Thursday, April 06, 2023

Metformin (15) ROS

Time to talk about insulin signalling, metformin and the phosphorylation of AKT.

I borrowed this image
















from this paper

An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

because, unlike most images you will pull out by searching "insulin cascade", this one actually features a role for ROS and so forms a good basis for discussing metformin. So once agin it's PowerPoint doodle time. I'm going to miss out everything from the paper about anti-oxidants and PGC-1𝛼 etc.

First of all let's simply reduce the diagram to the canonical insulin signalling pathway by using a few blottings out:
















In the simplistic world of insulin signalling, insulin arrives and this happens:
















As part of the process AKT is phosphorylated and this is one of the core signals to activate the translocation of GLT4 and CD36 to the cell surface, facilitating caloric ingress:
















There are several AKTs and they can be phosphorylated in various places but the simple message is that

Insulin -> insulin cascade -> pAKT -> caloric ingress

It is now very well accepted that the trigger for this cascade is the generation of ROS by NADPH oxidase 4 (NOX4) in response to the docking of insulin with its receptor. Like this:
















Of course the glucose and fatty acids which enter the cell have to go somewhere so we can add in a mitochondrion:
















which produces its own ROS
















There is also a signalling cascade which carries information about these ROS. My supposition is that low levels of mitochondrial ROS act, as do those from NOX4, to facilitate the activation of insulin signalling.
















However once the cell is calorie replete ROS generation rises markedly and the resulting generated high level of ROS acts to shut down insulin signalling at the insulin receptor substrate 1 (IRS1 on the diagram) point.
















At this stage the whole insulin cascade stops functioning, as it should, because the cell is calorie replete. As part of this shutting down process the level of phosphorylation of AKT cannot be increased, no matter how much insulin is applied:
















Think about what is happening. There is nothing wrong with the system. The failure to further phosphorylate AKT is not a fault for some drug developer to "correct". It is the direct result of evolution happening on to the ideal system for monitoring and controlling calorie ingress.


The substance which is the best for a cell to monitor, for maximal survival, is mitochondrial superoxide (+/-H2O2).

It's not insulin, it's not pAKT, it's not ATP, it's not NADH.

It is ROS.

So we can observe that phosphorylation of AKT, as a core part of the activation system for insulin signalling, is only allowed to occur provided the resultant ROS generation is within evolutionarily acceptable limits.

Now let's revisit

Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

and add some detail to this graph:













I have pointed out in the past that the three concentrations of insulin used to generate this graph are five times, seventeen times and one hundred and seventy times the approximate upper limit of physiological exposure. All three levels produce exactly the same level of AKT phosphorylation because all three concentrations produce the maximal ROS tolerable to the cell. These ROS disable signalling at the level of IRS1.

I'm now going to modify the above diagram to include just the red box and stretch it to make it easier to see:














and add in some imaginary, more physiological, insulin concentrations:










I've assumed insulin in cell culture acts within the same five minutes as the supra-maximal doses do and the amount of pAKT formation stays near constant once set, as it does for supra-maximal exposure. These features may not be strictly correct.

If we wanted to construct an imaginary dose response curve it would look like this, here we are converting the above graph in to one showing the amount of phosphorylation of AKT produced by a given concentration of insulin. Again, the curve will not be accurate but the principle will be. As a rule of thumb 1000pM of insulin, ie 1.0nM, is peak insulin exposure after an high carbohydrate meal in an healthy person, which lets me put some very approximate absolute levels of insulin exposure:


















It is quite possible to move the horizontal red line of response to supra maximal insulin exposure up or down. If you are insulin "resistant" you will have less pAKT at supramaximal insulin exposure. If you are insulin sensitive you will have more.

Now it's very simple. If you wanted a single measure of "insulin resistance" just look at the maximum level of pAKT under extreme hyperinsulinaemic conditions. If pAKT is low this signifies inadequate maximal insulin signalling and so insulin resistance.

If pAKT is high this signifies insulin sensitivity. This is the concept encapsulated by the hyperinsulinaemic euglycaemic clamp from back in the days when measuring AKT and pAKT involved more than buying a kit from Sigma-Aldrich.

All of which is missing the point. Completely.

What is actually important is the level of ROS generation from the mitochondria.

