Sunday, February 23, 2020


It came up in conversation with Ally as part of the Paleo Canteen podcast that I like coffee but that it doesn't like me.

Over the years before LC my coffee ingestion had stabilised at around 7 or 8 mugs per day. That's quite a lot. At the time I started on LC I did Atkins induction and cold turkey-ed from all methyl xanthines. The headache was tolerable, especially as I knew exactly why it was there and that it would be gone by about seven days in, which it was. The need for an evening stimulant also disappeared because I no longer fell asleep during the hyperinsulinaemic phase of the post prandial period.

For which I was infamous.

Over the years I have reintroduced coffee a couple of times but  stopped it again due to either minor lower GI upsets or worsening of either low back pain or finger arthritis.

I had done a desultory Pubmed search to see if there was any evidence for clear cut, lectin induced GI damage from coffee which might explain my own signs. When the penny dropped that coffee "beans" were actually seeds rather than legume-like beans I sort of gave up hunting.

So I was avoiding coffee and expected to do so long term. My issue was that I quite like the jittery restlessness which comes from an acute large dose.

In the aftermath of chatting to Ally I received an e-mail for Mason about Dr Paul Mason, his local Dr in Sydney. I have a lot of time for Dr Mason and I really enjoyed his lecture from the 2019 conference.

It turns out that Dr Mason is pretty sure there is a lectin in coffee. Not only that but the lectin is heat labile.

If you boil your coffee for 10 minutes you appear to pretty well destroy the lectin.


I can boil down a double strength cafetiere of coffee to the volume and bitterness of a double espresso in 10 minutes.

The caffeine is still there and absolutely produces the desired pharmacological effect.

For myself, drinking two or three double espressos per day produces tachyphilaxis to the caffeine within a week or two. Withdrawal is mild and sensitivity is pretty well restored within about 4-5 days. I have no interest in using caffeine to blunt caffeine withdrawal, so coffee is probably a weekend treat.

Plant poison, undoubtedly. Contains disgusting antioxidants too, no doubt. At the moment I feel that there is an acceptable trade-off.


For those who enjoy confirmation bias and worm studies:

Lifespan Extension Induced by Caffeine in Caenorhabditis elegans is Partially Dependent on Adenosine Signaling

Lard makes hungry mice live longest

Over the past few weeks I've been looking for papers where Barja's group might have run longevity experiments. This does not seem to have been their forte. They have done lots of observational comparative studies looking at long vs short lived species and lots of interventions to modify mitochondrial membrane lipid composition but no hard-core lifespan measuring studies that I can find.

So Barja threw in the rather off comment about avoiding "excessive intake of animal proteins and fats typical of western diets" in his review without obvious direct testing of these variables on lifespan.

I have to leave the mechanism of calorie restriction, aka protein restriction, aka methionine restriction for another day.

What we can do today is to look at Barja's dreaded animal fats. Like lard.

The data are, sadly, only available from CRON fed mice. This is the study:

The Influence of Dietary Fat Source on Life Span in Calorie Restricted Mice

Diets had their fat source modified thus and also had their calories restricted by 40%:

"The modified AIN-93G diets (% of total kcal) each contained 20.3% protein, 63.8% carbohydrate, and 15.9% fat. Soybean oil was the dietary fat in the control group (standard AIN-93G diet). The dietary fats for the CR groups were soybean oil (high in n-6 fatty acids, 55% linoleic acid, Super Store Industries, Lathrop, CA), lard (high in monounsaturated and saturated fatty acids, ConAgra Foods, Omaha, NE) and fish oil (high in n-3 PUFAs, 18% eicosapentaenoic acid, 12% docosahexaenoic acid, Jedwards International, Inc., Quincy, MA). To meet linoleic acid requirements, the fish oil diet contained 1% (w/w) soybean oil".

Here are the survival curves:

The left hand curve of green circles is from (nearly) ad-lib feeding of crapinabag. The yellow squares showing best survival are from feeding the dreaded animal fats from lard, combined with CRON. The fish oil group, full of EPA and DHA, did worst of the three CRON groups with soy oil being intermediate.

