I'm hoping we all remember Sauer. If not there's a post here:
Sauer vs Lisanti
And a brief summary at the start of this one:
Sauer and 13-HODE
Sauer demonstrated that food withdrawal from rats carrying tumour xenografts makes those tumours grow like wildfire. He went on to show that it was 13-HODE which made the tumours grow and that either linoleic acid or arachidonic acid (both 13-HODE precursors) were essential for tumour growth in his model. Fasting released these carcinogenic PUFA from adipocytes when the rats were starved.
You cannot make 13-HODE without linoleic acid. Or arachidonic acid if you prefer.
Do you want to make a tumour grow? Feed your model linoleic acid. It's easy. Or you could try using a Ketocal based ketogenic diet for glioblastoma multiforme management in real live humans. There was a trial doing this recently:
Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study
which didn't really pick up any benefit, it was only a pilot study. Serious concern about the composition of the ketogenic diet was expressed in this letter to the editor:
Problems associated with a highly artificial ketogenic diet: Letter to the Editor Re: van der Louw EJTM, Olieman JF, van den Bemt PMLA, et al. ‘Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study’
link tweeted by Miki Ben-Dor.
Much of the diet was Ketocal based "consisting of refined vegetable oils from sunflower, soy, and palm fruit..."
This looks like an excellent source of the 13-HODE precursor linoleic acid, which Sauer might have recognised as the growth promoter in his rat models.
I would suspect that the ketogenic diet supplied benefit from ketosis, but this was largely offset by tumour promotion from the linoleic acid content.
Is there any end to the damage done by the lipid hypothesis?
Probably not.
Peter
Sunday, October 20, 2019
Friday, October 18, 2019
Total Cholesterol and major cardiovascular events
This is a pure observational study:
Low total cholesterol is associated with increased major adverse cardiovascular events in men aged ≥70 years not taking statins
As such, let's generate an hypothesis.
Let's assume total cholesterol (TC) is utterly, totally and completely meaningless. About anything.
Let's assume that TC is a surrogate for "something" (Something Good) which is really important.
Let's assume that people with high TC are doing something right. Something which the study never even thought about, let alone measured.
Let's assume that statins do absolutely nothing (being generous).
Let's assume people only get put on a statin if their TC is high, ie, they are doing Something Good.
The Something Good behaviour pattern persists despite the statin.
The statination makes the TC number decrease, which makes the statin victims look as if they are doing the Something Bad which, obviously, lowers your TC. But they're not. They do well despite the statin and despite the artificially lowered TC.
EPIC Norfolk suggests looking at HbA1c if you want to look at cardiovascular and all cause mortality. Hints about Something Good here in Norfolk?
Peter
Edit: No one (least of all me) would suggest HbA1c elevation is causative of all cause mortality. But at least it starts you looking at the correct metabolic pathways! End edit.
Low total cholesterol is associated with increased major adverse cardiovascular events in men aged ≥70 years not taking statins
As such, let's generate an hypothesis.
Let's assume total cholesterol (TC) is utterly, totally and completely meaningless. About anything.
Let's assume that TC is a surrogate for "something" (Something Good) which is really important.
Let's assume that people with high TC are doing something right. Something which the study never even thought about, let alone measured.
Let's assume that statins do absolutely nothing (being generous).
Let's assume people only get put on a statin if their TC is high, ie, they are doing Something Good.
The Something Good behaviour pattern persists despite the statin.
The statination makes the TC number decrease, which makes the statin victims look as if they are doing the Something Bad which, obviously, lowers your TC. But they're not. They do well despite the statin and despite the artificially lowered TC.
EPIC Norfolk suggests looking at HbA1c if you want to look at cardiovascular and all cause mortality. Hints about Something Good here in Norfolk?
Peter
Edit: No one (least of all me) would suggest HbA1c elevation is causative of all cause mortality. But at least it starts you looking at the correct metabolic pathways! End edit.
