HbA1c: Low glucose and acid (palmitic)

If anyone would like to combine a look at the pathology of low blood glucose levels with the psychology of diabetes research they might do worse than to look at this paper.

Hypoglycaemia is bad, very bad. At the vascular endothelium level and at the mitochondrial delta psi level. The sort of low levels of blood glucose frequently visited by people like Steve Cooksey and myself are a complete disaster. The group is looking at levels of blood glucose that I can easily achieve by skipping a couple of meals combined with a little mild aerobic exercise, walking or cutting the lawn. I’ve seen 2.7mmol/l on my (admittedly relatively inaccurate) Freestyle Lite. I felt fine at the time and I did nothing to adjust my blood glucose level before having supper a few hours later...

Perhaps I should be carb loading, just a little, to avoid hypoglycaemia induced damage? However this might drop my free fatty acid levels, which I would prefer to avoid.

The abstract of any paper is word limited and the role of FFAs in the findings don't get a mention, so you might assume FFAs have no significant bearing on hypoglycaemic injury.

The discussion section of the paper tends to confirm this:

“Our findings with respect to fatty acid and L-carnitine suggest mechanistically that free fatty acid utilization in vivo would not be sufficient to suppress LG induced NO suppression and excessive mitochondrial superoxide production…”

They seem pretty certain, but do they have data to support this? Flicking to the results section we see that the group looked at a palmitate with L-carnitine combination and found that it worked beautifully:

“We found that combined treatment of endothelial cells with 1% palmitate and L-carnitine reduced LG-induced mitochondrial superoxide production to normal levels (Supplemental Figure IIIa)”

Want the picture?

I think we will all agree that the combination of palmitate with L-carnitine completely, totally normalises superoxide production in the low glucose cells and was utterly harmless in the normal glucose cells. The graph speaks against the discussion.

This normalisation of superoxide generation appears to have been too much to bear, the concept that palmitic acid might be beneficial, so they separated the palmitate from the L-carnitine and tried them separately.

“mitochondrial superoxide production increased under LG conditions with the addition of 1% palmitate while L-carnitine alone returned mitochondrial superoxide levels to those similar to the NG condition (Supplemental Figure IIIb)”

Now, this sticks in my craw. This is wrong. Completely.

Here is Supplemental figure IIIb.

Any reading with an * above it is higher than the normal glucose (NG) reading. This includes the low glucose plus L-carnitine. The low glucose with carnitine value is greater than the normal glucose value, p < 0.05.

There is, however, a crucifix above the LG+LC. The superoxide production here is significantly less than that in the LG group with added neat palmitate, that’s the meaning of the crucifix. But because of the asterix we KNOW that the superoxide here is still higher than the normal glucose value, p < 0.05.

Stating that

“L-carnitine alone returned mitochondrial superoxide levels to those similar to the NG condition”

would require that you (could) remove the asterisk from the low glucose plus carnitine column.

You can't.

You might just as well say the normal glucose plus palmitate (NG+palm) is "similar to the NG condition". Which they don't. Asterisk.

Sigh. End rant.



There are many other things which are both good and bad about this paper. But, as a lipophile living in what sometimes feels like a sea of lipophobia, it really ticks me off to see frankly incorrect and unsupported statements like this. I still scratch my head about motive.

It’s quite clear that palmitate/L-carnitine normalised the excess superoxide production of low glucose completely. I have lots of palmitate in my blood stream, though perhaps not the 1% chemical grade palmitic acid used here! I've probably got reasonable amounts of L-carnitine in my cells too, being a moderate meat eater and highly fat adapted. But the big giggle would really have been to use ketones in the study. I have ketones. As Veech pointed out, many years ago now, ketones can completely replace the whole glucose/insulin metabolic pathway in an isolated rat myocardium. Very effectively.

The flip side is that the paper is looking for information about insulin overdose rather than simple low-normal glycaemia. My BG of 2.7mmol/l was in the presence of utterly basal insulin, markedly elevated free fatty acids and modestly elevated ketones. A diabetic on a sugar based diet having a little (or even quite big) accident with their insulin to starch balance will undoubtedly have suppressed FFAs waaaaay before they hypoed and will probably have a metabolism that can't remember what a ketone body is. The metabolic milieu of parenteral insulin overdose is radically different to that of ketogenic eating. You have to engage thought processes before deciding that any blood glucose below 5mmol/l produces graded superoxide overproduction and failure of nitric oxide signalling. It's understandable from a modern diabetologist point of view, just wrong to bury data which do not support your preconceptions.

