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!

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:

ON THE DOCTRINE OF ORIGINAL ANTIGENIC SIN

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.

Peter

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.

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.

Somewhat.

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.

Peter

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

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:

How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake

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.

Peter

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

The carbohydrate-insulin model: a physiological perspective on the obesity pandemic

but I'm also looking at

Food intake in diabetic rats: isolation of primary metabolic effects of fat feeding

Hyperphagia in Rats with Experimental Diabetes Mellitus:A Response to a Decreased Supply of Utilizable Fuels

and this one is pure Protons and ruminants

CALCIUM SOAPS OF FATTY ACIDS WITH VARYING UNSATURATION ASFAT SUPPLEMENTS FOR LACTATING COWS 

ditto this

Effect of supplementation with corn oil on postpartum ovarian activity, pregnancy rate, and serum concentration of progesterone and lipid metabolites in F1 (Bos taurus x Bos indicus) cows

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.

Peter

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:

Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake

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:

How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake

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.

Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial

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.

Peter

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...

Peter

COVID-19

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.

Peter

Update

Lots of posts part written but currently I'm getting camping gear ready for our family holiday with kayaks, hills and tents. At the same time the essential big car is in the garage getting it's rear differential fixed/replaced and I'm not sure we would all fit into the MX5...

Normal service will be resumed when I get some time!

Peter

Nourish Balance Thrive Podcast

I had a chat with Megan Hall of Nourish Balance Thrive. I feel it went quite well and I got most of the core ideas of the Protons/ROS hypothesis over in a relatively concise manner. The microphone continues to work:

Here it is on Apple Podcasts

The True Cause of Insulin Resistance and Obesity (and What To Do Instead)

and on the NBT website

The True Cause of Insulin Resistance and Obesity (and What To Do Instead)

Peter

Jay Bhattacharya in conversation with Lord Sumption

This came to me via Ivor and Facebook. I keep struggling with the worry that the current pandemic might be the beginning of the end of western liberal democracy. The interview is not encouraging and Lord Sumption does encapsulate exactly where this feeling I have might be coming from.

A Conversation with Lord Sumption

If anyone is hopeful that we are getting out of this mess anytime soon then they had better not watch it.

Peter

More time wasted on vaccines

My thanks to Jonathan Engler for the tweet. This is HMS Queen Elizabeth.

She has a complement of 1,600 when fully staffed (dirtied my hands in Wikipedia to check that) so 1,400 on board sounds very plausible.  All are fully vaccinated and work under navy orders specifying social distancing, masks and track-n-trace. Those 1,400 people service a set of warplanes with armaments which you would not want to be on the receiving end of.

There are 100 COVID-19 cases so far, no deaths. I wonder if the case numbers might not have peaked yet.

This is the Diamond Princess.

She had a crew of 1045, looking after a passenger list of 2,666 whose demographic included 14 people sufficiently elderly (and I presume diabetic enough) that they died of COVID-19.

So the crew, who continued to service the passengers at some level throughout the infection period, were exposed to SARS-CoV-2 containing aerosols much of the time. 

In this case 145 contracted COVID-19. None died.

Considering that the HMS Queen Elizabeth's COVID-19 count is likely to be incomplete you have to ask yourself what, exactly, has the vaccine achieved?

Then if you look at the UK, which had a decent COVID-19 wave in spring of 2020, a completion of that wave in autumn 2020 and a marked atypical spike in Jan/Feb 2021 coincident with vaccine roll-out, the two summer nadirs are indistinguishable, you could even argue that summer 2020 had a slightly lower 7 day average death rate than we have currently.

Matt Hancock oversaw massive care-home fatalities in the first wave and failed to set up any way of separating COVID-19 patients from the elderly needing hospital treatment during last winter. So many of the people who might die of COVID-19 today are already dead. Another thing which disgusts me. But if this winter turns out to be a standard influenza year, with real influenza, no doubt the vaccines will get the credit.

Finally, I'd missed Peter Doshi's BMJ letter making some pertinent points about the Pfizer initial trial (or should I call it an advertising campaign?)