I think beef dripping would have done better than lard and beef suet even better still, but then I would think that.

Peter, saturophile.

Saturday, February 22, 2020

Insulin sensitivity makes you fat: growth hormone receptor deletion

TLDR: Excessive insulin sensitivity sets you up to become obese.

I have to apologise for citing Valter Fastingbar Longo, sometimes you have little choice. This paper

GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity

documents the physiology of humans who are homozygous for a large growth hormone receptor gene defect. They make their GH, lots of it. It does absolutely nothing, having no receptor. GH normally works in opposition to insulin on adipocytes, causing both lipolysis and systemic insulin resistance.

Also, in the absence of GH signalling, these people make no IGF-1 so are of dwarf stature. They are exquisitely insulin sensitive. As in here are the OGTT results. Dark lines are the GHR deficient people:

Plasma glucose is comparable to that of controls throughout, matched for BMI (and lots of other things). But just look at that insulin level, peaking at 25microIU/ml vs 80microIU/ml in controls. The dwarves are very, very insulin sensitive.

And very fat.

Despite having a mean BMI of 27.6 (controls are higher at 29.4) the dwarves have 48% of their weight as fat mass compared to 41% in the controls.

Let's put this in to context: The GHr deficient people are fat because they are insulin sensitive. There is no paradox. We are not thinking that their obesity should have caused insulin resistance, it's that their failure to generate one type of physiological insulin resistance has allowed pathological insulin sensitivity to prevail, hence obesity.

Oh, and leptin:

Leptin in the dwarves with 48% body fat is 7.32ng/ml. Leptin in controls with 41% body fat is 10.36ng/ml, p is just over 0.02 if you are wondering or care.

It looks to me as if these excessively insulin sensitive individuals have yet to reach their "ideal" metabolic level of obesity to counteract their lack of GH signalling. Interesting to wonder what determines the level of adiposity at a given age in the absence of GH signalling. That's not simple.

We have no data on RER under fasting or post prandially. But we can be fairly confident that the fasting RER will be low, reflecting high basal lipolysis from distended adipocytes and post prandial RER will be high as insulin action facilitates glucose metabolism and locks lipids in to adipocytes.

A bit like those insulin sensitive pre-obese humans a couple of posts ago. But these dwarves will have to become very, very obese to behave like normal overweight insulin resistant people.


Addendum, not worth a post in its own right but on-topic:

Does Weight Gain Associated with Thiazolidinedione Use Negatively Affect Cardiometabolic Health?

Epic quote of failed perception:

"This review paper discussed the mechanism of action of TZDs on weight gain and the so-called “glitazone paradox”, the phenomenon that TZD-associated weight gain improves rather than exacerbates insulin resistance".

There is no paradox. Insulin signalling improves with glitazones, this makes you fat.

Tuesday, February 18, 2020

CPT1aL479 resurfaces nicely

Originally from Erik Arnesen, via a retweet by Miki Ben-dor:

Inuit metabolism revisited: what drove the selective sweep of CPT1a L479?

as in

Coconuts and Cornstarch in the Arctic?

The P479L gene for CPT-1a and fatty acid oxidation

The abstract looks very nice, I can't wait to get hold of the full text!


Edit: The paper is long and somewhat repetitive. There is a much neater paper from Amber which people might enjoy:

Evidence on chronic ketosis in traditional Arctic populations

End edit.

Monday, February 17, 2020

Insulin sensitivity makes you fat

TLDR: Excessive insulin sensitivity sets you up to become obese. Becoming obese makes you insulin resistant. Eventually excessive adipocyte size will induce systemic insulin resistance. Further weight gain is still possible given a diet which induces systemic hyperglycaemia combined with a pancreas of steel. Here we go.

I picked this paper up from Pubmed while looking for something else:

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

It's very interesting.

Over the years I have collected various models, mostly mouse/rat models, which generate obese, insulin resistant rodents.

