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!

Peter

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.

Dietary fats and prevention of type 2 diabetes

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:

Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity

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.

Peter

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)

Weights:

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."

You can make the same case for trans vaccenic acid using whole rats:

Diets enriched in trans-11 vaccenic acid alleviate ectopic lipid accumulation in a rat model of NAFLD and metabolic syndrome

"...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.

Peter

Is vaccine efficacy a statistical illusion?

Just a twitter-ish one liner:

Is vaccine efficacy a statistical illusion?

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.

Peter

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.

Peter

!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:

Mongongo: The ethnography of a major wild food resource

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.

Peter

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.

Peter

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.

From https://t.me/JohnDeesAlmanac/639

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