Sunday, January 19, 2014

Acipimox and insulin action

I just wanted to put up a brief mention of this paper on acipimox.

Acipimox is an inhibitor of lipolysis. It's essentially useless as a therapy for anything, partly because it is derived from an incorrect paradigm but mostly because it's impossible to get it to work for any extended period of time. It's good for a week though.

So let's take a few diabetics, do some lab work on them, drop their FFAs using acipimox, then repeat their lab work a week later.

Fasting FFAs drop from 563 micromol/l (not actually very high) to 230 micromol/l (verging on pathologically low) and FBG drops from 8.5mmol/l to 7.0mmol/l. All highly significant, statistically.

Does this mean that they are fixed, i.e. they can go out and eat pizza all day and be normoglycaemic?


A diabetic person who drinks 75g of glucose in water will hit a 2h blood glucose of about 16mmol/l. With markedly reduced FFAs they will be graced with a 2h blood glucose of a mere 14mmol/l, which does not look like dropping. They're f*cked, metabolically. Last time I did this (2008ish??) my 2h BG was 3.4mmol/l.

It looks to me as if acipimox removes the normal physiological uncoupling associated with abnormally elevated FFAs and leaves the insulin resistance of a broken set of mitochondria there for all to see.

There is physiological insulin resistance associated with elevated FFAs. Then there is pathological insulin resistance from mitochondrial dysfunction.

Just wanted to say...



Gretchen said...

Peter, Postprandial BG in people with diabetes is not just because of insulin resistance. It's mostly because of a lack of the phase 1 insulin response.

Your link to the paper gave a 404 error, so I couldn't check details of this paper.

Gretchen said...

test; sometimes your site doesn't offer choice of e-mailing comments until after you've hit Post.

Bob said...

Hi, Gretchen.

The link to the pubmed abstract is

The link to full paper is

Peter said...

Gretchen, yes, there is no first phase insulin response but at 60 mins insulin is up to 250pmol/l and stable, with stable hyperglycaemia. Down from about 400pmol/l before acipimox.

Fixed the link


Gretchen said...

Peter and Dennisr2: Thanks for link. Easier to understand what's going on when you have more information. Too bad they didn't show intramuscular LCFA-CoA levels in controls.

I was in a study of high-dose aspirin analog (salsalate) at Joslin, and that actually increased my phase 1 insulin response from zero to about 70% of normal.

Do you know what the effect of aspirin on mitochondria is?

Puddleg said...

Not directly relevant, but interesting - Fatty acid content from frozen specimens of Paleolithic (Pleistocene) megafauna.
Indications that mammoth hibernated may make them a sometimes easier prey animal than previously thought.

Peter said...

George, wow! Of course the mammoths may have died out due to CVD from all that palmitic acid in their adipose tissue....



Peter said...

Gretchen, not sure what the problem is. I only ever use blogger from a computer, usually at home, very rarely from work. It seems to do what I ask, but I'm usually signed in as the blogger so I don't get all of the "prove you're not a robot" stuff...


Gretchen said...

Peter, I think you have to sign in first and then post your comment. Once you're signed in, you get a chance to subscribe to posts. Makes sense because how could they subscribe you if they don't know who you are.

I know this but keep forgetting to do so.

Scott Russell said...

This is interesting, although to be fair, insulin-mediated glucose disposal did go up for the acipimox group. So their utter failure at the GTT might be better explained by an increase in hepatic glucose output and not merely a failure to become insulin sensitive in the presence of low FFAs.

Gretchen, I know aspirin is sometimes quoted as increasing mitochondrial uncoupling (in the liver I think), but its not something I've looked into much.

kathryn said...

hello, not a scientist here,i am living this dream and trying to figure it out.

75g of glucose would send this T1 way over 16, possibly as far as 20 or more. i've been strictly keto for several months because i know it's my only option.

wonder if coq10 supplementation makes any kind of sense in this situation. is the mitochondria likely salvagable ? do they renew ?

is this disfunction a done deal ?

many thanks to anyone who can help

marie said...

Hi Kathryn. I don't know if it will help your situation, but you can induce the creation of additional mitochondria by doing HIIT (high intensity interval training) and may also be helped by fasting 22-24hrs at a stretch (eg.dinner to dinner).