Peter Doshi: Pfizer and Moderna’s “95% effective” vaccines—we need more details and the raw data

I guess the real question is: Can you develop and market a massively profitable product to the whole world which doesn't actually work?

The pharmaceutical industry did this in slow motion with the biggest blockbuster drugs of all time.

The statins.

Are the vaccines any better? I hope so. Not looking good at the moment.

Peter

Lockdowns Summit

You can register for free on-line access. Donations are optional.

Lockdowns Summit

Someone has to map out a route out of the current political cesspit. I wonder if the press will turn up or report it? Last anti-lockdown demo in London was probably genuinely over half a million people, nothing on the BBC.

Peter

Mongongo nuts

Just recently Raphi had a very interesting and very thought provoking chat with Herman Pontzer.

They touched upon honey and the Hadza but didn't mention mongongo nuts and the !Kung San people.

So I will. I might get back to honey in another post.

Mongongo nuts are a major problem for the ROS hypothesis of obesity.

The !Kung San people live on the edge of the Kalahari Desert, as do mongongo trees. The nuts are freely available, storable and edible cooked or raw. They sound quite nice. They go by several names, Manketti nut is the one used in this paper:

Characterization of Schinziophyton rautanenii (Manketti) nut oil from Namibia rich in conjugated fatty acids and tocopherol

With a linoleic acid content just over 30%, and frequently providing a large proportion of the !Kung San people's calories, they should cause obesity, by the ROS hypothesis. If you read the abstract and look at the commas very carefully it almost suggests that the LA is actually conjugated linoleic acid but absolutely doesn't confirm this in the fine print of the full text. With the locations specified for double bonds at 9 and 12 this really is your normal, common-or-garden LA.

So the !Kung should be obese and/or hungry. And they're not.

How come? Another 30-ish% of the fatty acids in the nuts are from alpha eleostearic acid, a triple double bond isomer of alpha linolenic acid. This really is a conjugated fatty acid with double bonds at 9, 11 and 13. Conjugated means the double bonds alternate with single bonds. For ordinary PUFA there are two single bonds between each double bond.

Alpha eleostearic acid is something of a wonder drug, curing everything from cancer to whatever you fancy. It also is very easily converted (by rats at least) in to conjugated linoleic acid (CLA), presumably by hydrogenating the 13 double bond to give cis-9, trans-11 CLA:

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

CLA is, undoubtedly, a weight/fat loss drug. I glossed over it when it was reported in this paper

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

but it seems to be real as in

Isomer-specific effects of conjugated linoleic acid (CLA) on adiposity and lipid metabolism

The CLA/safflower paper was using 6.4g of mixed CLA isomers per day, on a high linoleic acid background (by definition, the subjects were type 2 diabetics with BMI >30, ie LA intoxicated), and got steady weight loss over 18 weeks from this small supplement.

Eating a 1000kcal portion of mongongo nuts would give around 30g of alpha eleostearic acid to convert to CLA. Subsisting on primarily mongongo nuts might supply twice that. Sixty grams of eleostearic acid being converted to just under 60g of cis-9, trans-11 CLA might be enough to offset the LA content.

The situation for the !Kung San seems quite unique and I can't quite imagine any other nut providing an almost year round supply of high fat calories. Any examples gratefully received. In temperate climates nuts are very seasonal and largely supply linoleic acid.

Peter

Addendum from Tucker via twitter; it's not completely clear how important mongongo nuts really are to the !Kung:

Mongongo: The ethnography of a major wild food resource

however there will always be a roughly 1:1 ratio of LA to CLA precursor when they are consumed, in whatever quantities.

Obesity and diabetes (3) Acipimox

I first went looking for papers on Acipimox in 2014. I had read that it was an inhibitor of lipolysis and I was interested in how much weight gain it caused. Back in those days I was still fairly attached to the most basic of carbohydrate-insulin-models of obesity. If you consider that insulin causes weight gain by the inhibition of lipolysis, giving a non-insulin inhibitor of lipolysis should do the same... Shouldn't it?

