Hyperlipid by Petro Dobromylskyj
You need to get calories from somewhere, should it be from carbohydrate or fat?
I would guess that everyone is aware of the study by Ebbeling et al, Ludwig's group, looking at the metabolic effect of low carbohydrate diets on total energy expenditure (TEE, all graphs show kcal/d) in the aftermath of weight loss on a conventional diet.
Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial
I'd like to summarise their data using numbers taken from Tables 2 and 3 which, with a little arithmetic, allows me to produce this graph of TEE at various time points. These are as follows: when the subjects walk off the street (Pre on the graph), after a period of semi-starvation on a conventional diet (Start) and then during weight stability on a high, medium or low carbohydrate diet (End). The plot looks like this:
In the study they compared the change from the Start TEE to the End TEE, ie they used these data points:
They took the absolute changes from Start to End thus and got a resultant p of less than 0.05
This, obviously, is completely unacceptable. Well, it is if you are Kevin Hall. So now we have this
No Significant Effect of Dietary Carbohydrate versus Fat on the Reduction in Total Energy Expenditure During Maintenance of Lost Weight
What Ludwig's group did wrong (amongst the many other things pointed out by Hall and Guo) is that they used the wrong data points.
Recall the original graph:
According to Hall: If you want to ask about the effect of low carbohydrate diets on the depression in TEE produced by conventional semi-starvation you should NOT compare the semi-starved TEE (as in Start) to the TEE on a high, medium or low carbohydrate diet (End). You should instead use the TEE expenditure at randomisation (Pre on the graph). Like this:
Using Pre as your anchor point you can draw the same data thus:
Which obviously gives us p greater than 0.05 and all of the benefits of low carbohydrate diets are lost. Phew. Happy Hall. But why should anyone use the Pre values as an anchor point?
Now, no one is an unbiased researcher. Hall is, surprisingly, no exception. Hence the current exchange of half bricks in the BMJ.
As I see it the Ebbeling paper looks at the effect of LC eating on the damage done to TEE by conventional dieting.
What Hall wants the analysis to do instead is to look at the overall effect of damage done to TEE by conventional semi-starvation combined with partial rescue during weight-stable LC eating vs the combined damage done by conventional semi-starvation followed by maintained damage done by HC weight-stable eating. As he writes:
"However, the final analysis plan was modified to make the diet comparisons with the TEE measurements collected in the immediate post-weight loss period rather than at the pre-weight loss baseline"
To me Hall is stating that Ebbeling et al almost did make the "Hall" mistake of using the "Pre" TTE as anchor point but corrected this at the 11th hour, still before blinding was unmasked. What puzzles me is how Ebbeling could have ever even considered using the "pre weight loss baseline" as the anchor point in the original study design.
The massive benefit to Hall of including the conventional semi-starvation active weight loss period along with the intervention weight stability period is to dilute the remedial biological effect of LC eating out of statistical significance.
The core information which the study provides is about the remedial effect of LC eating on correcting the damage done by a conventional semi-starvation period. That effect only happens between "Start" and "End", which is when carbohydrate restriction is applied.
That's one of the MASSIVE problems with carbohydrate restricted eating. It only provides benefit when you don't eat carbohydrate!
Including data from "Pre" right through to "End" dilutes the clearly demonstrable biological effect of carbohydrate restriction on reduced TEE post conventional dieting.
So what doe the title and text of Hall's rebuttal tell us? Either about Hall or about TEE? Don't over think it!
I would also declare that my own biases are a conflict of interest but if you need me to say that then you have probably arrived here by accident, you know where the back button is.
However I would say that I am ambivalent about the importance of the TEE changes, though I suspect they do happen. What really matters to me is what happened in Aberdeen over a decade ago.
Raphi tweeted this paper recently
Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS
which is nice provided, as he comments, it can be replicated. There is absolutely no possible conflict of interest anywhere so long as you accept it looks like an in-house Nestlé study. I haven't knowingly bought a Nestlé product in over 30 years.