Saturday, October 12, 2019
Metformin (11) a SHORT paradox
I'll just throw this one out there as I found it while looking for something else:
Metformin paradoxically worsens insulin resistance in SHORT syndrome
SHORT syndrome is a (very, very rare) genetic failure of insulin signalling at the PIK3 regulatory subunit 1 level. Insulin binds to its receptor but signalling fails due to a single downstream gene defect giving severe insulin resistance. People with this syndrome are, needless to say, very thin. They maintain normoglycaemia using a very high level of insulin which does, given a high enough concentration, produce normoglycaemia. There doesn't appear to be any problem with secreting insulin from the pancreas. In fact, to overcome the failure of insulin signalling during her OGTT the patient's pancreas produced a plasma insulin of 688mIU/l*. In new money that is just under 5000pmol. As in roughly ten times what you might expect. Severe, but not quite insuperable, insulin resistance.
*The paper specifies insulin in mIU/ml. I'm assuming this is a typo or a font failure because clinical insulin concentrations are usually expressed as microIU/ml or mIU/l. Obviously if it really is 688mIU/ml the concentrations will be 1000 times those quoted. Gulp. People really should use the SI system.
Back to the patient. The obvious thing to do is to give an insulin sensitising agent, number one in popularity nowadays being metformin.
This turned out to be a bit of a boo boo.
During an OGTT under metformin the patient's insulin resistance worsened and mild hyperglycaemia ensured but this was despite a plasma insulin concentration which was simply too high to measure. The lab could measure up to around 7000pmol (pax typos) and it looks like the curve went MUCH higher than that.
That is despite metformin's predictable and recently found ability to suppress insulin release from mouse islets.
From the Protons perspective metformin blunts insulin signalling via blockade of mitochondrial glycerol-3-phosphate dehydrogenase. Its beneficial effects to increase insulin sensitivity come from reduced exposure to insulin signalling in peripheral cells. The peripheral cells of a person with SHORT syndrome barely see insulin signalling at all even without the metformin. You would hardly expect further blocking any residual insulin signalling to help matters. It doesn't.
It's the sort of paradox which only happens when you are in the wrong paradigm of metformin's mechanism of action. Might have been a chance to make progress...
Peter
Addendum: The lady in question did not seem to enjoy her experience with the medics too much:
"As we intended to check the effects of this approach, an extended 75 g OGTT was performed on metformin 4 days later. This showed dramatic and paradoxical worsening of insulin tolerance with insulin concentrations above the upper assay detection limit (Fig. 1b). Metformin treatment was discontinued. She was discharged home on Dydrogesterone and vitamin D supplementation. We planned to perform investigations on other family members, and particularly on her younger brother, but despite several reminders they failed to attend clinic appointments as well as declined admission to the hospital".
Metformin paradoxically worsens insulin resistance in SHORT syndrome
SHORT syndrome is a (very, very rare) genetic failure of insulin signalling at the PIK3 regulatory subunit 1 level. Insulin binds to its receptor but signalling fails due to a single downstream gene defect giving severe insulin resistance. People with this syndrome are, needless to say, very thin. They maintain normoglycaemia using a very high level of insulin which does, given a high enough concentration, produce normoglycaemia. There doesn't appear to be any problem with secreting insulin from the pancreas. In fact, to overcome the failure of insulin signalling during her OGTT the patient's pancreas produced a plasma insulin of 688mIU/l*. In new money that is just under 5000pmol. As in roughly ten times what you might expect. Severe, but not quite insuperable, insulin resistance.
*The paper specifies insulin in mIU/ml. I'm assuming this is a typo or a font failure because clinical insulin concentrations are usually expressed as microIU/ml or mIU/l. Obviously if it really is 688mIU/ml the concentrations will be 1000 times those quoted. Gulp. People really should use the SI system.
Back to the patient. The obvious thing to do is to give an insulin sensitising agent, number one in popularity nowadays being metformin.
This turned out to be a bit of a boo boo.
During an OGTT under metformin the patient's insulin resistance worsened and mild hyperglycaemia ensured but this was despite a plasma insulin concentration which was simply too high to measure. The lab could measure up to around 7000pmol (pax typos) and it looks like the curve went MUCH higher than that.
