Saturday, December 11, 2021

Protons (67) a formula revised for butter oil

A couple of months ago Tucker emailed me this study

Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome

The study itself, while interesting, is not the point. The point is that the diet used contained the infamous 42% of calories from fat and was obesogenic. In common with a number of other studies I have been mulling over, the fat was butter oil. This is the butter oil composition

which has 2.3% linoleic acid in 42% of calories giving just over 1% of calories as LA. All I am interested in here is the comparison between 14 weeks on control low fat diet (CD) vs 14 weeks on a low linoleic acid Western Diet (WD). Here are the fat mass data (bodyweight mirrored this)

and here are the IPGTT results. We're just comparing the black control (CON) with the red western diet (WD) lines

So I think we can say that 14 weeks on butter oil is obesogenic and has the appropriate insulin resistance as we expect from any obesity with its increased basal lipolysis of large adipocytes coupled with Protons effects on the non adipose tissues.


The diet looks like this:

If anyone thinks this looks like fudge, here is the recipe for a kilo of the stuff

Take 340g of table sugar, add 200g of anhydrous butter fat, bulk it up with 150g of corn starch to help it set and throw in some casein if you feel like it. Mix and extrude (you could cut in in to cubes for human consumption).


Looks yummy. Rewarding. Don't snigger!

End aside.

Butter oil is one of those features of study designs which produce obesity without linoleic acid.

Again, prompted by Tucker, I re-drafted the F:N ratios of MUFA and PUFA in the last post to account for the consumption of one NADH to provide an NADPH for rearranging each double bond during beta oxidation and we can add these revised ratios and some for selected saturate values to the composition table of butter oil like this:

In red are linoleic acid and the short chain fatty acids of an equal or lower F:N ratio cf LA. I threw in oleic acid and C8 caprylic (blue numbers) too to point out that caprylic acid, though higher than LA, is now lower than oleic (I view oleic acid as the mammalian default for "normal" insulin sensitivity) and so might be obesogenic.

So, from the F:N ratio Protons perspective, we have a modest supply of short chain fatty acids of potentially greater insulin sensitising ability (hence obesity promoting) than linoleic acid itself.

The effect of butyrate as a dietary supplement on obesity is controversial and reviewed here

Butyrate: A Double-Edged Sword for Health?

Conclusions totally depend on how you set your study up, what you consider good and what you consider bad. Bear in mind that butyrate is the darling of fibre-philes so consider publication bias too. Conversely it is to a large extent consumed by the colonic epithelium, so not a lot gets through to the systemic circulation. But some clearly does. The snippet of Figure 2 which caught my eye was this section:

I would just point out that anything which decreases lipolysis and increases adipocyte glucose uptake is NOT going to make you skinny. It might make you insulin sensitive (bravo), at least until you get fat enough to leak excess FFAs via augmented basal lipolysis.

You could of course just say butter oil fudge is highly Rewarding, so makes rats and mice fat. How can you tell it's Rewarding? Because it makes rats and mice fat. Except corn oil is also very Rewarding but ad-lib preferential consumption fails to induce obesity. For obesity there is the absolute necessity of calories to enter adipocytes and then stay there. Long term. Dopamine release in the brain might make you choose to eat something over something else but without pathological energy storage... Shrug.

My own concept of how butter oil/sucrose causes obesity is limited by the clear fact that there is no way of simply saying a given F:N ratio will always produce obesity. Too many variables for this to be set in concrete, which allows the hypothesis to side step conflicting evidence. You have been warned.

Random thought: Sucrose (when it doesn't produce a slim insulin sensitive phenotype) usually produces hyperinsulinaemia and insulin resistance (often "skinny fat"). The higher the insulin levels the more effective insulin sensitising dietary components (linoleic acid and now possibly SCFAs) are at allowing that high level of insulin to generate obesity. Probably why the cornstarch is added to the fudge, to augment the insulin response.

As always, alternative explanations welcome.

My thanks to Basti in the comments after the last post which crystalised a lot of this current post. And to Tucker twice over.


Wednesday, December 08, 2021

Protons (53) a formula revised

Back in Protons (53) a formula I wrote down how to work out the F:N ratio of (even chain) fatty acids with varying double bonds:

F/N = (n-1-db)/(2n-1)

where n is the length of the carbon chain and db is the number of double bonds.

Oleic C18 is 18-1-1 divided by 36-1, ie 16/35 = 0.457
Linoleic 18-1-2 divided by 36-1, ie 15/35 = 0.423

This is fine up to C18 but C20 and above are targeted to peroxisomes rather than mitochondria so the need for an F:N ratio fades. Peroxisomes have their own signalling systems but research on them is in its infancy.

Anyhoo, Tucker mentioned off blog that during the multistep processing of double bonds there is a step which consumes NADPH. This will have to be re-reduced from the resultant NADP+ by the Krebs Cycle where NADH producing steps have iso enzymes capable of generating NADPH instead of NADH. That reduces the NADH supply to the electron transport chain by 1 NADH per double bond requiring NADPH, so complicates the formula.

The formula ends up as:

F/N = (n-1-db)/(2n-1-db)

It makes a relatively small change to the ratio as the denominator is a much larger number than the numerator.

Oleic acid, originally 0.457 becomes

18-1-1 divided by 36-1-1, ie 16/34 = 0.471

and linoleic acid, originally 0.423 becomes

18-1-2 divided by 36-1-2, ie 15/33 = 0.455

The latter is interesting as it moves linoleic acid upwards towards MUFA and the saturates because the denominator drops.

The value for caprylic (shortest saturate in common consumption) is 0.467 and with the new LA now at 0.455, they are getting closer. Also caprylic is now at lower F:N ratio than oleic. I just wonder if this is part of the explanation of the coconut based diets used by Surwit to induce obesity with LA still limited to 4% of calories...

Thanks to Tucker for the NADPH requirement insight.


Tuesday, December 07, 2021

!Kung Bushmen and mongongo nuts yet again

Well, I got that wrong about conjugated linoleic acid (CLA) from mongongo nuts.

The !Kung people eat their mongongo nuts and the large amount of alpha-eleostearic acid converts to 9cis, 11trans CLA:

Alpha-eleostearic acid (9Z11E13E-18:3) is quickly converted to conjugated linoleic acid (9Z11E-18:2) in rats

This 9c, 11t CLA is exactly the same isomer as rumenic acid, the primary CLA of ruminant meat/dairy fats.

