Sunday, July 04, 2021

Obesity and diabetes (3) Acipimox

I first went looking for papers on Acipimox in 2014. I had read that it was an inhibitor of lipolysis and I was interested in how much weight gain it caused. Back in those days I was still fairly attached to the most basic of carbohydrate-insulin-models of obesity. If you consider that insulin causes weight gain by the inhibition of lipolysis, giving a non-insulin inhibitor of lipolysis should do the same... Shouldn't it?

Well, no, it doesn't. Acipimox produces a profound fall in free fatty acids and a marked improvement in glucose tolerance. Very, very occasionally I found snippets in discussion fora that it could increase hunger but this was not by any means routine. These give the flavour:

Effect of the Antilipolytic Nicotinic Acid Analogue Acipimox on Whole-Body and Skeletal Muscle Glucose Metabolism in Patients with Non-insulin-dependent Diabetes Mellitus

Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients

All of which sounds very good (unless you are into the CIM of obesity!) and you have to wonder quite why Acipimox has not become standard of care and have largely reversed the current global diabetes pandemic. In fact, a recent 2020 meta-analysis of niacin (the parent compound from which Acipimox is derived) trials suggests we might be remiss in failing to do so:

But then you could go on to ask why giving niacin itself  might actually make people with impaired glucose tolerance flip in to frank type two diabetes (amongst other medical catastrophes) with worrying regularity

Effects of extended-release niacin with laropiprant in high-risk patients

Of course you could blame the laropiprant, given to suppress the niacin flushing. Or you could more usefully think about the metabolic consequences of dropping plasma FFAs by using a potent inhibitor of lipolysis.

If we work on the basis that DMT2 is essentially the down stream consequence of the inability of distended adipocytes to limit basal lipolysis, it comes as no surprise that artificially shutting down release of FFAs might improve markers of metabolic health.

The cost would be larger adipocytes.

But this doesn't happen, at least not much. The explanation is contained in this paper from 1992, largely looking at the reasons for the long term failure of Acipimox to control FFA levels:

It's simple. Making adipocytes retain their lipids increases their size. There is no suggestion that tolerance develops to this. All that happens is that there is a rebound increase in basal lipolysis as the Acipimox wears off. The drug-induced transient fall in FFAs produces a transient decrease in the oversupply of calories from FFAs, so cells should and must adapt to by reducing insulin resistance. Numbers improve at the cost of bigger adipocytes. As soon as the drug wears off the adipocytes, now bigger, reinstate basal lipolysis at their previous high rate plus some extra due to the extra distending effect of Acipimox. As they off-load their extra size by releasing FFAs, the physiological need of other cells in the body to resist insulin is both restored and augmented.

There is no net benefit and all the drug might do, if it does produce any increase in adipocyte size, is to convert IGT people, with some reserve function remaining in their adipocytes, in to very sightly heavier diabetics who have less ability to suppress adipocyte size-induced increased basal lipolysis.

If you are pre diabetic but not glycosuric and you become glycosuric in the periods between Acipimox/niacin doses you will convert from pre-diabetic to diabetic, assuming you use glycosuria as your marker for diabetes.



Passthecream said...
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Passthecream said...
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TempusFugit said...

Big fan of this blog. I came across this niacin HFD mouse study which may be of interest.

Niacin fine-tunes energy homeostasis through canonical GPR109A signaling

From the abstract:
Using high-fat diet–induced mouse model of obesity, we demonstrated that niacin treatment apparently protected against obesity without affecting food intake in wild-type mice but not in GPR109A-deficient mice. Further investigation showed that niacin treatment led to a remarkable inhibition of hepatic de novo lipogenesis. Additionally, we demonstrated that niacin treatment triggered brown adipose tissue and/or white adipose tissue thermogenic activity via activation of GPR109A. Moreover, we observed that mice exposed to niacin exhibited a dramatic decrease in intestinal absorption of sterols and fatty acids. Taken together, our findings demonstrate that acting on GPR109A, niacin shows the potential to maintain energy homeostasis through multipathways, representing a potential approach to the treatment of obesity, diabetes and cardiovascular disease.

Some highlights:

We also performed a GTT and ITT and documented that niacin-treated mice were less glucose tolerant but exhibited insulin tolerance comparable to control mice (Fig. 3C). Quantitative analysis showed that niacin treatment results in a significant reduction in blood insulin (Fig. 3E); however, HFD-fed mice treated with niacin exhibited a marked decrease in HOMA-IR values compared to vehicle-treated mice.

