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