Well, no, it doesn't. Acipimox produces a profound fall in free fatty acids and a marked improvement in glucose tolerance. Very, very occasionally I found snippets in discussion fora that it could increase hunger but this was not by any means routine. These give the flavour:

Effect of the Antilipolytic Nicotinic Acid Analogue Acipimox on Whole-Body and Skeletal Muscle Glucose Metabolism in Patients with Non-insulin-dependent Diabetes Mellitus

Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

All of which sounds very good (unless you are into the CIM of obesity!) and you have to wonder quite why Acipimox has not become standard of care and have largely reversed the current global diabetes pandemic. In fact, a recent 2020 meta-analysis of niacin (the parent compound from which Acipimox is derived) trials suggests we might be remiss in failing to do so:

Effectiveness of niacin supplementation for patients with type 2 diabetes: A meta-analysis of randomized controlled trials

But then you could go on to ask why giving niacin itself  might actually make people with impaired glucose tolerance flip in to frank type two diabetes (amongst other medical catastrophes) with worrying regularity

Effects of extended-release niacin with laropiprant in high-risk patients

Of course you could blame the laropiprant, given to suppress the niacin flushing. Or you could more usefully think about the metabolic consequences of dropping plasma FFAs by using a potent inhibitor of lipolysis.

If we work on the basis that DMT2 is essentially the down stream consequence of the inability of distended adipocytes to limit basal lipolysis, it comes as no surprise that artificially shutting down release of FFAs might improve markers of metabolic health.

The cost would be larger adipocytes.

But this doesn't happen, at least not much. The explanation is contained in this paper from 1992, largely looking at the reasons for the long term failure of Acipimox to control FFA levels:

Effects of prolonged Acipimox treatment on glucose and lipid metabolism and on in vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus 

It's simple. Making adipocytes retain their lipids increases their size. There is no suggestion that tolerance develops to this. All that happens is that there is a rebound increase in basal lipolysis as the Acipimox wears off. The drug-induced transient fall in FFAs produces a transient decrease in the oversupply of calories from FFAs, so cells should and must adapt to by reducing insulin resistance. Numbers improve at the cost of bigger adipocytes. As soon as the drug wears off the adipocytes, now bigger, reinstate basal lipolysis at their previous high rate plus some extra due to the extra distending effect of Acipimox. As they off-load their extra size by releasing FFAs, the physiological need of other cells in the body to resist insulin is both restored and augmented.

There is no net benefit and all the drug might do, if it does produce any increase in adipocyte size, is to convert IGT people, with some reserve function remaining in their adipocytes, in to very sightly heavier diabetics who have less ability to suppress adipocyte size-induced increased basal lipolysis.

If you are pre diabetic but not glycosuric and you become glycosuric in the periods between Acipimox/niacin doses you will convert from pre-diabetic to diabetic, assuming you use glycosuria as your marker for diabetes.

Peter

Obesity and diabetes (2) Basal lipolysis and weight gain

This is a paper at the "dislike" end of my bias spectrum:

In Vitro Lipolysis is Associated with Whole Body Lipid Oxidation and Weight Gain in Humans

which can be summed up by the first line of the introduction

"Positive energy balance results in greater triglyceride storage in adipose tissue and resultant accumulation of body fat."

which explicitly states that they have the arrow of causation at 180 degrees to the correct direction. So don't expect too much from the paper. I also hate that they omitted to mention in the title that the association with weight gain is negative.

Beyond that the methods are sketchy and the results are limited to a number of model derived correlations subjected, eventually, to multiple unspecified adjustments. So not a lot of hope for the group or for the largely Pima Indian population under their misguided care. But I digress.

Once again adipocyte size is quite tightly correlated with basal lipolysis, like this

which looks quite linear until we convert the log numbers to normal numbers like this

which shows us that basal lipolysis rises progressively sharply with adipocyte size. There is an upper limit to adipocyte size, and this will be set by rising basal lipolysis equaling the obesogenic effect of linoleic acid facilitating the over action of insulin.