Anyway. The study looks at healthy brain biochemistry under MCT induced ketosis. The ketone oxidation (or possibly the CNS oxidation of MCTs) increases the NAD+:NADH ratio, ie moves it in the Good direction.
There is a lot of talk about the NADH generation and NAD+ depletion during glycolysis to pyruvate, shifting the ratio in the Bad direction. The assumption (with which I disagree) is that the glycerophosphate shuttle is a rescue mechanism to regenerate essential NAD+ to allow glycolysis to continue, to which I will return in a moment.
The beauty of ketones is that they do not deplete cytoplasmic NAD+ at all and only consume one mitochondrial NAD+ during the conversion of BHB to AcAc. Because this happens within the mitochondria this, plus any NADH generated at the pyruvate dehydrogenase complex, is sitting next to complex I, the most prolific re-generator of NAD+ in the cell...
All well and good and bully for ketones and the manufacturers of Peptamen®1.5 Vanilla (Nestlé Health Science SA).
This got me thinking.
Of course no one in their right mind would expect glycolysis to be arranged in such a manner as to require the glycerophosphate shuttle for simple NAD+ regeneration. This is a wasteful loss of four pumped protons and this energy will appear as heat. Think of brown adipose tissue, full of mtG3Pdh, assuming insulin is plentiful. The correct pathway for the metabolism of glucose without insulin is to lactate without any overall depletion of cytoplasmic NAD+. Lactate can then be taken up by mitochondria exactly as ketones are. Lactate will, in the mitochondria, be reconverted to pyruvate, depleting mitochondrial NAD+ in exactly the same way as the conversion of BHB to AcAc does. Equally this happen right next door to complex I, just waiting to regenerate NAD+ and keep that NAD+:NADH ratio nice and high.
The whole point of the glycerophosphate shuttle (in Protons terms) is to facilitate insulin signalling. Insulin is the hormone of plenty, used to encourage caloric ingress in to cells. Loss of the four pumped protons due to bypassing complex I and using mtG3Pdh instead as part of insulin signalling appears perfectly reasonable under conditions of active caloric ingress. Sustained insulin signalling causes sustained loss of cytoplasmic NADH, which generates NAD+. Once this has happened there is no longer the surfeit of cytoplasmic NADH over NAD+ from glycolysis, which is essential to drive lactate formation. Glycolysis must therefor stop at pyruvate under insulin.
Summary: For insulin signalling the glycerophosphate shuttle is active and loss of NADH requires glycolysis to abort at pyruvate.
Without insulin signalling glycolysis runs to lactate which enters mitochondria without any depletion of cytoplasmic NAD+. The lactate should enter the mitochondria, under normal physiology.
Sooooooo. This had me thinking about what would happen if, in the presence of copious glucose and copious oxygen, there was to be a sudden profound fall in absolute insulin levels. I was particularly interested in systemic lactate levels.
A sudden, profound fall in insulin levels in the presence of glucose is pathology. It generates ketoacidosis, classically from acute beta cell destruction during the onset of DMT1. There is always a profound metabolic acidosis from the failure to suppress glucagon-induced lipolysis and subsequent massive acidic ketone generation. Under the canonical view the absence of insulin should not stop NAD+ regeneration by the glycerophosphate shuttle.
What I wanted to know was whether the Protons predicted shutting down of the glycerophosphate shuttle due to hypoinsulinaemia would result in diversion past pyruvate to lactate as the end result of glycolysis. In the presence of massive levels of ketones I would also expect this lactate to appear in the systemic situation.
Yep. Ten seconds on Google says so.
Lactic acidosis in diabetic ketoacidosis
Very nice. I had no idea this was the case because it has no direct influence on treating DKA clinically...
Of course you have to think about the chicken and egg situation with insulin and mtG3Pdh activation (I have been for years!). Which comes first? I think insulin appears to be essential, as above. I do wonder if the insulin receptor will turn out to dock with the glycerophosphate shuttle in some way...