Niacin treatment caused a remarkable increase in number and size of mitochondria with improved cristae organization in HFD-fed WT mice (Fig. 5D). Furthermore, we assayed the expression of genes involved in BAT thermogenesis by real time PCR analysis. As shown in Fig. 5E, the mRNA expression of uncoupling protein 1 (UCP1), a critical player in allowing electrons to be released as heat rather than stored, and PR domain containing 16 (PRDM16), a well-known BAT transcriptional regulator, were significantly up-regulated in HFD-fed WT mice in response to treatment with niacin.

Passthecream said...
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Passthecream said...

Thanks for that TempusFugit.

Peter said...

Thanks TempusFugit. Very interesting. It fits well with the observations of Abraham Hoffer on the accidental benefits of long term rapid acting niacin, used by himself for schizophrenia management, on long term longevity (it's good). It's possible the long term benefits stem from the increased lipid delivery between the acute lipid suppression periods which actually increase mitochondrial numbers and possibly also activates AMPK. I'm also toying with the idea that ATGL and HSL have differing preferences for which FFAs they liberate with ATGL releasing saturated fats preferenyially. Which would fit with niacin increasing exposure to palmitate so raising HDL... If anyone cares about HDL.

Of course I think it raises NAD+:NADH ratios too, considered to be a Good Thing.


Justin said...

Tempusfugit, thanks for sharing. I've been wanting to toy with fast niacin to see what it does to my HDL levels. They are already in the upper 80's/lower 90's. My mom used to make me take it every morning before school when I was a teenager. Man that flushing could be no joke. Lol!

Passthecream said...

I recently found this paper highlighting a different facet of nicotinic acid, they're looking at using na receptor agonists to enhance the anti-inflammatory aspects of it:

Passthecream said...

And this is an amusing case report with the punchline: "Surprisingly, his urine drug test was also negative for any drugs including cannabinoids."

cavenewt said...

@Pass re case report

"On examination, the patient had a blood pressure of 95/60...Our patient presented with hypotension...niacin has been documented to cause acute hypotension..."

Shucks, that's the range of my normal blood pressure. My record low for the top number is 85. Guess I should report to the ICU!

Justin said...
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Gyan said...

I am confused a bit. Rapid acting niacin is good for longevity but slow-release niacin is not?

Passthecream said...

Gyan, the only thing I know about slow release niacin is that it is easier to overdose on it because the levels stay higher for longer i.e it's not eliminated as quickly. I am curious as to why the nicotinamide form of but B3 doesn't cause flushing while the niacin form does. Does that mean it doesn't have the same effects as niacin in the paper linked by tempusfugit? Or just some of them?

In that paper this section :

"Subsequently, the ketone body β-hydroxy-butyrate was identified as an endogenous ligand for GPR109A (18). In adipocytes, upon stimulation by niacin, GPR109A functions via Gi/o proteins to lower intracellular cAMP production, leading to decreased PKA-mediated activation of hormone-sensitive lipase, which in turn reduces Tg hydrolysis to free fatty acids (FFAs) (19). This FFA hypothesis is supported by evidence that niacin failed to lower FFA and Tgs in GPR109A-knockout mice (15)."

Suggests to me that ketosis, or at least a high fat burning state which produces BOhB is what niacin imitates by hitting the same receptor. But my experience of B3, usually the nicotinamide form, is a mixed bag. Ups and downs. I wonder if someone is already in a mostly fat burning state then decreased activation of h.s. lipase, lowering of FFA would cause an energy deficit ( by interfering with the normal feedback loop for fat burning vs BOhB perhaps)?

Maybe not so desirable an effect if you are on a hflc type of diet, more effective for people on a standard type diet?

Peter said...

Gyan, yes, this seems to be the case. The difference looks like a brief inhibition of lipolysis will be followed by a rise in FFAs which will trigger mitochondrial biogenesis, especially if you are not diabetic or nearly so. Long acting niacin (or acipimox) does a much better job at suppressing lipolysis for longer periods so pushes you in to the level post-inhibition FFA release which causes more severe insulin resistance. That’s the logic as I see it.


Passthecream said...

This is reminding me of an experience I had with "separated" coconut oil a while back. I tasted a couple of spoonfuls as an experiment. Fairly soon I had a reactive hypo, shakes and all, quite unexpectedly. I think it is the same receptor dynamics since that coconut oil is distilled to contain mostly caprylic and capric acids, and as pointed out by Peter it is caprylate which generates ketones directly, quickly ime. So the BOhB from that ketogenesis hits the receptors which niacin can also glom onto with the same result. Local fat burning is suppressed, but too much in my case. It's not a nice experience! Perhaps it has the same good long term effect as the niacin does? This may explain my experiences the regular 500mg doses of vit B3. 16mg is the RDA of that fwiw.

I'll get some niacin and experiment with the dose and have some chocolate on hand in case I have a case of the munchies. I'll be fooling with my endocannabinoid system, but legally.