That is despite metformin's predictable and recently found ability to suppress insulin release from mouse islets.
From the Protons perspective metformin blunts insulin signalling via blockade of mitochondrial glycerol-3-phosphate dehydrogenase. Its beneficial effects to increase insulin sensitivity come from reduced exposure to insulin signalling in peripheral cells. The peripheral cells of a person with SHORT syndrome barely see insulin signalling at all even without the metformin. You would hardly expect further blocking any residual insulin signalling to help matters. It doesn't.
It's the sort of paradox which only happens when you are in the wrong paradigm of metformin's mechanism of action. Might have been a chance to make progress...
Peter
Addendum: The lady in question did not seem to enjoy her experience with the medics too much:
"As we intended to check the effects of this approach, an extended 75 g OGTT was performed on metformin 4 days later. This showed dramatic and paradoxical worsening of insulin tolerance with insulin concentrations above the upper assay detection limit (Fig. 1b). Metformin treatment was discontinued. She was discharged home on Dydrogesterone and vitamin D supplementation. We planned to perform investigations on other family members, and particularly on her younger brother, but despite several reminders they failed to attend clinic appointments as well as declined admission to the hospital".
Friday, October 11, 2019
Ketogenic diets are unhelpful and dangerous for managing mitochondrial diseases. Maybe.
I think this is probably an abstract from a short communication at a conference. I picked it up from Miki Ben-Dor on twitter
I think we can say that ketogenic diets are pretty rubbish for managing mitochondrial illnesses.
By chance there is also a twitter discussion on-going relating to omega 6 based ketogenic diets.
First, nutritionists LOVE omega 6 PUFA and HATE saturated fats. In case anyone hadn't noticed. This tweet came from laura cooper, this time picked up via Raphi and Tucker.
Supported by this
It seems very likely that we can combine these two concepts and come up with some sort of an explanation.
I think we can accept that the ketone induced metabolic changes noted by Veech in isolated working rat hearts, resulting in increased energy yield per ATP molecule, still apply even with poorly functional mitochondria, because there is comparable improvement in the control of abnormal mitochondria induced intractable epilepsy vs ordinary intractable epilepsy. The ketogenic diet is clearly doing something...
That's good.
Everything else is bad.
If there is a significant problem with the structure/function of complex I ketones will not be directly helpful. They deliver acetyl-CoA to the TCA and essentially nothing else. There will be a small FADH2 input from succinate dehydrogenase but all other electrons will be presented as NADH, which needs a functional complex I to do anything much.
To bypass a poorly functional complex I we really need input as FADH2 directly to the CoQ couple without having to turn the TCA. That means beta oxidation of fatty acids, in particular it needs those fatty acids to be fully saturated because electron transporting flavoprotein only receives electrons to form FADH2 from the first desaturation step at the start of beta oxidation. Any double bonds skip this step.
Using PUFA immediately reduces energy sourced via this route.
The next thing we need to realise that modern nutritionist derived ketogenic diets cause, amongst other things, pancreatitis. I posted about pancreatitis, Intralipid and propofol here. It should come as no surprise that the side effects (from here) of PUFA based ketogenic diets in children can be severe, they're probably a lot higher in PUFA than even F3666 rodent chow...
"Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia".
Then there are cardiolipins. Each cytochrome C molecule is anchored to the outer surface of the inner mitochondrial membrane by four lipid anchors. Their nature is largely controlled by the dietary lipid supply. Modern PUFA based ketogenic diets will result in highly unsaturated cardiolipin anchors. Damaged mitochondria produce an excess of ROS. ROS break PUFA based cardiolipins giving apoptosis or, if ATP levels are too low for this, necrosis. Not going to do your ragged red muscle fibres any good. Or you cardiomyopathic cardiomyocytes.
I could go on, but you get the flavour.
Is there any end to the damage done by the lipid hypothesis?
Probably not.
Peter
I think we can say that ketogenic diets are pretty rubbish for managing mitochondrial illnesses.
By chance there is also a twitter discussion on-going relating to omega 6 based ketogenic diets.