Metformin: What does it do? At pharmacological plasma levels it inhibits the action of the glycerophosphate shuttle. It reduces the conversion of NADH to FADH2 by this shuttle. Less FADH2 means less reverse electron transport (RET) as judged by the FADH2:NADH ratio. If this results in a pharmacologiocally reduced level of ROS under metformin this will allow more glucose signalling (ie pAKT) before cellular "satiety" kicks in due to generation of high physiological ROS to finally shut down IRS1 functionality. Like this


















So given that single measurement of pAKT (or the rate of glucose infusion needed for euglycaemia under the last 40 minutes of an hyperinsulinaemic clamp) then metformin is, absolutely, an insulin sensitising agent. But that's because you are looking at pAKT, not ROS.

The level of ROS at for both plateaux in the above graph will be identical. That is what evolution has determined to be the best peak "target" level of ROS. Metformin blunts ROS production so allows more pAKT to be formed before ROS generation becomes high enough to shut down insulin signalling.

I could suggest that metformin allows more insulin mediated ROS at peak physiological (or above) insulin exposures. That seems quite simple.


But is the above metformin graph actually correct? Partial reduction of ROS by inhibiting mtG3Pdh to allow a greater peak insulin effect is one thing. But what about reducing ROS from physiological levels of insulin exposure, where ROS are activating to insulin signalling? We are now looking at modifying this red arrow process:
















So if we lower ROS under these circumstances using metformin we will decrease insulin signalling. So our graph should actually look like this:


















The blue section of the metformin curve has reduced ROS so signals less insulin pathway activation compared to control cells. ROS never peak anyway, and so are simply proportionally reduced under metformin.

So "normal" people, who run their metabolism on the blue dashed part of the metformin curve will show as "paradoxically" worsened insulin signalling. As we saw here:









Now let's consider DMT2. At its simplest level diabetes is the over distension of adipocytes secondary to the insulin sensitising effects of linoleic acid in combination with an insulinogenic diet. Once adipocytes are large enough basal lipolysis allows FFA release which cannot be suppressed by insulin.

If you have elevated fatty acid oxidation which cannot be reduced by insulin acting on adipocytes then ROS will be being generated at all times. There will be elevated baseline ROS, being generated from this fatty acid oxidation. If we add glucose and insulin, as in an OGTT or an hyperinsulinaemic euglycaemic clamp, the additional ROS from this calorie source will not have to generate very much extra ROS to shut down insulin signalling at IRS1 and so limit pAKT.

I repeat, it's the ROS that count. Oxidising fatty acid generates ROS without phosphorylating AKT. There is then only limited "scope" in the ROS budget before insulin signalling (hence pAKT and/or glucose infusion under clamp) has to be shut down. Not because the cells are "insulin resistant", it's because they have largely already met their ROS quota from fat. Which should not be there, fat supply should shut down immediately with even a tiny increase in adipocyte insulin exposure. But excess FFA will always be supplied (and oxidised) if there is unstoppable basal lipolysis.

Under these circumstances pAKT will be low because the ROS quota is nearly full to begin with. Adding metformin will reduce the generation of ROS from the glycerophosphate shuttle and so allow more "room" in the ROS budget which will allow more AKT phosphorylation and more glucose uptake before the ROS quota is used up. Things appear to improve for DMT2 under metformin's action.

TLDR: Is metformin insulin sensitising? Wrong question. Ask instead what metformin does to the generation of ROS. You can ask the same question about BAM15, DNP and even semaglutide.

Balancing the ROS budget explains everything.

I'll stop now.

If anyone has a better explanation I'm all ears.

Peter

38 comments:

  1. Interesting, good explanation. I wonder that H2O2 is elevated mainly for to compensate impaired PI3 kinase by elevated FFA. H2O2 slows down dephosphorylation and also decrease lipolysis. So it hels greatly. But as you suggest, it limits possible increase of IR stimulation by insulin.
    Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle
    https://pubmed.ncbi.nlm.nih.gov/12006582/

    Jaromir

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  2. Peter, What goes 'round comes around. Thoughts?...https://mistermedic.substack.com/p/how-to-cure-post-covid-syndrome-permanently?utm_source=post-email-title&publication_id=849551&post_id=113367440&isFreemail=true&utm_medium=email

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  3. Hi Cap'n. I have to say I have long held in my head that ME/CFS is likley to be an ROS driven problem. I think it's also likely to be an ROS derivative problem too, 4-HNE and its relatives. And, at a higher level, a cytokine driven problem. All a related hierarchy.

