Are you on clenbuterol? (3)

More from Risérus

Trans fatty acids and insulin resistance

"This is especially true [inducing insulin resistance] for conjugated TFA, i.e. conjugated linoleic acid (CLA), which clearly impairs insulin sensitivity."

I think is reasonable to assume that Risérus expects ordinary trans fatty acids to impair insulin sensitivity too, though not quite as effectively as CLA does. He just needs a big enough intervention study to prove it.

Of course he is wrong in this. He's also correct.

There is a saying that the dose makes the poison. CLA warrants a post or two on its own but it's enough to say for now that there is a toxicity syndrome, reliably induced in rodents, because it's ability to induce lipolysis can be frankly too effective. Including death of adipocytes.

Trans fatty acids are the little brother to CLA as far as lipolysis is concerned.

From the Protons point of view oxidising fats, any fats, will be better than glucose, even with insulin, at inducing reverse electron transport through complex I.

Weight loss, ie fat loss, necessitates the oxidation of lost fat. The better the lipolytic agent, the more fat to oxidise and the more insulin resistance.

Extended fasting is classically a state of profoundly increased fatty acid release from adipocytes and the oxidation of those fatty acids, with insulin resistance being intrinsic to this state. And essential for survival. Protons.

So it is impossible to lose fat without the development of some degree of fat oxidation induced insulin resistance.

CLA is good at lipolysis, trans fats less so but still better than a poke in the eye with a sharp stick.

The thought train which goes on from here is that lipolytic agents should acutely reduce insulin sensitivity directly related to the degree of fat loss. In the long term a lipolytic agent which enforces sustained fat loss will provide the low rate of basal lipolysis intrinsic to small adipocytes and so increase insulin sensitivity, especially if the lipolytic agent is not currently active.

I'm going to talk about clenbuterol next but the other agent of interest is metformin. From the Protons view metformin simply blocks the glycerophosphate shuttle, drops the FADH2 input to the electron transport chain so blunts insulin signalling which needs some degree of ROS generation to happen. Blunting insulin signalling allows lipolysis and suppresses hunger in proportion to these fat loss calories. Once adipocytes are small enough from this blunted insulin signalling we are back in to small adipocytes with low basal lipolysis so increased insulin sensitivity, especially if the metformin has worn off... In humans metformin takes a few weeks to "work". I doubt the degree of fat loss needs to be gross, just enough to reduce basal lipolysis a little.

Back to clenbuterol. Calves this time (at least it's not Bl/6 mice!).

Clenbuterol-Induced Insulin Resistance in Calves Measured by Hyperinsulinemic, Euglycemic Clamp Technique

Basically it's looking at acute treatment with a lipolytic agent. Here are the glucose infusion rates under an hyperinsulinaemic clamp:

The black squares are the infusion rates after clenbuterol, the open squares before injection. 

It's clear from the bottom graph, while the drug is active, that the treated  calves are insulin resistant, requiring significantly less glucose during the hyperinsulinaemic clamp compared to before treatment.

The upper graph shows no effect if you wait 16-25 hours before the clamp, ie until the clenbuterol has worn off. Interestingly the square colours are reversed in this upper graph. Even if the rates are ns different, we still have the calves showing as more insulin sensitive in the aftermath of a period of lipolysis. You can't force lipolysis without shrinking adipocytes. Shrunken adipocytes will always have lower basal lipolysis compared to larger adipocytes. This should show as less insulin resistance. There is a suggestion of that here.

Here are the results tabulated

I was going to go on to talk about chronic clenbuterol and the enhanced insulin sensitivity it provides. Undoubtedly chronic, high dose clenbuterol induces low adipocyte size, muscle hypertrophy and markedly improved insulin sensitivity. But the mechanism becomes complex and convoluted. I spent a little time on this fascinating paper which is comprehensible from the Protons point of view but horribly convoluted by beta receptor down regulation leading to blunted adrenaline signalling. Which affects insulin sensitivity directly.

Clenbuterol prevents epinephrine from antagonizing insulin-stimulated muscle glucose uptake

Fascinating but I'll leave that can of worms alone. It does leave me wondering a little about the acute effects of clenbuterol on fully active beta receptors and their interaction with insulin signalling. Messy. I'll leave the above post unchanged but bear in mind a lot is going on when you take an adrenergic agonist drug, in addition to lipolysis!

Peter