I 'discovered' this in myself (turns out it's common knowledge in performance circles, eg. mountain climbers, long-distance runners....) when I consented to a muscle biopsy after surviving severe hypoxia about a year ago (massive double pulmonary embolism, caused by the combination of a badly bruising accident and a genetic mutation for clotting). Turns out I had about double the usual amount of mitochondria. Doc asked what I did for exercise and nutrition and said the HIIT was likely the reason "and the periodic fasting probably helps".
Peter of course has a lot of info on the effects of fasting and ketosis.

As for HIIT, If you type it in Google, you'll get all kinds of sites with info on how to do it, with simple to bizarrely complicated routines.
Basically though, it's very simple : one does rowing or running (or whatever the favorite) as fast and hard as they possibly can for 30seconds, rest for 30seconds (should be breathing like a bellows if done right!) and repeat the sequence until they literally can't drag feet/stay upright anymore - surprisingly this takes maybe 2-3 reps for beginners, so maybe 2-3 minutes in all.
Rest for 3 days. If body doesn't feel 'heavy', Repeat. If still feel heavy, wait another day. Never more than twice a week, higher frequency defeats the purpose.
That's it :)

marie said...

Peter, or anyone who might have info on this (!),
the secondary short-term effect of acipimox on BG reminded me to ask here : do you know of an agent or method that will induce hypoglycemia in a non-diabetic person? Something other than an injection of insulin :)

MCT oil, eg. coconut, helps of course and also helps combat some unpleasant effects of hypoglycemia since it's absorbed across the blood-brain barrier, but I'm looking for something that will specifically Stop or much reduce the gluconeogenesis by the liver, which seems to act to maintain BG above about 65mg/dl in fasting or ketogenic folk.

The catch is it needs to be something natural, since would need a prescription for anything pharmaceutical, for example for Metformin or the like.
Do you think coconut oil plus fasting might drop BG below 60mg/dl? Is coconut oil not concentrated enough and would need an isolated MCT oil? Something else entirely?

Any thoughts on this subject would be a terrific help to me...

kathryn said...

hello marie, thanks for being both speedy and helpful.
i will look into the scary sounding exercise even though i am a dedicated yoga type. last time i ran saw me start off on around 8mmol/L and a half hour run later i tested 23mmol/L. rather scary and pre keto so i assume my liver panicked and dumped its entire store of glucogen. also i know enough about blood type science to believe that type Os do best with athletic stuff, i'm an A hence the yoga. I do intermittent fast at least until noon and usually longer. it does help maintain a sense of overall control. the less i eat the less i seem to need to eat.

on your other thing, chromium and alpha lipoic acid are both purported to do this

marie said...

kathryn, thank you for the quick tips back to me - will look into.

Unknown said...

Regarding aspirin and mitochondria:

Nick Lane also mentions it in Power sex suicide.

ItsTheWooo said...

"It looks to me as if acipimox removes the normal physiological uncoupling associated with abnormally elevated FFAs and leaves the insulin resistance of a broken set of mitochondria there for all to see."

Its like poetry for nerds. All true nerds are visual thinkers, anyway.

A+ & true talk as well.

Gretchen said...

Jack, Thanks. Interestingly, they didn't even mention nFkB, which is what was postulated to cause the effect on inflammation.

Aspirin blocks the phosphorylation of IKKbeta, so IKbeta and nfKB remain bound together and inactive.

IKKbeta is activated by high blood glucose, and oxidative stress, among other things.

IKKbeta also blocks the pathway to Glut4 translocation to membrane.

At least all this was postulated a few years ago. Maybe theories have changed. We really know so little about complex systems.

I've found papers that say that aspirin *increases* levels of nfkB in cancer.

Unknown said...

Gretchen NFKappa beta acts differently depending upon signaling in the cell at the time it rises. This is why biology confuses so many. It i snot linear or congruent. The same key can open the doors of hell or just need to understand the context. Most of the literature on this topic never includes that context for us to decipher it easily.

Gretchen said...

Jack, the context here is inflammation.

I agree that every system in the body depends on many other factors, some of which we probably haven't discovered yet. We have to start somewhere, and the outline I gave was Joslin's hypothesis 10 years ago of how aspirin helped to improve type 2 diabetic symptoms. If you think their interpretation is wrong, I'd be interested.

(I think it's NFkappa [roman B] not beta.)