If non-injecting (and non sulphonylurea popping) folks want to reduce their FFAs and eliminate ketones in order to avoid low-normal glucose levels by eating a few extra grams of carbs, that is absolutely fine. We can all ignore the biochemistry if we so wish, serious researchers do it all the time.

Personally, I still like to have a few ketones around. And rather a lot of free fatty acids.

Peter

HbA1c: Crack vs smack for a lower reading?

Having lived a great deal of my life in Norfolk, I’ve always rather liked the EPIC Norfolk publications. This was the first paper that I found which demonstrated, at the population level, that HbA1c is an excellent marker for your risk of both CVD and all cause mortality.

HbA1c is one of the most simple biomarkers to manipulate. If there was one single biomarker which you might want to modify, HbA1c is the one.

In Norfolk, people don’t.

Here people generally eat CIAB, more politely known as the UK version of the SAD or a mixed diet.

I doubt very much that anyone eats far enough away from “normal” or “unremarkable” macronutrient ratios that it has any significant effect on the distribution of HbA1c in the population. So, if you take a large group of people and set them free to eat whatever they want, HbA1c is probably a surrogate for mitochondrial health, particularly the mitochondria in adipocytes but more probably those throughout the body.

Nobody doubts that hyperglycaemia is damaging. Hyperinsulinaemia appears to problematic in its own right too. But my impression is that whether you succumb to a disease which is the result of hyperglycaemia directly or due to hyperinsulinaemia, this is just the label. The core problem is the underlying failure of mitochondrial function which signifies to a cell that it’s time to shut up shop. How this shows macroscopically, at the whole organism level, is probably up to a host of factors which I find of limited interest.

Sooooooo. Let’s be very specific: I consider, in the general population, that the linear positive relationship between HbA1c and all cause mortality is a reflection of failing mitochondrial health.

HbA1c is also the easiest of biomarkers to fudge, adjust or fake, call it what you will.

While diabetologists agonise over the inexorable progression of diabetes and wet their knickers at clinically insignificant drops in HbA1c on a calorie restricted mixed diet, those of us who eat LC are well aware that the 5% club is wide open to diabetics and the 4% club is not difficult for those of us who learned LC before mitochondrial damage became widespread. Most, although perhaps not all, people can drop their HbA1c to physiological levels with carbohydrate restriction, possibly with modest supplementation using metformin if they are significantly injured.

Dropping your HbA1c is easy. Very easy.

I have been thinking about this for a long time.

The really difficult question is whether an HbA1c of 4.4% achieved through the strict avoidance of post prandial hyperglycaemia is quite the same as an HbA1c of 4.4% achieved by a random chance combination of accidentally reasonable food choices, a functional pancreas, functional muscles, reasonable parental/intrauterine environment and good luck. Plus anything else you care to think of.

The LC eater is producing an effect on HbA1c which has never been investigated on a population basis, certainly not using modern, insulin resistant people who choose to normalise their blood glucose levels through diet. Whether it is as good for health and/or longevity as achieving it accidentally remains to be seen. No one need ask where my suspicions lie, but there are no hard data. There is absolutely no reason to doubt that being insulin resistant while eating A MIXED DIET indicates that you are in trouble, mitochondrially speaking. Sidestepping this with low carbohydrate eating will undoubtedly reduce your risk of those diseases which are a direct result of the hyperglycaemia and hyperinsulinaemia and which become inevitable on a mixed diet if you are insulin resistant. My own feeling is that this step is vital. I also suspect that some degree of reparation in mitochondrial health might be possible with long term near or frankly ketogenic eating.


OK, enough on the EPIC findings and my thoughts about adjusting HbA1c.