First, nutritionists LOVE omega 6 PUFA and HATE saturated fats. In case anyone hadn't noticed. This tweet came from laura cooper, this time picked up via Raphi and Tucker.
Supported by this
It seems very likely that we can combine these two concepts and come up with some sort of an explanation.
I think we can accept that the ketone induced metabolic changes noted by Veech in isolated working rat hearts, resulting in increased energy yield per ATP molecule, still apply even with poorly functional mitochondria, because there is comparable improvement in the control of abnormal mitochondria induced intractable epilepsy vs ordinary intractable epilepsy. The ketogenic diet is clearly doing something...
That's good.
Everything else is bad.
If there is a significant problem with the structure/function of complex I ketones will not be directly helpful. They deliver acetyl-CoA to the TCA and essentially nothing else. There will be a small FADH2 input from succinate dehydrogenase but all other electrons will be presented as NADH, which needs a functional complex I to do anything much.
To bypass a poorly functional complex I we really need input as FADH2 directly to the CoQ couple without having to turn the TCA. That means beta oxidation of fatty acids, in particular it needs those fatty acids to be fully saturated because electron transporting flavoprotein only receives electrons to form FADH2 from the first desaturation step at the start of beta oxidation. Any double bonds skip this step.
Using PUFA immediately reduces energy sourced via this route.
The next thing we need to realise that modern nutritionist derived ketogenic diets cause, amongst other things, pancreatitis. I posted about pancreatitis, Intralipid and propofol here. It should come as no surprise that the side effects (from here) of PUFA based ketogenic diets in children can be severe, they're probably a lot higher in PUFA than even F3666 rodent chow...
"Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia".
Then there are cardiolipins. Each cytochrome C molecule is anchored to the outer surface of the inner mitochondrial membrane by four lipid anchors. Their nature is largely controlled by the dietary lipid supply. Modern PUFA based ketogenic diets will result in highly unsaturated cardiolipin anchors. Damaged mitochondria produce an excess of ROS. ROS break PUFA based cardiolipins giving apoptosis or, if ATP levels are too low for this, necrosis. Not going to do your ragged red muscle fibres any good. Or you cardiomyopathic cardiomyocytes.
I could go on, but you get the flavour.
Is there any end to the damage done by the lipid hypothesis?
Probably not.
Peter
Saturday, October 05, 2019
Confirmation bias is so nice
Excellent work:
Scientific discourse in the era of open science: a response to Hall et al. regarding the Carbohydrate-Insulin Model
Via raphi on twitter
Peter
Scientific discourse in the era of open science: a response to Hall et al. regarding the Carbohydrate-Insulin Model
Via raphi on twitter
Peter
Tuesday, October 01, 2019
Personal update 2019
Okay, personal update time.
Back in the middle of May this year Paul emailed me to let me know that Dr Kwasniewski had died at the age of 82. The possibility of his having had bowel cancer several years ago is apparently nearly impossible to follow up on but it doesn't appear to have been directly related to his passing away. I'd been meaning to post on this but never quite got round to it until Marco also emailed me with the same news last week. The Optimal Diet (OD) has served me well for about 17 years or so.
May was an interesting time for me. For a set of reasons not at all related to my own health I had been tempted to try the scenario of a paleolithic ketogenic diet, much along the lines of the Paleomedicina PKD protocol. I was basically interested in the level of practicality involved before suggesting it to a friend with a "modern-ketosis" resistant neurological problem. The practicalities eventually proved too problematic so the PKD option was never taken up.
I personally never expected that the PKD would change much for me.
I was wrong.
First, I stopped snoring. As far as I am aware, completely. Within a few days. I have a severely deformed nasal septum, probably traumatic in origin (if playing "toss the caber" as a kid with a larch pole, don't throw it straight up in the air in case it comes vertically back downwards directly on to your nose. Ouch). Both nostrils are severely narrowed. I never expected to ever stop snoring.
Second, the low back pain from which I got enormous relief with the OD, went. I've had three minor positional back injuries in five months but each resolution has been incredibly rapid with minimal analgesic needs.