It's not a lipolytic agent. Not from monongo nuts, not from ruminants.

For lipolysis you want 10trans, 12cis CLA.

Manufacturing a bulk supply of CLA for marketing as a fat loss drug uses a process of treating ordinary linoleic acid with a catalytic industrial process which isomerises the LA in to roughly a 50:50 mix of 9c, 11t CLA and 10t, 12c CLA plus some odds and sods

The 10t, 12c isomer is a lipolytic agent of some potency. There's a nice review here:
However it does not appear to be found as a normal component of any biological system as far as I know, though I'm open to someone finding a source. At the moment it looks like it is a drug, manufactured from linoleic acid by an industrial process. The chemical formula might be identical to rumenic acid but on a "shape", charge distribution and metabolism basis (the location and orientation of the double bonds really matters to enzymes) the two have nothing what so ever in common.

In addition to weight loss 10t, 12c CLA can also trigger adipocyte apoptosis. A little apoptosis might be fine if you have adipose tissue hyperplasia (too many adipocytes, rather than too distended adipocytes) but if you have normal levels of overly large adipocytes it will place the burden of accepting excess insulin mediated lipid for storage in to the remaining, already overly large, adipocytes. Or your liver.

This is essentially a lipodystrophy, certainly if taken far enough. As in congenital and acquired lipodystrophies, this will be associated with glucose intolerance, insulin resistance and functional type 2 diabetes. In rodent models you can drive this process somewhat further than you can in human clinical trials. So this study uses mice:

Conjugated Linoleic Acid Supplementation Reduces Adipose Tissue by Apoptosis and Develops Lipodystrophy in Mice

Bear in mind this is a model and has been set up to produce an extreme black/white result and it delivers.

Oral glucose tolerance test and intraperitoneal insulin tolerance tests:

Here are the weights of various organs of interest (check the liver):

Note that the model was set up so there was no weight loss with the 10t, 12c CLA treated group. There is massive adipose tissue loss, adipocyte number loss but no weight loss (it's a model, people are clever). All of the lipid which should be in adipocytes ends up in the liver. What does a 4.44g liver look like in an adipocyte depleted mouse? Like this:

This is the diet:

"The semipurified diet was a low-fat diet and on a calorie basis contained 63% carbohydrate, 11% safflower oil, and 26% protein. Safflower oil was used as a source of fat. Safflower oil (high-oleic type) contained 46% oleic acid (18:1 n-9) and 45% linoleic acid (18:2 n-6) from total fatty acids. CLA was prepared as a free fatty acid at Rinoru Oil Mills (Nagoya, Japan) and stored frozen in plastic bottles blanketed with nitrogen. Linoleic acid was isomerized to CLA with isomers (34% c9, t11/t9, and c11; 36% t10 and c12; 3% c9, c11/c10, and c12; 2% t9, t11/t10, and t12 from total fatty acids). In the CLA-fed group, to keep fat intake constant in the 2 groups, 25% of the safflower oil was replaced with CLA"

That's a quarter of 11% of calories as mixed isomer CLA, the sort you might take as a supplement, ie around 3% of calories. About a third of this is the active 10t, 12c CLA, ie around one percent of calories.

If a human consumes 2000kcal/d then that's 20kcal or 2g of 10t, 12c CLA per day. In this now rather well thumbed study

Comparison of dietary conjugated linoleic acid with safflower oil on body composition in obese postmenopausal women with type 2 diabetes mellitus

they were using 6.4g/d mixed CLA isomers. That will be around 3g/d 10t, 12c CLA. That's exactly the ball park used to produce lipodystrophy and diabetes in mice. The same phenomenon occurs in pigs where after slaughter back fat can be extracted, weighted and processed to detect apoptosis:

Supplementation with conjugated linoeic acid decreases pig back fat deposition by inducing adipocyte apoptosis

Comparable studies would be difficult in humans but least pigs aren't mice.

Where does this leave the !Kung and their mongongo nuts? Well, they certainly never see any 10t, 12c CLA, our liver only converts alpha-eleostearic acid to rumenic acid (assuming we're like rats). This latter is either a weak or non lipolytic/apoptosis agent. Does that leave the !Kung as inexplicable?


It turns out that alpha-eleostearic acid is a rather potent lipolytic agent in its own right, it also induces apoptosis in fat cells in a similar manner to 10t, 12c CLA. Bitter melon seed oil is another, quite well studied source of alpha-eleostearic acid. This gives the flavour:

Mongongo nuts are lipolytic until their alpha-eleostearic acid content is detoxified to rumenic acid. To me, this suggests that living on mongongo nuts may carry weight control benefits at some risk of generating a degree of lipodystrophy, however small. I doubt anyone has gone studying adipocytes from the !Kung for markers of apoptosis. It looks like there will be a trade off between degree of lipolysis, giving small, low basal lipolysis adipocytes vs lost adipocytes giving larger, more basally lipolytic remaining adipocytes. I suspect the dose makes the poison.

I think it's probably unimportant to go in to detail about how alpha-eleostearic acid and 10t, 12c CLA induce lipolysis/apoptosis but, not surprisingly, it involves the generation of ROS for both.


Monday, November 29, 2021

Are you on clenbuterol? (3)

More from Risérus

Trans fatty acids and insulin resistance

"This is especially true [inducing insulin resistance] for conjugated TFA, i.e. conjugated linoleic acid (CLA), which clearly impairs insulin sensitivity."

I think is reasonable to assume that Risérus expects ordinary trans fatty acids to impair insulin sensitivity too, though not quite as effectively as CLA does. He just needs a big enough intervention study to prove it.

Of course he is wrong in this. He's also correct.

There is a saying that the dose makes the poison. CLA warrants a post or two on its own but it's enough to say for now that there is a toxicity syndrome, reliably induced in rodents, because it's ability to induce lipolysis can be frankly too effective. Including death of adipocytes.

Trans fatty acids are the little brother to CLA as far as lipolysis is concerned.

From the Protons point of view oxidising fats, any fats, will be better than glucose, even with insulin, at inducing reverse electron transport through complex I.

Weight loss, ie fat loss, necessitates the oxidation of lost fat. The better the lipolytic agent, the more fat to oxidise and the more insulin resistance.