The next big step is to leave Norfolk’s EPIC beauty and wander over to the USA and look at the catastrophic association of a low HbA1c with death. As everyone undoubtedly knows, this link came to me from the exchange between Paul Jaminet and Ron Rosedale over safe starches. I was unaware of the study until Paul brought it up as a foil to the EPIC Norfolk findings.

It too, is a nice observational study.

I have to look at the data here in exactly the same way as I have looked at the data from EPIC. What might it mean? These are observational studies, their use is to generate hypotheses. What is the Hyperlipid view of an HbA1c of 2.8% (that is not a typo) on a mixed USA diet?

The easiest question to answer is whether this might be a surrogate for exceptional mitochondrial health. If you assume that the formula for conversion of HbA1c to average blood glucose levels holds true at the 2.8% level of HbA1c (which it obviously doesn’t), it would represent an average blood glucose of 1.0mmol/l. The lady would be dead. So, before we make idiotic assumptions about average blood glucose levels and mitochondrial health here, we had better think very carefully about what, exactly, a very low HbA1c might really mean. We can say for a start that it is not a simple reflection of glycaemia.

By far the most plausible explanation is not that the red blood cells have been exposed to 1.0mmol/l for the last three months, it’s more likely that these red cells have been exposed to a higher level of glucose, possibly somewhat physiological, for a significantly shorter period of time i.e. the red blood cells are young. Always young. They don’t hang around for long enough to become old and glycated before they are lost. Obviously the study group was well aware of this possibility and corrected for it as best they could.

The lowest HbA1c group had the lowest haemoglobin count, the highest red cell width variability (suggestive of regenerative anaemia) and the highest red blood cell volume (each RBC having relatively little haemoglobin). If you don’t think this group contained some seriously anaemic people you’re probably mistaken. Correcting for red blood cell variables in model 2d of Table 2 gave the bottom limit of the 95% confidence intervals closest to 1.0 of all of the adjusted low HbA1c models.

A quick glance at the ferritin levels, paradoxically, shows that these folks also appear to have iron overload. This may or may not be real as the group also contains 11% people sero positive for hepatitis C virus. As ferritin is an acute phase protein its elevation in a hepatitis C patient may be related to inflammation rather than to iron overload. Correcting for iron based parameters (model 2e) resulted in a worse "higher lowest" limit of confidence intervals than the basic correction for age, ethnicity and sex. You have to wonder if this might be due to an incorrect assumption about ferritin levels.

Of course there were four times as many hep C carriers in the low HbA1c group as the reference group. Model 2f tried to correct for this but I doubt they were able to control for those people using iv heroin (glycaemia neutral) vs those on iv crack vs those on oral stimulants (glycaemia lowering). Anorexia and hypoglycaemia are not uncommon under extended periods of recreational stimulant use. This information seems unlikely to be available to allow adjustment in the NHANES III models.

So I see two studies and each generates a different hypothesis. EPIC suggests that progressive mitochondrial failure on a mixed diet shows as raised HbA1c. The second, from NHANES III, is that sub-physiological HbA1c readings correlate to changes other than physiological glycaemia. Many of these changes appear to bad news, and HbA1c here is the messenger, just as it is in Norfolk.

Using this sort of observational data to convince yourself to increase your starch intake may be a mistake. Avoiding iv drug use and the metabolic consequences there-of might be a better approach.

If anyone can achieve an HbA1c of 2.8% by avoiding starch consumption I'll plaster it all over this post as an edit.

Above all of this, in the realms of sensible living, is the fascinating question of whether an HbA1c of 4.4% achieved by VLC eating has the same (positive) health implications as an HbA1c of 4.4% on a mixed diet.

Peter

BTW the EPIC researchers had a look at low HbA1c in Norfolk. Looks like speed is not the preferred recreational drug here. This fits with my experience dealing with the general population where I live.

Eat as much starch as you wish

It has been interesting to watch the discussions about safe starches on those rather limited areas of the internet which I frequent. Now, you have to understand that I have always eaten a certain amount of starch. Usually chips deep fried in beef dripping to go with a fairly standard high fat supper. Sweet potatoes and parsnips are the two usual sources. Certainly two or three times a week. I’m not obese and certainly not post-obese, so I have some freedom in this. I’ve never been zero carb though I am very low carb and I run in mild ketosis pretty much all of the time nowadays.