These mostly involve damaging the hypothalamus in some way and letting the mice eat ad lib until they reach the desired level of obesity, with the associated insulin resistance. There is the ventromedial hypothalamic injury model

Molecular and metabolic changes in white adipose tissue of the rat during development of ventromedial hypothalamic obesity

The MSG injury model:

Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate (MSG) treated-rats

Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats

The gold thioglucose injury model:

Adiponectin expression is paradoxically increased in gold-thioglucose-induced obesity

What they all have in common is that the models are always more insulin sensitive in the first weeks after injury compared to the non-injured controls. This excess sensitivity persists until a certain level of obesity is achieved. As obesity increases so does systemic insulin resistance increase (a separate mechanism) until it overwhelms the excess insulin sensitivity and rate of weight gain markedly reduces. The model is now insulin resistant.

Inappropriate insulin sensitivity is what generates the obesity. Insulin resistance limits its progression.

Insulin resistance in adipocytes can, undoubtedly, occur but this is not a feature of the adipocytes in the early stages of obesity. They are insulin sensitive. Insulin acts easily. Adipocytes distend.

Back to the paper. It enrolled young, male, non-obese offspring of obese parents. Let's call them pre-obese. Sadly the paper is from 2004, it's now 2020, I would expect the "pre" prefix might nowadays be redundant. Here are the subject characteristics:

To me it is interesting that the pre-obese chaps were carrying more fat mass than the controls. There is a 1.7kg excess, statistically ns but the trend is there. You have to wonder how close to 0.05 the p value might have been.

Here are the fasting metabolic parameters for both groups:

Notice that the fasting insulin is lower in the group with higher fat mass, provided they have obese parents. It's also interesting that their fasting FFAs are higher than those of the folks with slim parents. This difference is also ns but the numbers after the +/- sign are standard deviations, not standard errors, so my guess these too are close to significance (for what that is worth). I also like the ns elevated trigs, I suspect related to repackaging the elevated fasting FFAs. Which are elevated due to increased adipocyte size allowing increased basal lipolysis. All speculation.

Next we have the insulin response to a quite pleasant sounding, mixed macro, highish fat meal:

The fasting insulin is the one from Table 2, p being 0.007 and for a large percentage of the post-meal eight hour period insulin stays significantly lower in the pre-obese group than in the normal-weight parent group. The pre-obese subjects are consistently more insulin sensitive.

Here is the FFA graph for the same eight hours:

Converting the FFA levels to real money terms it appears that the lean parent group had FFAs of 280micromol/l and the pre-obese people had 390micromol/l. I've already speculated that the elevated FFAs in the pre-obese group are from increased basal lipolysis, not insulin resistance. As soon as insulin is released after the meal FFA levels become identical for eight hours. I've not copied the trigs graph but the trend is for chylomicrons to be the same between groups for 4 hours and then lower in the pre-obese as insulin sequesters fat in adipocytes.

Which group will be metabolising most fat under hypoinsulinaemic, near-basal lipolytic conditions? Pre-obese have elevated fasting FFAs and they're oxidising more fat, 1150 vs 740mg/kg FFM/d,  ns but you can see the trend:

However, as soon as insulin rises fat oxidation drops because insulin sequesters fat in to adipocytes at levels way below those which translocate GLUT4s. It will also divert intracellular FFAs in to intracellular triglycerides. Lipid oxidation under insulin drops to 90mg/kg FFM x 8h compared to 163mg/kg FFM x 8h in the more normal individuals. Giving p less than 0.007.

BTW FFAs stay high in both groups because the meal was around 50% fat. I would predict that a high carbohydrate, low fat meal would have produced a marked drop in FFAs and a rise in RER, both more pronounced in the people with obese parents. No data on that one.

I do not think these pre-obese people have an injury to their hypothalamus. It is more likely the problem is with their adipocytes causing the excess insulin sensitivity.

I think we can ignore discussion comments about the influence of medium chain acyl CoA dehydrogenase variation as a red herring because the pre-obese folks are oxidising more fat under fasting conditions, ie when more lipid is available. The leptin receptor comment is lovely because we know that in mice with a complete leptin receptor deficiency that providing less than 5% of calories from PUFA is highly protective against obesity while providing 15% PUFA in the diet is grossly obesogenic (first link in the blog post). Clearly dietary fatty acid composition trumps even gross leptin signalling deficiency.