Extended fasting is classically a state of profoundly increased fatty acid release from adipocytes and the oxidation of those fatty acids, with insulin resistance being intrinsic to this state. And essential for survival. Protons.

So it is impossible to lose fat without the development of some degree of fat oxidation induced insulin resistance.

CLA is good at lipolysis, trans fats less so but still better than a poke in the eye with a sharp stick.

The thought train which goes on from here is that lipolytic agents should acutely reduce insulin sensitivity directly related to the degree of fat loss. In the long term a lipolytic agent which enforces sustained fat loss will provide the low rate of basal lipolysis intrinsic to small adipocytes and so increase insulin sensitivity, especially if the lipolytic agent is not currently active.

I'm going to talk about clenbuterol next but the other agent of interest is metformin. From the Protons view metformin simply blocks the glycerophosphate shuttle, drops the FADH2 input to the electron transport chain so blunts insulin signalling which needs some degree of ROS generation to happen. Blunting insulin signalling allows lipolysis and suppresses hunger in proportion to these fat loss calories. Once adipocytes are small enough from this blunted insulin signalling we are back in to small adipocytes with low basal lipolysis so increased insulin sensitivity, especially if the metformin has worn off... In humans metformin takes a few weeks to "work". I doubt the degree of fat loss needs to be gross, just enough to reduce basal lipolysis a little.

Back to clenbuterol. Calves this time (at least it's not Bl/6 mice!).

Clenbuterol-Induced Insulin Resistance in Calves Measured by Hyperinsulinemic, Euglycemic Clamp Technique

Basically it's looking at acute treatment with a lipolytic agent. Here are the glucose infusion rates under an hyperinsulinaemic clamp:

The black squares are the infusion rates after clenbuterol, the open squares before injection. 

It's clear from the bottom graph, while the drug is active, that the treated  calves are insulin resistant, requiring significantly less glucose during the hyperinsulinaemic clamp compared to before treatment.

The upper graph shows no effect if you wait 16-25 hours before the clamp, ie until the clenbuterol has worn off. Interestingly the square colours are reversed in this upper graph. Even if the rates are ns different, we still have the calves showing as more insulin sensitive in the aftermath of a period of lipolysis. You can't force lipolysis without shrinking adipocytes. Shrunken adipocytes will always have lower basal lipolysis compared to larger adipocytes. This should show as less insulin resistance. There is a suggestion of that here.

Here are the results tabulated

I was going to go on to talk about chronic clenbuterol and the enhanced insulin sensitivity it provides. Undoubtedly chronic, high dose clenbuterol induces low adipocyte size, muscle hypertrophy and markedly improved insulin sensitivity. But the mechanism becomes complex and convoluted. I spent a little time on this fascinating paper which is comprehensible from the Protons point of view but horribly convoluted by beta receptor down regulation leading to blunted adrenaline signalling. Which affects insulin sensitivity directly.

Clenbuterol prevents epinephrine from antagonizing insulin-stimulated muscle glucose uptake

Fascinating but I'll leave that can of worms alone. It does leave me wondering a little about the acute effects of clenbuterol on fully active beta receptors and their interaction with insulin signalling. Messy. I'll leave the above post unchanged but bear in mind a lot is going on when you take an adrenergic agonist drug, in addition to lipolysis!


Sunday, November 28, 2021

Are you lino-philic? (2)

Why do Risérus, Willet and Hu get it so wrong? Apart from habit of course. Out by a Ferguson is their usual standard.

Just to regurgitate:

"Taken together, the evidence suggests that replacing saturated fats and trans fatty acids with unsaturated (polyunsaturated and/or monounsaturated) fats has beneficial effects on insulin sensitivity and is likely to reduce risk of type 2 diabetes. Among polyunsaturated fats, linoleic acid from the n-6 series improves insulin sensitivity."

Looking at this study is informative:

Here are the intervention diets

The intervention does exactly what it says on the can. Two five week periods with crossover. The subjects were rock steady for bodyweight throughout the study. Clearly it could not be blinded and the authors speculate that caloric intake might be under reported on the high PUFA arm because there are decades of indoctrination that the PUFA period was "healthy" eating (my phraseology!). I would add that they might even have subconsciously "accidentally" genuinely under eaten rather than under reported. It was only five weeks after all.

Here are the clamp results:

I think it's worth noting that at 120 minutes (Stage of clamp 6) that the glucose infusion rate per unit plasma insulin was still rising in the PUFA period but in the sat fat period the increase had stopped. From the Protons perspective this is the onset of insulin induced insulin resistance, apparently lacking in the PUFA rich period. Not commented on by the researchers but I have the eye of faith. Nice.

Converting the above graph to actual numbers here we have the results table here:

This is all classic Protons.

Protons says insulin signalling makes you fat. Improving insulin sensitivity, ie signalling, will ergo make you fat. Linoleic acid does this better than anything else, pax glitazones. Eventually insulin resistance will occur but only when adipocytes get big enough. This takes longer than five weeks, especially if you succeed in transiently limiting calories to less than those needed to replace calories lost in to adipocytes.

Back to Risérus, Willet and Hu.

To them life appears simple. Skinny people are insulin sensitive. Fat people are insulin resistant. If you could make fat people have the insulin sensitivity of thin people they would become thin. Or at least not diabetic.

Hahahahahahahahahahahaha! Bonk.

They really need Protons.


Are you trans-phobic? (1)

I've had this paper lying around on my hard drive for some time

Trans-palmitoleic Acid Reduces Adiposity via Increased Lipolysis in a Rodent Model of Diet-Induced Obesity

I don't like it much in terms of writing style, details included/omitted and perspective of the authors but their data look okay and confirm my deepest biases, so I like this aspect.

The usual Bl/6 mice on high fat diet (around 6.5% LA, linoleic acid) vs low fat (around 3.7% LA)


We can see that 4% of calories as trans palmitoleate partially offsets the obesogenic effect of just over 6% linoleic acid in Bl/6 mice.

In terms of adipocyte size the mean surface area on a histology section is normalised:

I would expect normal sized adipocytes to have normal basal lipolysis and not be causing excess FFA release in the presence of insulin. The study didn't look at insulin or insulin resistance but they mention various papers in passing where there are suggestions of this being the case.

You could, from isolated adipocyte studies, make a similar case for elaidic acid (ie shock horror, trans oleic acid, mmmm Crisco).