They fed the subjects a fixed macro, calorically calculated diet for three days before a day in a metabolic chamber, where they ate three similarly fixed macro/calorie meals.

People turned out to have differing RQs (they use RQ, respiratory quotient, as their term rather than RER, respiratory exchange ratio. My brain works this way too, it's about the only bit of the paper I like, even though RER is probably the correct term) on a fixed macro diet. So clearly something is happening on a fuel partitioning basis.

People who oxidised the most fat in the metabolic chamber were the least likely to gain weight over the following eight or so years. Those oxidising the most carbohydrate were likely to gain the most weight.

Funny that.

I can't see any explanation in the discussion of why that might be.

From the ROS/Protons perspective it is quite clear that people with smaller adipocytes have not finished gaining weight. They are part way to becoming obese because they are consuming LA in combination with an insulogenic diet so are over-storing fat. When they eat a fixed macro/calorie diet they sequester lipid in to adipocytes, fail to retrieve it and run their metabolism on the more accessible carbohydrate. They're probably the most hungry, in my book.

Those with maximum sized adipocytes eat the same fixed macro diet, sequester the same lipids in to their large adipocytes via LA augmentation of insulin's fat storage signal but then go on to release much of that extra stored fat by the increase in basal lipolysis which is associated with trying to further stretch large adipocytes. This supplies continuously elevated FFAs, with subsequent fat oxidation, despite the presence of glucose and insulin at the same time. They should be the least hungry.

What can a cell do when presented with a ton of FFAs and a ton of glucose, both having their uptake facilitated by insulin?

That's right. Resisting insulin is the correct option. That's what the systemic cells do.

The cost shows as elevated glucose in combination with the elevated fat oxidation (eventually FFAs rise measurably but early on the fat oxidation increase precedes the rise in plasma FFAs).

It is metabolic inflexibility encapsulated.

Of course the obvious question is whether that increased fat oxidation, associated with reduced rate of weight gain, is positively associated with insulin resistance. Alongside the reduced weight gain.

From the same institution, back in 1991 and forgotten about during the last 30 years, we have this paper:

Insulin Resistance Associated with Lower Rates of Weight Gain in Pima Indians

Insulin resistance is, indeed, associated with limited weight gain. As you would expect.

Summary overall:

Fat oxidation a major mechanism of insulin resistance. Increased basal lipolysis is a mechanism of both increased fat oxidation and decreased weight gain. Linoleic acid is the mechanism of increased adipocyte size to drive increased basal lipolysis. Some degree of insulin signalling is essential for linoleic acid to drive adipocyte size increase.

Life is logical.

Peter

Extra thoughts: During weight gain, while calories are being lost in to adipocytes, the rest of the body is in caloric deficit. Calories lost to adipocytes must be replaced by extra food. This is the correct arrow of causation. There is insulin sensitivity.

Once adipocyte basal lipolysis equals or occasionally outstrips fat sequestration in to adipocytes, the rest of the body is being provided with supplementary FFAs. It is in caloric surplus. Insulin resistance is then physiologically appropriate.

There is a gradual transition between the two states.

Obesity and diabetes (1)

There is absolutely no doubt in my mind that adipocytes can become insulin resistant. The most convincing paper I've come across is this one

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

They took adipose tissue from a group of mice which had been made insulin resistant, and obese, by feeding a high coconut fat/sucrose (ie Surwit-like) diet and extracted a supply of adipocytes. Whether these cells were large or small, provided they had been exposed to Surwit-derived conditions for eight weeks, they were all equally insulin resistant. Big ones and little ones. Size made no difference. Insulin resistance is real but not associated with adipocyte distention.

What they also found was that size of adipocytes was very closely and positively associated with basal lipolysis, that is with the rate of lipolysis in the absence of insulin or sympathomimetic agents.

This is not a new finding. From 1972:

Effect of cell size on lipolysis and antilipolytic action of insulin in human fat cells

I like this paper. I have certain biases, one of the strongest of which is that I like papers in which you are given the concentration of glucose which is used in their cell culture medium. Here they happen to have used 1mmol/l, which might rightly be considered a little low, but at least they tell you. Unlike many papers.