    I struggle badly with the term long covid. We could equally well call it Long Epstein Barr Virus or Long Influenza. But the reality, whatever the label applied, looks to be profoundly mitochondrial in pathophysiology, ROS mediated. It might be as easily solved as eliminating all linoleic acid from all lipid stores... ie bloody difficult!

    It's notable that of all of the people I know it's common for the most medically educated to be the most resistant to the concept of a low carb, low LA dietary approach. Going through a medical degree course does absolutely nothing to encourage broad thinking and insight. If you suggested to a run of the mill medic that eating half a block of beef dripping and 5 McDonald's burger per day might reverse obesity, DMT2, hypertension etc etc they would simply go quiet, look at you strangely and edge away....

    Peter

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  4. Long Covid is distinguished from the others in that one of its long-term sequelae is unlimited research funding.

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  5. Tks Peter, Yes, the more educated the folk that I tell/show that I put cocoa butter, or whatever SF in my coffee, the more apoplectic their reaction. It's often hilarious! For me, the mix all depends on the bean, as experimentally I add small quantities of butter and it does very acceptedly alter the taste. However, I'm not a big coffee drinker, but I do eat loads of SF's. Moreover, a big issue it would seem is those bloody wrecking-ball blobs of LNP's. How do folk flush that crap from their system? I have a good rebel golf mate, an ex male nurse, who is (very regretfully) double-jabbed, and has since had covid twice. I suggested Nattokinase to him for his various covid/jab ailments and he has really, really picked up with that. Anyway, many of my everyday thoughts, a bit late in life, are... to look after your mitochondria and it will look after you. Simples. Need-less-to say I bore my 4 kids stupid, and all to no avail. Hey ho.

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  6. Meanwhile, back at the ranch…cows are the new scapegoat.

    'Bill Gates Wants Cows to Eat Bromine-Containing Seaweed. Is it Good For Us?'

    https://igorchudov.substack.com/p/bill-gates-wants-cows-to-eat-bromine

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  7. cave, yes, but the chances of that research funding being allocated to work which might implicate the bulk of modern pathology being an iatrogenic illness directly attributable to the cardiology community, is vanishingly small.

    Nowadays I own six methane factories as pets. I don't know how long they will have to burp for to match the USA's successful destruction of the Nord Stream pipeline but I guess my goats will get the blame for some bad weather in 50 years time.

    But not Bill Gates' private jet travel (if I believed climate models, which I don't).

    Oooh, should be change the term to scapecows? If we're going to blame the dairy industry in bulk?

    Peter

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  8. Cap: "wrecking-ball blobs of LNP's. How do folk flush that crap from their system"

    The medical meaning of that acronym temporarily eludes me ... however we do have a Liberal National Party here that does amount to crappy blobs which are to difficult to flush from the system. Imho.


    Peter, to compensate for the loss of NordStream might it be possible to run the German manufacturing sector entirely on goat farts?

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  9. Pass, that would be Lipid Nanoparticles.

    Peter, I will officially start using the word "scapecow". Excellent.

    Also Peter, when I think of that kind of funding, I always picture local-government-funded road worker crews, where six guys stand around leaning on shovels watching one guy work. Can't imagine why…

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  10. One of those surprising models, like RLIP:

    "The increased insulin sensitivity in Gpx1−/− mice was attributed to insulin-induced phosphatidylinositol-3-kinase/Akt signaling and glucose uptake in muscle and could be reversed by the antioxidant N-acetylcysteine"

    "Reactive Oxygen Species Enhance Insulin Sensitivity"

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  11. Tucker, yes. I am also chasing fructose ROS at relatively plausible low diet exposure as activating the pathway to pAKT. All fructose ROS might be NADPH oxidase generated so -> facilitated insulin sensitivity at low fructose exposure. Then as exposure rises ROS rise -> block insulin pathway at IRS1. But the studies are messy and the mechanism from fructose to NOX seems currently unknown. And while one study measured AKT (marked rise with chronic moderate fructose) it doesn't look at the phosphorylation level. Still hunting.