Over the years I've been convinced that carbon monoxide derived formaldehyde/formate are probably the initial molecular precursors of acetate at the origin of life. All that is needed is a supply of electrons at a sufficiently negative potential to reduce CO2 to CO and so to CH2O then to HCOOH, formate. Clearly a 1.5 volt battery applied across an anoxic CO2 rich reactor might do this. In the Life series of posts the best candidate in reality is the alkaline hydrothermal vent environment such as the Lost City complex, working under anoxic, CO2 rich Hadean ocean conditions.
Native iron reduces CO2 to intermediates and endproducts of the acetyl-CoA pathway
from a french institute, suggests that metallic iron alone might provide electrons of sufficiently negative potential to perform the process, this is the basic premise:
Fe0 → Fe2++ 2e-
These electrons have a sufficiently negative potential to allow:
CO2 + 2e- + H2O → HCOOH + O2-
Obviously the Fe2+ would combine with the O2- to give FeO, leaving a formate moiety as the start of the process essential for the origin of pre-biotic metabolism.
In the event the two most common experimental products were acetate and pyruvate, a highly plausible step or two onward from formate, which they also found under certain conditions.
The circumstances of temperature and pressure were, in some experiments, plausible for pre-biotic chemistry.
The problems, compared to the Lane and Martin hydrothermal vents concept, seem to be:
The products are bound to the surface of the iron deposit, potassium hydroxide was needed to hydrolyse them off for measurement.
The process is reactive rather than catalytic, ie the metallic iron is consumed in the process of providing electrons. This contrasts starkly with the continuous supply of electrons supplied by hydrothermal vent conditions over geological time scales.
Then there is the concentration problem. If the organic products were to be freed from the iron surface they need to be somewhere other than the open deep ocean or they will simply be lost by dilution.
Finally the group did not cite any of the work from Nick Lane and his lab excepting one rather general review link. Naughty.
So. Some interesting chemistry and it's good to have multiple groups thinking about a given problem but I don't see the hydrothermal vent hypothesis being abandoned any time soon. Certainly not by believers like myself.
I must admit that I have not read this paper, just the abstract. My excuse is, once again, that I have no access to any ondansetron.
Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality
As always the results of statin therapy are, to say the least, dramatic.
"In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%".
Wow. But why the need for a composite end point?
If we leave aside soft end points which include coronary re-vascularisation (never influenced by serum lipid levels. No laughing at the back there!) and concentrate on the hard end point of all cause mortality we end up with, for non statinated people:
9 deaths per 4,892 person-years, which I make 1.8 deaths per 1000 person-years.
On a statin we have 17 deaths per 11,674 person-years, 1.5 per 1000 person-years.
That looks like a reduction in mortality of 0.3 people per 1000 person-years.
Or, being more whole numberish, 1 person saved by treating for 3,300 person-years on a statin.
Does that convert to treating 100 people for 33 years to avoid one premature fatality? We're all going to die one day so no one avoids death permanently, even by taking a statin. Unbelievable as that sounds.
If you have heterozygous FH your chances of dying tomorrow are rather low but not quite zero. If you take a statin it will reduce this chance by a vanishingly small amount.
Taking the difference between "rather-low-but-not-quite-zero" and "a-vanishingly-small-amount less than rather-low-but-not-quite-zero", dividing this difference by "rather-low-but-not-quite-zero" and multiplying by 100 we get a massive 17% reduction in all cause mortality. Which means diddly squat, but sounds good if you are a statinator. Admittedly not as good as 44% for the composite end point but hey... Neither means anything.
The main benefit of a statin appears to be that the number it gives you on a lab report might just influence a cardiologist to leave your coronary arteries alone.
Just doing my bit
Vegetables, nine dead of listeriosis
Quick edit for when the link dies:
"9 people dead following Listeria outbreak – Tesco, Aldi, Waitrose, Iceland, Lidl, Aldi – Issue Product recall. Please please check on old people and loved ones who may not be in the loop, listeria can be more serious for people who have weakened immune systems.
Full 43 product list for recall is shown as follows issued by the FSA".