Replacing Cis Octadecenoic Acid with Trans Isomers in Media Containing Rat Adipocytes Stimulates Lipolysis and Inhibits Glucose utilization

"Compared with oleic acid, both trans isomers reduced (P < 0.01) the amount of glucose converted to cell lipid in both experiments. Glucose oxidation to carbon dioxide also was lower for both trans fatty acids in Experiments 1 (P < 0.05) and 2 (P < 0.06). Lipolytic rates were increased (P < 0.01) in both experiments by replacing oleic acid with either of the trans isomers."

"...and decreased adipocyte size (−44%) versus control rats."

also worth noting

"[trans vaccenic acid] supplementation also increased metabolic rate (7%)"

Trans vaccenic acid stops the development of metabolic syndrome just as trans palmitoleic acid does. For those of us who consider metabolic syndrome to be the replacement of insulin/sympathic system controlled lipolysis by elevated, uncontrolled, adipocyte size determined basal lipolysis this is exactly what you might expect.

In this next study they replaced 7.2% trans vaccenic acid and 3.4% elaidic acid (original Primex) with palmitate (Primex-Z) while maintaining 24% of the fat as LA. Much as I love palmitic acid it is not an active lipolytic agent in the way that the trans fats are.

Chronic ingestion of Primex-Z, compared with other common fat sources, drives worse liver injury and enhanced susceptibility to bacterial infections

Here are the weights at 16 and 30 weeks, first column is the control Bl/6 mice, second is the trans fat mice, third is the unopposed LA:

and here are the adiposity index results:

Sadly again no assessment of insulin function was made but with comparable adiposity to the control mice I wouldn't expect them to be insulin resistant. The corn oil group will have been pushing uncoupling levels of LA. By 30 weeks everything looks pretty much as I would expect it to.

So I might claim not to be trans-phobic. Except I support JK Rowling.

Why do Risérus*, Willet and Hu disagree?

[* That's Risérus as in The Muffin Study and Willet and Hu are the Usual Suspects]

Dietary fats and prevention of type 2 diabetes

"Taken together, the evidence suggests that replacing saturated fats and trans fatty acids with unsaturated (polyunsaturated and/or monounsaturated) fats has beneficial effects on insulin sensitivity and is likely to reduce risk of type 2 diabetes. Among polyunsaturated fats, linoleic acid from the n-6 series improves insulin sensitivity."

Which is, of course, absolute, total bollocks.

There is a reason they make this mistake but this post is too long and rambling already.


Monday, November 15, 2021

Is vaccine efficacy a statistical illusion?

Just a twitter-ish one liner:

Insight delivered on a plate. A clear explanation of the John Dee's Almanac concept. Look how the sizes of populations shift with time on a fixed death rate giving the illusion of efficacy. And also of apparent waning efficacy with time. So elegant, so neat, love it.


Addendum if it helps:

EDIT Just to clarify, there is no need for the "vaccine" to do anything, you can even assume it's a placebo injection. The effect still occurs. END EDIT

After a chat with Raphi on twitter this might make it clearer. Campaign starts at day one. No results are collected for a week 'cos that's how long it takes. No one know exactly when a given person died because mortality stats are like that and this is not a controlled study situation we're talking about.

The numbers of deaths collected a week after the campaign started are attributed to week two because that's when they are recorded. This is the source of the error.

If 15 people a day die during week one but are recorded as week two they will be put in to incorrect population sizes because the vaccinated population is rising rapidly and the unvaccinated population size is falling rapidly. A week is a long time in a vaccine roll out.

So the small number of deaths in the initially tiny vaccinated group of week one will be attributed to the significantly larger vaccinated group found in week two. Very few deaths from a very small population are now spread out over a now larger population.

The much larger number of deaths from the much bigger unvaccinated population of week one will be attributed to the now smaller unvaccinated population of week two. The population is smaller because vaccines have been given, which rapidly reduces the size of the unvaccinated population.

In the vaccinated group too small a number of deaths is spread through too large a number of people, hence a low incidence/person days. Vaccine appears to work.

In the unvaccinated too many deaths (it was a very big group in week one) are attributed to a population reduced by the number who have been vaccinated by the rollout. So a much higher figure per person days is found.

Don't start me on how this makes being unvaccinated intrinsically dangerous and how the 'rona vacc appears to protect agains all cause mortality. Just more artifact.

The graphs come out as in the linked blog post.

The need for graphing mortality curves by date of death vs date of reporting is well known from plotting peaks of waves from peaks of deaths. If a study uses date reported rather than date of occurrence, it's possibly junk. It can take months to get death numbers by date of occurrence vs reported in the real world. Some mortality data from the UK ONS will be delayed by the time needed for a coroner's inquest.


Thursday, November 04, 2021

!Kung Bushmen and mongongo nuts again

Back in the mongongo nuts post I suggested that conjugated linoleic acid (CLA), which shows the hallmarks of a lipolytic agent, derived from the alpha eleostearic acid in the nuts might offset the obesogenic effect of the common or garden linoleic acid (LA) present in roughly equal amounts.

We have the !Kung consuming anything from zero to 1000kcal/d of mongongo nuts per day, average 800kcal/d, ie about 40% of calories:

You can download the full text from Scihub. It's a nice read.

So. If this is the case you have a pair of opposing effects, from the Protons point of view the LA is insulin sensitising and will allow excess insulin signalling to distend adipocytes when they should be signalling that they are full. Under fasting it can allow relative hypoglycaemia, encouraging food intake, but that's not a feature of this study. All subjects were only fasted for four hours.

At exactly the same time the alpha eleostearic acid derived CLA will be facilitating the release of FFAs from adipocytes which means that fat cells stay approximately the correct size and those FFAs are available to be perceived by the brainstem. So, from the adipocyte point of view we have excess calories-in and excess calories-out concurrently. If the adipocytes never distend we will never have to deal with size-derived excess basal lipolysis and the associated appropriate insulin resistance.

Now we can look at how that might explain the observation in this paper

Metabolic Responses to Oral Glucose in the Kalahari Bushmen

"Since an overnight fast would probably have been broken (owing to the almost continuous eating pattern of the Bushmen when food is available), we performed tests in the afternoon, after four hours of observed rest and fasting."

The Bushmen eat very frequently when food is available but never enough in total to become obese.

What does an oral glucose tolerance test look like in a !Kung bushman?