    Pass, might need more than my six.

    cave, good plan! I think it might be the management brigade who nowadays stand around watching a lone worker...

    Peter

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  12. Hey Peter!

    Brilliant post, really really interesting! Thank you!

    Stole this from your reply to Captain Sunset above:
    "It's notable that of all of the people I know it's common for the most medically educated to be the most resistant to the concept of a low carb, low LA dietary approach. Going through a medical degree course does absolutely nothing to encourage broad thinking and insight. If you suggested to a run of the mill medic that eating half a block of beef dripping and 5 McDonald's burger per day might reverse obesity, DMT2, hypertension etc etc they would simply go quiet, look at you strangely and edge away...."

    - You're not kidding. My sister is studying to be a Neonatalogist, (she's a registered nurse right now, and has had a pretty brilliant career success so far, but decided to go on to become a dr), and a super dedicated, hardworking person. I'm a wishy-washy arts major with an obesity problem since childhood, and therefore a life-long obsession with reading everything I can about nutrition, trying to solve the bloody things. Nowadays I'm eating essentially a beef/salmon/eggs/salt/water diet, and infuriatingly slowly things are moving in the right direction.
    The thing is that even though I see a huge difference, if not in weight, but in general well-being. My depression and anxiety are gone. I actually sleep. Dental health. I'm not in pain, and i'm not starving/hangry 24/7. - but she's absolutely convinced that eating meat "in excess" is a horrible idea, and nothing I say or show or tell her is making the slightest difference.
    I've spoken to hardwoord furniture with better results, lol. Not that I expect her to take me at my word of course - but I'd expect her to at least be curious about why what I tell her and what she knows already are so different. But nope.
    And this is the case with pretty much everyone around me. My husband's family, all our neighbours, literally everyone around are sick with some metabolic disease, and there they all sit, discussing how such-and-such has heart disease - but eats every piece of sausage and bacon and steak in sight - and how they heard of this new way to cook beans and lentils.
    And the moment that you mention that maybe it's not the fat, you're get the smile and nod and move away slowly and "but my cardiologist said".

    SIGH.

    Sorry for the rant.
    Can you tell i've spent Easter with the family?

    Anyway!

    Happy Easter everyone. Thank you all for being a corner of sanity in a bewildering bloody world. :)

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  13. Sigh. 'Tis true.

    Also be careful about mentioning that saturated fat is good and hearthealthypolyunsaturate fat is obesogenic and diabetogenic.

    Hello nice lady, just put on the nice white jacket and come with me to the nice white car outside and we'll go for a ride to the nice long stay mental hospital...

    P

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  14. Pretty new paper you might like:

    https://www.cell.com/cell-reports/fulltext/S2211-1247(23)00166-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723001663%3Fshowall%3Dtrue

    *Limiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress

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  15. Hehe, I'm keeping the ticket to *that* ride for when I decide that world is absolutely and terminally insufferable, and a padded cell is preferable to dealing with people :P

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  16. Peter, fructose mechanism of reducing ROS is described here
    Dietary fructose improves intestinal cell survival and nutrient absorption
    https://www.nature.com/articles/s41586-021-03827-2

    Try to search preprint with sci-hub. The mechanism is, as I understand it, that fructose changes activity of pyruvate kinase PKM2 by attaching to it, without being metabolized. This drives glucose metabolism to lactate production.

    My post about it here
    https://mct4health.blogspot.com/2023/02/sugar-prolongs-life-of-cells-in.html

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  17. Hi Jaromir,

    I do recall fructose as a major component of NMRs adaptation to relative hypoxia but is was a long time ago. Haven't tied it to pseudohypoxia.

    At the moment I'm deeply involved in fructose and metabolic syndrome and, as you are aware, that much of the damage done by fructose at high levels in the diet under normoxia are mediated through ROS. This interests me at the moment. There can be a lot of ROS from fructose exposure.

    P

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  18. Hi John,

    There's a lot to unpack there. On first skim there is a lot about HIF alpha which has some relevance to Jaromir's interests...

    P

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  19. Lapis, one of my favourite singer songwriters...

    https://www.youtube.com/watch?v=d0NxhFn0szc

    P

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  20. Peter perhaps this current series should become "Electrons()" to follow on from Protons()!

    Not that you can keep them apart for long.