My routes in to LC, other than the initial window through Atkins, were Kwasniewski, Bernstein, Groves and Lutz. Lutz was such a nice chap, certainly in his writing. He was perfectly willing to work at mere LC levels rather than VLC (72g/d was his advice) and he was very up front that LC would not work for everyone. For inflammatory bowel disease (he was a gastroenterologist) he expected progressive improvement over two years, not two weeks. He discussed that people experiencing failure of LC for weight loss might eventually need to go to simple calorie restricted diets (and I guess he knew they would fail on that too). He had an awareness that exposing an immune system, crippled and ineffective through years of hyperglycaemia, to sudden onset normoglycaemia might render if truly functional for the first time in decades and so exacerbate auto immune attack. Being a medic he would just reach for a 5 day prednisolone course as a simple expedient. For MS patients, many of whom respond very well to LC diets, he took them to around 100g/d initially then down to 72g/d after a few weeks. This is old stuff.

For people to convert from any particular macronutrient ratio to what is a modest, rather than very, low carbohydrate diet is fine by me.

What I have found very disturbing is the long list of potentially catastrophic problems reported to be associated with the type of food choices I make, where there is an edge of ketosis present much of the time. I have said before, I like to have a few ketones available.

It is quite possible that I, and virtually every lab rodent ever placed on a ketogenic diet, might be oddities. Or it might be that 12 years on a very low carbohydrate diet is too soon for the scurvy, thyroid deficiency, auto immune attack or glucose deficiency to get me. Perhaps it will happen tomorrow. But imagine how much money you could save on genetically the modified mice needed for auto immunity research if a simple ketogenic diet gave you a virtually free supply.

There is a saying in the medical community (used by those of us with any sense of self questioning) which goes along the lines of “Clinical experience is no guide to therapeutic efficacy”. One has only to look at a cardiologist with a statin prescription in their hand to understand this. My favourite example is that old chestnut from the siege of Turin during 1536 when Paré realised that pouring boiling oil in to gunshot wounds (the Gold Standard medical treatment of the day, to flush out the toxic carbon particles from the gunpowder residue dontchano) was, to put it mildly, a bit of a booboo.

So I had a listen to the AHS panel discussion on safe starches. The first thing I realised was that no one was making a case for metabolically safe starches, the "safe" referred to a lack of specific plant poisons. Metabolic safety seemed to be a given. I rather liked the lady clinician, she sounded just like Lutz. I loved Chris Kessler too, on C. elegans research. The world is full of people who seem to think humans are unique, free from the metabolic constraints which affect mere nematodes. When my own clients query, in wonder, that cats can get Alzheimers, diabetes, hypertension etc, my reply is that there is nothing special about humans. Failure to learn from C. elegans will lead to some interesting booboos, hopefully not as painful as the boiling oil fiasco.

Ron Rosedale was the only person who came over as making any metabolic sense or having any deep understanding of the processes involved in the signalling subsequent to metabolism.

I have an approach to life. I resist insulin. Running on the edge of ketosis, with a major preponderance of long chain saturated fatty acids as metabolic substrate, I expect to be insulin resistant. I am. It is pure physiology. I like to have uncoupled mitochondria running with a relatively low delta psi, high oxygen consumption and low free radical leakage. On isolated occasions, a few times a week, my parsnip chips will spike my blood glucose and delta psi for an hour or so and generate a few extra superoxide/H2O2 molecules above basal levels. I hope that’s enough for generating a decent number of healthy mitochondria. I don't know if I am correct.

So. I think people should feel free to make their own choices about starch intake. I can't see anything convincing in the concerns that very low carb eating will run you in to a host of medical problems. I'm very uncomfortable with the rhetoric. Quote of the year for 2014 comes from Sid Dishes, relating to the rise of auto immunity caused by VLC eating (I'm possibly only approximately accurate): "Hypothyroidism is so 2011". Sid keeps coming up with these lovely phrases on Facebook. Personally I see no need to add extra starches to what I already eat (between 30 and 60g/d of carbs). This is my rut. I like it.

As we all know only too well, we only get one shot at this. As the Red Hot Chili Peppers said “This life is more than just a read-through”.

Peter