Like this:

As the authors comment

"Mean glucose levels were higher in the Bushmen at all stages, with significant differences at 0 and 120 minutes. Indeed, by lax criteria of evaluation (Jackson et al., 1970), their mean two-hour post-glucose level of 121 mg/ 100 ml could be regarded as falling within the "diabetic" range. Conversely, the Bushmen exhibited insulinopenia throughout the test, and this was significant at 0 and 60 minutes."

These people are insulin sensitive, as you would expect from a high LA intake. However they don't become obese because they never secrete very much insulin, ignoring the CLA. Does anyone recall this image of an isolated, perfused rat pancreas?

The closed circles are perfusion with LA. So perhaps it's not too surprising that the !Kung are hypoinsulinaemic. And it doesn't matter because they are also very insulin sensitive. This balances out.

In some ways they remind me of Jim Johnson's reduced insulin gene dosed mice in which, during early life, some glucose intolerance was present secondary to hypoinsulinaemia but this self corrected with age. Clearly the !Kung, with normal insulin genetics, are quite capable of becoming obese on an high LA diet simply by ramping up their insulin secretion in response to a mixed diet and it is the CLA which stops this. So they never develop the problems secondary to distended adipocytes.

Other explanations welcome.

What would have been really interesting would have been an insulin tolerance test which looks at insulin sensitivity without needing any confounding contribution from (decreased) pancreatic insulin secretion. I think we can assume that there would have been a profound fall in blood glucose in response to exogenous insulin.


Tuesday, November 02, 2021

Are COVID-19 vaccines useful? (3)

Here is an interesting twitter thread by a mainstream author in which he discusses the problems in the Swedish observational study preprint

Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study

where vaccine efficacy drops to zero by 200 days and becomes negative there-after. 

Life is probably not that simple and natural infection means that by the 200 day mark you are comparing recovered field infected people with naive vaccinated people, at least I think that's his argument. So apples are being compared to progressively ripening oranges.

What’s more interesting is a related second twitter thread of his in which he discusses this study of the fully vaccinated only (ie more than 14 days post second dose, mostly) 

Immune Responses in Fully Vaccinated Individuals Following Breakthrough Infection with the SARS-CoV-2 Delta Variant in Provincetown, Massachusetts

which looks at the short term consequences of vaccine failure (“breakthrough” infections) on a number of parameters. The vaccinated study population were jabbed in the near absence of circulating virus so the normal 14 days of immunosuppression didn’t cause an infection problem. Later on a wave of field infection passed through the area as the virus "virused" in its normal manner, though somewhat out of season.

Here’s the most important figure, it's as close as the study got to asking useful questions:

Section A simply tells us that having a vaccine systemic anti-spike antibody titre of around 1 in 200-ish derived from the vaccine does nothing to protect against infection and that field virus exposure bumps this up to 1 in 2,000-ish in recovery. Shrug, we should expect that there would be a marked response to the original antigen seen by the immune system, especially in the systemic circulation.

What is much more interesting is section B. This shows systemic IgG response to nucleocapsid antigen, which as essentially zero in people who were vaccinated but not infected, on the left side of the graph. The right hand side, filled circles, shows people who were vaccinated and then became infected. There is an anti-nucleocapsid systemic IgG response of a magnitude comparable to the anti-spike IgG response produced by the initial vaccination. This suggest that OAS is present but does not eliminate the response to other antigens of the field virus.

Now, whether a spike-only antibody titre of 1:200 is protective against anything is an open point, so whether a broad antigen antibody response, illustrated by anti nucleocapsid response, is effective against anything either is also a somewhat open point. All of the infected people were survivors and all had mild illness. It seems like a religious question as to whether mild disease was due to huge anti-spike response or modest multi-epitope response. Or catching the virus in July in northern latitudes.

Ultimately the vast majority (but clearly not all) of people are going to survive exposure to SARS-CoV-2, especially if it happens in mid summer. The vaccine appears to allow field infection to produce a broad antigen, probably sterilising immunity. OAS still shows as the marked anti-spike response to field virus but this does not stop recovery or a more general immune response.

And because the vaccine does nothing to eliminate spread we will eventually have enough people infected to then limit transmission to endemic levels.


Controversial addendum: This link is to a less-than-preprint conversational musing piece from someone who has access to NHS data of a detail beyond anyone's wildest dreams in Twitterland, hence it's on Telegraph. So some serious caveats have to be applied but his conclusion is that the vaccines do absolutely nothing. At all. An interesting idea.


Consider with caution. There appear to be lots of ways of looking at lots of data!

Sunday, October 24, 2021

Are COVID-19 vaccines useful? (2)

I really, really don't like this:

Nasal prevention of SARS-CoV-2 infection by intranasal influenza-based boost vaccination

I picked it up via a tweet from Gabor Erdosi in the aftermath of the excellent discussion he had with Raphi, available on Youtube.

The only fundamental problem I have with their discussion was about original antigenic sin and the above pertains directly to this.

I was very pleased to receive the OAS source paper from Mike Eades (thanks Mike!) and it's a great read. An old paper from 1960, written in the style of the time, giving a basic idea discussed in almost conversational terms by a single author, with enough data to back up the idea, explaining where it came from. I can't see the original paper on tinternet although there are lots citing it:


EDIT location for the first page provided via eugyppius END EDIT

NEXT EDIT Full text here, thanks to Raphi END EDIT AGAIN

So. My fundamental difference in viewpoint to Gabor is that my expectation is that OAS from the mRNA vaccines would be limited to the systemic immune system and the respiratory mucosal immune system would be free from OAS and so able to mount a broad, effective response to produce sterilising immunity to a field infection. Whatever the evolution of spike protein to antibody avoidance, the respiratory mucosal system should stay clean.

The above technique of giving an intranasal live attenuated influenza vaccine at the same time as a systemic IgG inducing mRNA based vaccine appears to trigger respiratory mucosal IgA formation to the systemic spike protein antigen. You "kick" the respiratory system with an attenuated influenza vaccine and the "awake" respiratory immune system "notices" and responds to what should have been a systemic-only spike protein stimulus.

In the UK we already have routine childhood intranasal influenza vaccines. I'm not anti-vax, my kids get the intranasal flu vaccine, FWIW. Assuming mRNA Covid vaccines are made mandatory for children (peak stupidity, but nothing surprises me) I can see that the logistics of delivering both vaccines on the same day might favour doing both at once.