    So, maybe a goat for each household? :)

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  21. Vis a vis fatsanity, it is much easier to get people agreeing about eating less sugary food, cakes, sweets etc and drive in the thin end of the veg that way. Then lead on to how good cream and butter taste, and steak and chops, without every mentioning the words saturated or fat.

    I have one heavily statinated friend, lost to science but every time we eat together he hoes into the chops or cheeses or eggs and real butter. Ya gotta make up the deficit somehow.

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  22. Ahhh Marianne <3<3<3
    ...and then https://www.youtube.com/watch?v=Q712oEHjlVA ?

    Her voice is like a hammer wrapped in crushed velvet </3

    (But then, I haven't lost faith yet. There are still plenty of smart lovely people around to offset the balance and keep me from throwing in the towel :))

    Thank you for that, I haven't listened to her in a long long while, and that was a nice reminder :)

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  23. Passthecream - that person's body seems smarter than he is, unfortunately. :/. It knows what it needs.
    So sad when it's people you care about.

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  24. Lapis,

    Broken English is very dear to me too. I *never realised* that my dad had a broad, heavy slavic accent. Until my first ever "meet the parents" girlfriend could barely understand him! Native Ukrainian, probably passable in Russian, enough German to cope as a conscript in their late WW2 army, Italian to get by as a POW in Rimini and then English as a POW near Nottingham. If I had half the languages he had to cope with....

    P

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  25. It's a beautiful song, and I can sympathize with that, because that will probably be the case for me once my two girls start dating :P (Luckily I have at least 10 years before that happens (25 if my husband gets his way). I speak Hebrew, Russian (native) and English - and have a pretty heavy accent in all three.

    Still, with Ukrainian, Russian, German, Italian and English your dad has me easily beat. Your dad sounds like a fascinating person with an incredible life story. I hope he told you some of it!

    (People like this make me selfishly wish there was a way to magically receive their biography in book format, so I could read stories of their lives. Seriously, If there ever was a superpower worth having!)

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  26. Dad didn't ever say anything about his journey to the UK, just little snippets from his childhood. As the oldest child I have inherited his memorabilia. I met Mike Melnyk purely by chance and he recognised my surname as from Galicia. He filled me in with the relevant history and put my inheritance items in to context.

    https://tinyurl.com/32brd9jz

    I also inherited dad's copy (his only book in English) of Victor Kravchenko's 1947 book, published while dad would have still been "interned" in the UK.

    https://tinyurl.com/8ztex2vr

    It was a turbulent time. My heart goes out to those suffering through Biden's war in Ukraine today.

    Peter

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  27. Hi Peter,
    I haven't looked much into fructose yet, but it gives me the impression that the main effect is to prolong the life of otherwise disrupted diseased cells. Simply conserve energy from glucose as unsaturated fats conserves energy from saturated fats. As with fat cell overgrowth, these cells are diseased and should undergo apoptosis, but continue their dysfunctional lives. ROS are not caused by fructose itself, but by another malfunction. But I could be wrong.
    Jaromir

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  28. Peter — your mention of that book got me looking for it. Used copies are pricy. A PDF can be downloaded here: https://ia601505.us.archive.org/14/items/i-chose-freedom/I%20chose%20freedom.pdf

    An interesting history, including "the trial of the century" in France. https://en.wikipedia.org/wiki/Victor_Kravchenko_(defector)

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  29. I bought a copy each for my brother and sister a few years ago for a few pounds each copy. Times change. Dad would have been 12-13y old at the time of the engineered famine. He said Kravchenko's book was accurate.

    Peter

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  30. Yeah. I can understand that. In Israel there was an entire generation of ex-european jews that didn't talk about their past, and raised a generation that had to learn about what happened to their parents from books and stories of those who did speak about it. I can't imagine how it must have felt to find out at least in this indirect way some of the things your dad went through.

    "In June 1944 my father Petro Melnyk was taken at gunpoint from his home village of Koropets in western Ukraine, by retreating German troops and their Hungarian allies, to serve in the '14. Waffen-Grenadier-Division der SS (galizische Nr. 1)'.
    His elder brother Dymitri was forcibly conscripted by the Soviets into the Red Army, although he managed to escape and spent the duration of the war in hiding. Both were ardent Ukrainian patriots but due to circumstances beyond their control, they would have found themsleves facing each other on the battlefield. Fortunate to have survived the conflict, they went on to raise families and live out the remainder of their lives, Dymitri in his home village in Ukraine and Petro in exile in England."

