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