So for kids OAS would be effectively extended from systemic IgG to mucosal IgA. Which might well blunt a correct, broad antigenic response within the airway at the time of a subsequent field virus infection.

This sounds like a very, very, very stupid thing to do.

So it will probably become standard practice, even mandatory.


On the plus side the mucosal IgA might be sterilising, if anti-spike antibodies are enough to kill all of the virus. This will limit time available for selecting an anti-spike antibody evading strain of virus. But the pressure will be still there.

It's like giving a full therapeutic dose of methicillin to a patient with a methicillin susceptible staphylococcal infection. It works. You have to do it. You have to kill the staph completely. But one day you will still successfully select for MRSA... It will happen. It already has.

Friday, October 22, 2021

Are COVID-19 vaccines useful?

Mike Eades updated the current copy of the Arrow to include Alex Berenson's observation that the COVID-19 vaccine surveillance report Week 42 from the UK Health Security Agency (ie the UK Government, such as it is) details that the phenomenon of Original Antigenic Sin is clearly being demonstrated in the UK covid antibody data.

This concept is very simple and predicts that if you are exposed to a single antigen (here the spike protein derived from an mRNA vaccine) your immune system will prioritise a response to that single antigen in preference to other antigens when presented with a mixed antigen soup, as in the whole virus during a subsequent field infection.

So, in double vaccinated individuals you have preferential response to the spike protein over nucleocapsid protein as assessed by antibody titres. Page 23 if you want to have a look:

"recent observations from UK Health Security Agency (UKHSA) surveillance data that N [nucleocapsid] antibody levels appear to be lower in individuals who acquire infection following 2 doses of vaccination."

ie the vaccine screws your immune response to nucleocapsid.


However the UKHSA only monitor anti-spike protein and anti-nucleocapsid antibodies because these allow us to distinguish between vaccine exposure and field infection. Obviously field infection triggers many more immune responses in addition to those against spike and nucleocapsid proteins, none of which need to be monitored to get this information.

As we vaccinate using the spike protein alone we will actively favour the survival of vaccine evading mutations. Boosters will speed this up.

So, are we all going to die?

I think not. UKHSA is monitoring antibodies. These are being surveyed in recovered patients.

"Recovered" is the word. 

Ultimately triple (and greater, eventually) vaccinated people, so long as the vaccine is spike protein based, will eventually end up behaving as though they are unable to even "see" the spike protein, their anti-spike antibodies will be present but will do nothing. Spike evasion will have happened and the selection pressure will no longer be present. Lots of anti-spike antibodies, no interaction with the spike, no further selection pressure.

Vaccinated people will have to run on non-spike immune response, which will still be broad and still work. It may not be as effective as in the non vaccinated, because the immune system prioritises large amounts of useless spike response, but most people will still survive (unless they have chosen to be a poorly controlled diabetic, diagnosed or in-situ of course) as they are doing currently.

In some ways I can see some use for the vaccine and the idea of vaccine passports.

Aside: Of course using vaccine passports for anything, especially to pauperise and exclude the unvaccinated, will come with a sh!tload of human rights violations in addition to the health problems automatically generated by pauperisation per se. This is morally reprehensible and unforgivable. It's happening now if you live in the wrong country. Don't you love politicians? End aside.

At the start of the pandemic certain groups of people were thrown under the bus as regards covid. These are people who do actual work. Supermarket checkout cashiers, bus drivers, garbage collectors, postal workers, truck drivers, construction workers. Others, like myself, were given several months leave on 80% of salary with a big garden during some of the sunniest Spring weather I can recall. So we "let the virus rip" through people who actually do jobs ("essential workers") and paid loafers like myself ££££ of my children's and probably grandchildren's money to stay at home and "avoid" the virus. For a while.

Now the vaccine is here and the virus is in reality being allowed to rip through the rest of society, including the laptop classes. Clearly vaccine passports will actively concentrate vaccinated people in to crowded places and so maximise transmission. The UKHSE report cited above also reports vaccinated people are a lot better at getting infected compared to the unvaccinated, interestingly enough. Provided these people do survive (and most will) then they will end up with a ton of useless anti-spike "immunity" plus enough real immunity to other components of the virus to survive future exposure to that virus. We need this.

That should be enough.


PS I can live without the human rights violations which seem to be endemic at the moment. Or should I say epidemic or pandemic???

Saturday, October 16, 2021

Modelling energy intake (3): empagliflozin

In the aftermath of the of canfliglozin post I picked up this paper via Tucker:

Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition

It's the group including Hall again, with a different drug but still looking at glycosuria as an "insensible" caloric loss. If you feed the daily glucose loss in to their sophisticated CICO derived formula the weight loss over 90 weeks should be 11.3kg whereas the actual weight loss was 3.2kg.

This was correctly attributed to increased calorie intake, reverse modelled to an increase of calories in the region of 270kcal/day. What to do about this?

The best section of the abstract is the conclusion, which sums up the paper:

"Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss."

Translation, "starve the buggers". Starvation ALWAYS facilitates "major weight loss".

That was 2015. But even then Hall was well aware of the stupidity of this approach, as he detailed in his 2016 publication:

If caloric restriction where a feasible option I guess no one would ever get fat and, if they did, anyone could easily lose weight by caloric restriction, without the risk of fungal necrotising fasciitis (necessitating emergency removal of significant parts of a person's genitalia and possibly surrounding tissues) which comes as a real risk with the canagliflozin or empagliflozin deal. Sadly caloric restriction is generally associated with intolerable hunger and rapidly failing ability to maintain any large caloric restriction. An insight superbly documented Hall et al.

Ultimately in the real world of the CIM, the urinary loss of "x" glucose calories drops insulin. It appears that this drop in insulin releases a certain amount of FFAs from adipocytes, say "y" kcal, but y is never quite enough to fully compensate for the urinary loss x (no reason it should be). So a small amount of food is needed to make up the deficit as perceived by the brain stem. Back in 2015 I guess diabetics were being advised to eat low fat, high carbohydrate diets. So each patient eats a few extra calories, roughly x minus y extra. That food will be around 55% carbohydrate. Which will directly offset the urinary loss per se but more importantly, will increment the level of insulin in the bloodstream.

As insulin is incremented upwards by the extra food, so FFA release from adipocytes will increment downwards and so a spiral of rising food intake, rising insulin and falling FFAs (limiting weight loss) will ensue.