    Turbulent is putting it mildly. :(
    Same here. Both for the Ukrainians and the Russians, for everybody that wants no part of it.

    (And - thank you for using the term "Biden's war". Maybe it's because I only see the wrong parts of the online world, but sometimes it seems like nobody gets this. Once again, you're restoring my faith in humanity, sir.)

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  31. Cavenewt, Thank you for the link! <3

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  32. Is the tide turning when the guardian reports favorably about low carb?

    https://www.theguardian.com/society/2023/apr/09/british-doctor-pioneers-low-carb-diet-as-cure-for-obesity-and-type-2-diabetes

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  33. That would be great Eric, but over the decades as a LC-er you get to see the "healthy eating" paradigm crack repeatedly but so far I'm still not expecting "My Plate" to specify beef mince with added suet as the pinnacle of healthy eating! But one can always hope.

    P

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  34. Lapis, Mike's dad and my dad have common history. I have both dad's German army card and his civilian ID. Managing to retain your civilian ID -> "conscript intending to desert" and was an automatic death sentence. The card is well travelled, battered and water stained.

    No one would want to have been there.

    You can imagine what I think about our current UK policy of actively demonising "small boat people" as a political tool to win elections.

    P

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  35. Well, now you're getting controversial. I guess the simplest solution is that we didn't invade Afghanistan 20 years ago.

    Failing that then perhaps getting UK/USA affiliated Afghans out before Biden's crushing defeat by the Taliban might have been a good idea.

    The small boat people appear to be 1) genuine refugees such as Afghan families and 2) economic migrants, mostly Bulgarian young men.

    Genuine refugees are going to be granted asylum here in the UK, as they should be. Providing them with a ferry ticket would eliminate *all* motivation and profit for people trafficking in small boats.

    Economic migrants are slightly different. They need a ferry ticket plus a National Insurance number so they can get working and start paying taxes. I assure you the UK social security system is not so generous that anyone would risk their life to become a "benefits scrounger". These people want to work. Also, since the introduction of the SafeandEffective the UK birthrate has plummeted and we already have a deficit of people in work to pay taxes. The government approach to the latter is to cut benefits for the chronically ill to "encourage" them back to work. We *need* tax payers. How many of those chronically unwell are a result of the SafeandEffective is anyone's guess. Probably a large percentage.

    Ultimately UK voters receiving unemployment benefits might have to get used to tax payers with heavy Bulgarian accents providing the UK government with the taxes needed to fund their unemployment benefits.

    Tough. Not a vote winner.

    Peter

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  36. 'How many of those chronically unwell are a result of the SafeandEffective is anyone's guess.

    And how many other of those chronically unwell are a result of official dietary recommendations from industry-captured public health agencies is even less of a guess.

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  37. Peter - I guess I don't know what controversial means anymore, because it seems like everything that makes any kind of sense to me is controversial. (The diet. The SafeAndEffective TM. And so on and so on.) I am not trying to be, that's for sure.

    "I guess the simplest solution is that we didn't invade Afghanistan 20 years ago.
    Failing that then perhaps getting UK/USA affiliated Afghans out before Biden's crushing defeat by the Taliban might have been a good idea."

    Yes. Never waste a tragedy. If there is none - create one. That was a cluster. Biden (and his administration, because I don't think that he can pull up his own pants, not just make actual decisions) basically gifted the Taliban the nicest array of toys they've ever seen even in their wet dreams. I don't have words nasty enough for this infernal government anymore. (And I'm not even going into the SafeandEffective. I don't think that we've seen even the tip of the iceberg with the effects of it yet.
    (Me, husband and kids are probably the only "unsafeandeffectiv-ed" family around for miles where I am, and we have neighbors that are suffering some horrible effects from it.)

    I spent 6 months in the UK (south Wales) a few years ago, which is not enough to truly understand a country, but I think that what you are saying is making perfect sense. It's not about the accent - but whether the people coming in want to integrate in the local society, and play by the rules of the place they arrive at. At the end of the day I believe that hardworking and talented people are a gift to any society they arrive to.


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