money laundering front pretty sure. I will say my story as long as I can speak, until the day they make me disappear. For now i am kidnapped in my home, under surveillance, sold and raped.
Please watch my video telling my story. It is too late for me, but i want people to know the truth.

Please also read my story. Bill Lagakos, Dr "Tro" Kalayjian , Ted Naiman and MANY MORE are all involved in this plot. They are fake influencers, established by a criminal group, particularly Dr Tro who established a CASH ONLY MD CONCEIRGE service that is actually a criminal money laundering front. I do believe EMILY DEANS is the original who unleashed this on me in REVENGE for posting rudely to her friends. Melissa McEwen detailed and hinted of it, on her blog paleo drama. She posted the ominous comment to jimmy "cute is a word used for toddlers". They framed him to go down as a pedophile 10 years later, like they set me up to be kidnapped by a gang.

This is all real, and Emily Deans MD is the mastermind i am pretty sure. She's a complete psychopath, EVEN MANIPULATING Melissa McEwen and Evelyn Kocur to seem like the "suspects" in the future. She knew a hacker, and arranged these elaborate future plots against us.

It is too late for me, but i will do my best to share our stories, her victims.

It was EMILY DEANS MD who posted under the moniker "SIDEREAL" some of you might remember. That was her. She was fanatically preoccupied with these elaborate life theft plots, even going so far as to PERSONALLY involve herself and infiltrate from 2012-2014 as this "sidereal" character. It is for this reason, I do believe she is the mastermind, as well as the fact the "main" hacker who hinted he is af riend, is about her age. I believe her REAL MOTIVE was bored in house with small children, feeling a way about being "robbed" of professional greatness. She repurposed ALL HER FREE TIME and personal angsts, into plotting against me and adding Jimmy Moore. An ironic, slow theft of 2 lives, to compensate for having to be forced to invest, in her two children, cheated out of "her right" to greatness in the real world.

SHE MANIPULATED McEwen to seem like the source, even Kocur. It was her. She's a psychopath, will never face justice, but I will TALK as long as i can. I am not OFFICIALLY kidnapped yet, just virtual kidnap, sold and raped every day.

ItsTheWooo said...

OH, AND ONE MORE THING. For MONTHS they have been threatening to frame me in a lawsuit. I am pretty sure this will happen mid April. This group can make anything not real, real AND anything real, not real. They have hackers, that can hack WEBCAM DATA to make fake videos, fake audio, AI photos you name it. By the same TOKEN, they can hack databases, to set people up that they never held licenses, or never went to school.

I am not sure what their angle is, but i suspect it will be either manipulating evidence AFTER infiltrating legitimate cases I may have been involved in... or they will frankly WIPE all data that EVER held a RN license, that I went to school and was valedictorian of my class.

The truth is, I have held an active unblemished license in the state of NJ since 2008. FOR NOW this is public free available information. I put a screen shot on my blog.

I will not be able to stop OR defend myself against what they will do. But I can talk now, before it happens... while her WHITE MD ELITIST friend, mocks it will happen.