There is some sustained weight loss. I would guess that this is related to the residual fat content of the extra food eaten, which won't raise insulin the way the carbohydrate component will.

Which leaves you wondering if by providing the small food increment needed to off set the x - y deficit in the form of fat, perhaps a much more significant weight loss might have occurred. Not sure 11.3kg would be possible, but it might be.

And of course starvation would not be needed... But perhaps that smacks of LC eating and the CIM too much.


Tuesday, September 14, 2021

Modelling energy intake (2): Corn oil

This post has been waiting around for some time so I thought I'd just put it up before settling down to read

but I'm also looking at

and this one is pure Protons and ruminants

ditto this

and there might be at perhaps two more post on canagliflozin. Maybe.

When on earth I'll get to post on these I have no idea. Working on it!

Anyhoo. Back to today:

I thought it might be interesting to very, very crudely apply Kevin Hall's mathematic model to a much more interesting study. This one came my way via Jacob in comments quite a few weeks ago.

Response of body weight to a low carbohydrate, high fat diet in normal and obese subjects

This graph is an example of one single individual out of a total of five people in 1973, so we are talking about near-anecdotal data, but fascinating never the less.

The diet contained a fixed 168g/d of carbohydrate and 64g/d of protein plus a variable amount of fat over time. This is the weight change curve for subject "1", as far as I can make out:

This person lost around 2kg in the first 10 days on the diet then regained just a small amount over the following 25 days. For comparison if we now go on to look at Table 3 from Hall's

How Strongly Does Appetite Counter Weight Loss? Quantification of the Feedback Control of Human Energy Intake

we can see that a standard "lifestyle intervention" (Weight Watchers and exercise perhaps????) established an enforced caloric deficit of around 700kcal per day, which was eroded by hunger ("appetite") at something like an exponential rate, approaching the re establishment of baseline caloric intake with persistent ongoing hunger:

In the first month or so this caloric deficit triggered something around 2kg of weight loss. So if we took the graph for subject 1 at the top of the post we might reasonably assume an initial deficit of in the region of 700kcal with a rapid onset of hunger which would try to erode this weight loss effort. Something like:

Absolute CI decrease + CO increase = hunger, ie real life.

Except the subject in the graph at the top of the post was not in a weight loss study. He/she was in an overfeeding study. Carbohydrate and protein were kept fixed (and non-ketogenic) and progressively more fat was added to the diet, in steps, every five days. Here is the graph with the calorie intakes illustrated for this particular individual.

Yes, that is just under 6000kcal/d at a stable reduced weight.

Two things come to mind.

First is that it is stated that all subjects consuming over 2700kcal/d of fat felt warm all of the time and sweated easily. Second is that DLW measurement of TEE would certainly pick this up perfectly well and estimate a massive "calories out". Those would be as heat. Reversing-engineering weight loss to estimate changes in food intake is clearly completely out of its depth here. What happened?

The fat was corn oil.

Linoleic acid -> 4HNE -> activates uncoupling to blunt insulin signalling and causes insulin resistance per se -> hot, sweaty weight loss.

It takes a significant amount of linoleic acid to do this, well in excess of that needed to augment fat storage.

This effect appears to apply just as well to humans as it did to those mice in The ginger paradox (3), even when overfeeding is exogenously enforced. Clearly the mice which actively lost weight "effortlessly" (ie mice never do the human "appetite" battle unless they are exogenously semi-starved) on safflower oil used uncoupling to blunt insulin signalling and so increase lipolysis and adipocyte derived calorie supply.

Subject 1, on corn oil, had a peak of around 84% of calories from fat which put the linoleic acid percentage in the region of 40% of 6000kcal, well in to uncoupling levels. Corn oil in the 1970s was suggested to be around 45% LA.

Now, what would be expected to happen if we massively over fed with a lower LA, less uncoupling fat? The estimate for LA in olive oil in the 1970s was 7%. In this next graph the maximum LA percentage was 6% of calories, which is more akin to an obesogenic dose than to an uncoupling dose. Overfeeding olive oil does this:

That is 9kg weight gain in 40 days, and still going.

Now, what might we expect if we tried the same thing with beef fat? My expectations:

Weight gain would be even greater.

Metabolic syndrome would develop rapidly.

It should be much harder to sustain a 6000kcal diet of mostly beef fat than it was from either an uncoupling or  an obesogenic fat source.

The group didn't try overfeeding beef fat, sensibly.

There are a number of studies which I have picked up over the years which suggest that the uncoupling effect of double bonds kicks in at essentially all levels of their metabolism. At low levels the effect is over-ridden by the effect of failing to limit insulin signalling in adipocytes as per the Protons concept, leading to weight gain ie insulin still signals perfectly well and it does so more than is physiologically appropriate, especially in the immediate post prandial period. As uncoupling comes to predominate the ability of a low mitochondrial membrane potential to markedly suppress ROS generation becomes progressively more and more dominant, so insulin signalling becomes profoundly blunted. It will never get to high enough levels where insulin-induced insulin resistance should have kicked in, so the Protons concept becomes irrelevant. Under uncoupling, mitochondrial metabolism is functionally hypoinsulinaemic, it should resemble that of reduced insulin gene dose mice in Jim Johnson's lab where reduced insulin signalling was simply the end result of reduced insulin production, 24/7. It should also resemble ketogenic, hypoinsulinaemic eating.

Whether it is via 4-HNE/UCPs or 2, 4-dinitrophenol, high enough levels of uncoupling will absolutely blunt insulin signalling, with subsequent increase in access to adipocyte calories and consequentially suppressed hunger, leading to adipose tissue loss without increased food intake, with a few small caveats thrown in.


Monday, September 06, 2021

Modelling energy intake: Canagliflozin

It is quite possible to make a very reasonable estimate of how many calories a given person has consumed over the previous few weeks by estimating their total energy expenditure (TEE) using doubly labelled water (DLW), estimating the calories supplied from fat in adipose stores using the changes measured by DEXA scanning and applying a little arithmetic:

TEE (by DLW) - Fat mass change (by DEXA) = Food derived calories

Nice and simple. And very, very expensive.

