Fructose (07) Acipimox tangent II

Acipimox is a drug which keeps on giving. Before I get back to fructose thoughts there's this post and maybe another given over to acipimox.

This is the current paper of interest:

Overnight Lowering of Free Fatty Acids With Acipimox Improves Insulin Resistance and Glucose Tolerance in Obese Diabetic and Nondiabetic Subjects

It has good points and bad points. The worst is the fact that the figures are of such low resolution as to be illegible in places, especially numerical scales to graphs.

On the plus side the tables are fine and the data extraordinarily confirmatory to my biases. Today I'm just looking at the "normal" slim people.

Here is the effect of acipimox on HOMA-IR from an on-line calculator using numbers from the slim, non-diabetic group:

Despite these subjects not supposedly having impaired glucose tolerance the HOMA-IR score derived from their mean fasting values is >2.0 suggesting some degree of insulin resistance. It's not easy to be healthy even as a slim 40 year old in Brazil.

This is easily corrected by acipimox giving an HOMA-IR score of 1.13, well under the cut off for IR.

It does this by locking fatty acids in to adipocyte triglyceride droplets and keeping them there. This, fundamentally, is what acipimox does. It locks lipids in to adipocytes.

From the ROS point of view there is then minimal fatty acid oxidation, minimal superoxide produced by reverse electron transfer through complex I, minimal inhibition of the insulin cascade at the level of insulin receptor substrate so maximal insulin signalling. The end result, in the basal state, shows as increased glucose oxidation and decreased fat oxidation:

These changes are absolutely secondary to the suppression of lipolysis by acipimox at the level of the adipocytes.

I hope all of this is starting to sound familiar.

I can't get this table out of my head

taken from here:

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

Acipimox is reproducing both the low HOMA-IR score and reduced lipid oxidation seen in slim people who are destined to become obese. Ignore the comment about genetics at the end of the abstract. People with obese parents are going to become obese themselves via the action of linoleic acid locking triglycerides in to adipocytes.

Before obesity develops they have "excellent" insulin sensitivity because they are metabolically hypocaloric due to concurrently starting becoming obese via lipid *loss/sequestration* in to adipocytes. They will have to eat more [carbohydrate] to make up their metabolic needs by however much lipid is sequestered in to their adipocytes. They will only become insulin resistant once those adipocytes become large enough that lipolysis cannot be adequately suppressed by insulin.

Acipimox recapitulates linoleic acid's insulin sensitising and obesogenic effects, but only for 6 hours at a time.

Linoleic acid accumulates in your adipose stores (and deep fat fryer) and is available continuously for years making you hypocaloric [ie hungry], especially when you avoid saturated fat. As cardiologists have advised for decades.

Of course, if you took acipimox every 6 hours for the rest of your life you would get fat, wouldn't you? I only discovered acipimox in pre-Protons days when I worked from the simplistic, partially correct idea that insulin inhibits lipolysis to make you fat. Pubmed "lipolysis" "inhibitor" "obesity" and acipimox pops out.

BTW It doesn't make you fat. Basal lipolysis was another gift of acipimox.

Peter