What were the diets like in the pre-obese participants? All we know from this study is that the ratio of PUFA:SFA was higher in the pre-obese people:

"The polyunsaturated to saturated (P/S) ratio was 0.34+/-0.06 in the group with overweight parents and 0.31+/-0.09 in the control group".

However you try to reverse engineer the limited data from the results it's hardly 5% vs 15% PUFA, but these people have taken around 25 years of eating a slightly heart-healthier PUFA rich-er diet to gain an excess of 1.7kg of fat mass. My biases are willing to accept this as real.

Maybe it is, maybe not. I'm not exactly a bias free source of opinion.


BTW leptin is consistently lower in the pre-obese group carrying excess fat mass. My suspicion is that their fat cells "feel" empty, so are refusing to signal their true state of fullness. Once the adipocytes become full enough then leptin will increase to give a more accurate representation of the absolute fat mass. This will be associated with the onset  of the more expected insulin resistance of obesity.

Saturday, February 01, 2020

Looking in to the future of Low Energy Diets

I think I picked this up from Jan Vyjidak on Faceache but it's done the rounds on twitter too.

Low-energy total diet replacement intervention in patients with type 2 diabetes mellitus and obesity treated with insulin: a randomized trial

"At randomization, participants commenced a 12-week TDR [total diet replacement] formula LED [low energy diet]... followed by 12 weeks of structured food reintroduction and then ongoing followup in combination with an energy deficit diet at 3-month intervals until 12 months. For the first 12 weeks, all meals were replaced with four formula LED products per day (800–820 kcal/day, 57%
carbohydrate, 14% fat, 26% protein and 3% fiber) in addition to at least 2.25 liters of energy-free beverages. A fiber supplement was recommended, if required, to avoid constipation, a common side effect of using a TDR".

For three months patients were starved on 800kcal per day. At 56% carbohydrate that makes carbs come out at around 100g/d. Oddly enough, restricting carbs to this level allowed a drop in insulin usage. Indeed, there was such a marked drop in insulin usage that some patients coming off insulin all together. I wonder what these starvation subjects would think if you told them that they could have had equal reductions in insulin usage just by restricting the carbohydrate content of their diets to that 100g/d, while still allowing fat and protein to satiety... I suspect  that a) no one has told them this and b) they might not be best pleased to find out retrospectively.

For a second three months a little food was added to their diet, but not much. For the final six months patients were kept a little hungry but not so much as in the first six months of the study.

Here is what the abstract says:

"Results: Mean weight loss at 12 months was 9.8 kg (SD 4.9) in the intervention and 5.6 kg (SD 6.1) in the control group (adjusted mean difference −4.3 kg, 95% CI −6.3 to 2.3, p less than 0.001)".

Here is what the results show for the intervention group:

Here is the same graph but simplified in to three red lines representing the three phases of the study:

You can argue the exact slopes of the lines but overall the pattern is correct. Something like this:

Now it is time to look into the future. Usually this is difficult but I think that in this case the general shape of the graph lets us predict the shape of things to come when related to weight gain. Plus, because it becomes obvious in the later months of the study (from HbA1c values) that insulin is going to have to be added back in, at this time the rate of weight gain might actually increase (dramatically), but we can't know that.

Using a simple maintenance of the status quo (best case scenario) we get this, looking forwards to around about the 24 month mark:

Weight gain, in the aftermath of a year of hunger, might not stop at baseline mass either.

I think it is also possible to look in to the future of glycaemia too, by extending the plot of HbA1c with time, working from the published graph in the results. Taken forwards to 16 months or so, it looks something like this:

Maybe I'm being pessimistic. Maybe sudden tolerance of chronic hunger might kick in and reverse the adverse trends in weight and glycaemia clearly present at the end of the study. Maybe subjects might suddenly become slim and euglycaemic.

Maybe not.