Quite a few years ago Kevin Hall's group had the idea that you might be able to reverse engineer the intake of food calories simply from the change in weight over time using a mathematical model. They validated this against a two year conventional diet study where weight, TEE by DLW and fat mass changes by DEXA were repeatedly measured. They produced this paper:

Their model is pretty good within certain limits. You could trip it flat on its face pretty easily but that's not today's post. Just assume it works in the above study and also in this one:

The second study piggybacked on a diabetes study using canagliflozin, a sodium glucose co-transporter inhibitor which increases urinary glucose excretion. Canagliflozin produces the loss of around 90g/d of glucose, ie around 400kcal/d. This loss is insensible, other than via counting the number of trips to the bathroom. There was no specification within the study protocol to lose weight or to restrict calories.

Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study

The interesting questions are whether this silent caloric loss produces weight reduction, what does it do to caloric intake and what mechanisms might be at work.

Here are the weight changes:

So. Obviously losing 400kcal/day does produce weight loss. Or is that genuinely obvious? Surely, if the hypothalamus wants to "see" a certain number of calories to run metabolism, shouldn't it immediately increase calories eaten to counter that 400kcal deficit? Yes, it should. Immediately. Except...

Here is what happened to the energy intake. The solid black line is Hall's model which does not include the starting point at time zero with weight change zero. I've added the red curve to include this and roughed in the rest of the data points as well as a curve in powerpoint can manage:

It's quite clear from the data points that there was an initial drop in total energy intake to a nadir, somewhere within the first three weeks. DLW is an averaging technique so the location of the nadir is an unknown but it must have happened, to explain the data points generated where week three is below time zero.  The effect is more marked in the placebo group and probably represents simply being in the trial and tidying up, in both groups, the worst of the normally execrable diabetic diet prior to starting the study.

The effect is blunted in the canagliflozin group, presumably because of those 400kcal/d down from day one and their hypothalamus will have noticed this and have kicked their cortex in to doing something about it (hunger). By 15 weeks the extra calorie intake estimate (around +350kcal/d) is getting pretty close to the urinary calorie loss estimate (around -400kcal/d). 

But for the first 15 weeks calorie intake was estimated to be well below urinary calorie loss. Food was ad libitum. Why any weight loss?

That's interesting.

Also, despite increasing food calories to match urinary losses, weight remained stable at over three kilograms below baseline, with no suggestion of weight regain at the end of a year.

That's interesting too.

Hall goes on to treat the changes in weight as an engineering control system, a bit like a black box, without any attempt at integrating any basic physiology. A quick search of the text shows no mention of insulin in the whole paper. Not surprising, given the stance taken by Hall over the CIM of obesity.

But even the most basic, strawman-facilitating version of the CIM of obesity has no problem explaining the results in some depth. It takes about 30 seconds on PubMed to ascertain what canagliflozin does to the insulin requirement of people with DMT2.

It drops the requirement.

For patients still using their own pancreas for insulin this seems very likely to simply be reflected in a spontaneous fall in plasma insulin, triggered by the loss of 90g/d of glucose which exits through the bladder rather than requiring insulin to stuff it in to storage within the body.

If we assume insulin drops by a fixed amount in proportion to 90g less of glucose, and stays at this reduced level for as long the canagliflozin is given, there will be an acute rise in lipolysis which will supply adipocyte derived calories to partially make up for the urinary loss.

As the hypothalamus monitors energy status it will see 90g/d of glucose as absent but being replaced by, initially, roughly a kilo of fat from adipocytes over three weeks. More arithmetic:

400kcal glucose x 21 days = 8400kcal deficit from glycosuria.

Weight loss of 1kg over three weeks = 9000kcal of fat from adipocytes.

I would suggest that fat loss comes as a direct response to lowered insulin levels and will easily at least partially replace the glucose loss, certainly initially. The fat loss can be described as "calories-in" without actually eating them. So people with an acutely lowered insulin level eat less than you would expect.

Let's look at this the correct way round. An all-glucose caloric deficit of 400kcal/d was acutely established which directly resulted in rapid drop in plasma insulin levels. Lipolysis was acutely increased which largely offset the glycosuric calorie deficit. Because over several weeks lipolysis gradually slowed to an appropriate level determined by the the new insulin levels, food calories had to increase in proportion, to maintain an adequate energy flux to keep the hypothalamus happy. Eventually extra food-in will equal urinary glucose-out giving stable weight. But with lower insulin levels this will occur at a lower total fat mass.

The weight loss/calorie intake deficit were both caused, directly, by a fall in insulin levels. Utterly simplistic CIM.

Kevin Hall is a great source of data. Of insight?

Not so much.


Wednesday, September 01, 2021

Back to a semblance of normality: A couple of conversations

Hi all.

Life is back to a semblance of normality now. I've de-spammed/approved the comments on older posts and will try to read all of the comments as soon as practical.

As a brief update, Brian Sanders and I had a chat which is now up on the Peak Human website. It was fun. Nothing too detailed in the way of biochemistry and lots and lots of "I don't know about....." or "I don't have a framework to integrated that into..." sort of statements.

As life should be.

Peter from Hyperlipid on Are medical professionals giving the absolutely wrong advice?

The other thing which happened just before our vacation was a chat with Amber O'Hearn. She is really interested in sleep and diet, as in

The therapeutic properties of ketogenic diets, slow-wave sleep, and circadian synchrony

and it was a great privilege to throw in some ROS derived ideas which might have been helpful towards her presentation at AHS21

Does dietary mismatch affect us via sleep?

Very interesting. I have previously been sent a paper by a reader (long time ago) where death from sleep deprivation is an ROS phenomenon, largely centred on ROS damage to the gut. But, while fascinated, it didn't make a lot of sense to me until Amber filled in a lot of gaps. It still doesn't completely make sense but time and some thought might help with that!

I have to say, adenosine looks to be a very interesting molecule too, even if not directly ROS controlled...


Thursday, August 12, 2021


Brief one-liner:

There was a question in comments about what tweaks people might apply to themselves to minimise the risk of severe COVID-19 when they get around to being exposed to the SARS-CoV-2 virus, as we all will.

For subtleties anyone could do a great deal worse than follow George Henderson on Twitter.

For myself I rather like his tweet related to the Virta Health intervention:

which has been reinforced by this AI facilitated mining operation of the morass of published "risk factors" for severe COVID-19, with thanks to James for the link:

A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19

Clearly in 2021 DMT2 is currently due to either a lifestyle choice or to a lack of (accurate) information.

So for COVID-19 my specific medical advice to minimise serious illness is still the same.

Try not to be elderly. Try not to be diabetic.