Basal lipolysis correlated well with cell diameter. If basal lipolysis is related to the function of lipid droplet surface proteins this is completely plausible and almost predictable. Here's their graph:

The ability to suppress basal lipolysis using insulin appears to be completely determined by the conditions you use to incubate your cells, higher glucose appears to make insulin more effective on suppressing basal lipolysis, but that's an aside. This current study used a glucose concentration of 1mmol/l and showed absolutely no effect of insulin on basal lipolysis. In fact, as you increase the concentration of insulin from zero through high physiological to gross pharmacological the rate of basal lipolysis actually increases. Like this:

If anyone thinks this might represent insulin induced insulin resistance I might be tempted to agree, though the significance to anything physiological of exposure to 100,000microU/ml of insulin seems somewhat dubious.

They did find that physiological insulin exposure suppressed sympathomimetic induced lipolysis, an effect blunted by a grossly pharmacological overdose of insulin. Again, something confirmatory to my biases:

The take home message is that insulin is not particularly effective at suppressing basal lipolysis and that basal lipolysis increases with adipocyte cell size.

We have certain inter related processes here. Insulin facilitates lipid storage in adipocytes and we know that this function is both normally self limiting via ROS generation and is augmented pathologically by the oxidation of polyunsaturated fatty acids, leading to increased adipocyte size.

As adipocyte size increases the separate process facilitating basal lipolysis progressively increases, which cannot be suppressed by hyperinsulinaemia, certainly not completely.

Above a certain size it becomes almost impossible to suppress free fatty acid release from adipocytes using insulin. Under these circumstances there is a continuous supply of free fatty acids, despite the presence of insulin and a copious supply of post prandial glucose.

At a certain point the processes of augmented lipid storage and increasing basal lipolysis will come in to something approaching equilibrium.

The size of adipocytes at this point will be determined by the level of insulin being generated by the diet, the degree of augmentation of that insulin signalling by linoleic acid and whatever factors influence the rate of rise of basal lipolysis with increasing adipocyte size (currently unclear).

That's assuming a pancreas of steel which can crank out insulin at adequate levels to control glycaemia to non diabetic levels despite an increasingly un-suppressible fatty acid supply.

This will be relatively easy, provided adipocytes remain insulin sensitive. We know from 

Diet fat composition alters membrane phospholipid composition, insulin binding, and glucose metabolism in adipocytes from control and diabetic animals

that it is perfectly possible to have insulin sensitive adipocytes, adipocyte distention and systemic insulin resistance without those adipocytes becoming insulin resistant themselves. Under these circumstances the is ample scope for further weight gain. Provided the pancreas can hypersecrete insulin, glycaemia can stay fairly well controlled as weight increases.

Whatever causes adipocytes to change from insulin sensitive, as in this last paper, to insulin resistant, as in the first paper, will markedly increase the demand for insulin to maintain normoglycaemia. If the pancreas cannot meet this demand or beta cells start to undergo apoptosis secondary to exposure to elevated glucose and free fatty acids in combination, progression to DMT2 occurs where insulin secretion can no longer control glycaemia, let alone FFAs.

With the onset of DMT2 weight gain will stall. It is perfectly possible to facilitate the process of further weight gain (and associated increased basal lipolysis) by continuing to squeeze more insulin out of the pancreas using a sulphonyl urea drug or by the injection of exogenous insulin. Both approaches appear to be favourites with diabetologists once they've started with metformin.

To summarise: Excess insulin sensitivity from linoleic acid, combined with elevated insulin secretion, expands adipocytes. Expanded adipocytes increase basal lipolysis, which is difficult to suppress. With increased basal lipolysis fat oxidation, whole body, increases and induces the normal physiological insulin resistance which occurs via ROS/Protons mechanism. Eventually reduced pancreatic function leads to diabetes primarily via the inability to secrete enough insulin to normalise glucose levels while FFAs are elevated.

There's more to this.

Peter