My minor dry skin problems went within a few days, though this coincided with onset of decent access to sunlight in May, the Spring had been cool here in the UK.
Oh, and I dropped from 66kg to 62kg in a month, 11-12% body fat to 9%, estimated by lower body impedance on a set of Tanita home scales.
I carried on with the PKD.
So now I am stuck.
I really enjoy not being awakened by my wife to get me to roll back to sleeping on my side again, sometimes several times a night. I like having no back pain. I like the continued muscle strength development at the bouldering wall.
On the downside it is very socially uncomfortable. It has really brought home to me how utterly easy standard modern ketogenic eating really is. A bit of cooking and a few sweeteners and there is almost nothing you can't have within the diet.
Over the months on PKD I've added in very occasional cheese and a very, very occasional glass of Proseco on a Friday night, without apparent problems. Adding cauliflower or broccoli triggered low back soreness (I have to wonder if this is a nocebo effect, not exactly double blind!).
So nowadays I'm thinking about protein, GH, IGF-1 and insulin. I've always been cautious about protein levels but there are features about higher protein within a solidly ketogenic background that limits IGF-1 generation per unit GH secretion.
There are a number of posts there.
Currently I am, somewhat reluctantly, almost completely plant free. I'm no guru on this way of eating any more than on anything else, plus I'm very late to the party!
Peter
Back in the middle of May this year Paul emailed me to let me know that Dr Kwasniewski had died at the age of 82. The possibility of his having had bowel cancer several years ago is apparently nearly impossible to follow up on but it doesn't appear to have been directly related to his passing away. I'd been meaning to post on this but never quite got round to it until Marco also emailed me with the same news last week. The Optimal Diet (OD) has served me well for about 17 years or so.
May was an interesting time for me. For a set of reasons not at all related to my own health I had been tempted to try the scenario of a paleolithic ketogenic diet, much along the lines of the Paleomedicina PKD protocol. I was basically interested in the level of practicality involved before suggesting it to a friend with a "modern-ketosis" resistant neurological problem. The practicalities eventually proved too problematic so the PKD option was never taken up.
I personally never expected that the PKD would change much for me.
I was wrong.
First, I stopped snoring. As far as I am aware, completely. Within a few days. I have a severely deformed nasal septum, probably traumatic in origin (if playing "toss the caber" as a kid with a larch pole, don't throw it straight up in the air in case it comes vertically back downwards directly on to your nose. Ouch). Both nostrils are severely narrowed. I never expected to ever stop snoring.
Second, the low back pain from which I got enormous relief with the OD, went. I've had three minor positional back injuries in five months but each resolution has been incredibly rapid with minimal analgesic needs.
My minor dry skin problems went within a few days, though this coincided with onset of decent access to sunlight in May, the Spring had been cool here in the UK.
Oh, and I dropped from 66kg to 62kg in a month, 11-12% body fat to 9%, estimated by lower body impedance on a set of Tanita home scales.
I carried on with the PKD.
So now I am stuck.
I really enjoy not being awakened by my wife to get me to roll back to sleeping on my side again, sometimes several times a night. I like having no back pain. I like the continued muscle strength development at the bouldering wall.
On the downside it is very socially uncomfortable. It has really brought home to me how utterly easy standard modern ketogenic eating really is. A bit of cooking and a few sweeteners and there is almost nothing you can't have within the diet.
Over the months on PKD I've added in very occasional cheese and a very, very occasional glass of Proseco on a Friday night, without apparent problems. Adding cauliflower or broccoli triggered low back soreness (I have to wonder if this is a nocebo effect, not exactly double blind!).
So nowadays I'm thinking about protein, GH, IGF-1 and insulin. I've always been cautious about protein levels but there are features about higher protein within a solidly ketogenic background that limits IGF-1 generation per unit GH secretion.
There are a number of posts there.
Currently I am, somewhat reluctantly, almost completely plant free. I'm no guru on this way of eating any more than on anything else, plus I'm very late to the party!
Peter
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