Dr. Ben Bikman

If there is any lipid that's to blame, it's going to be a lipid called ceramides.

And those do not track the same across these, say, the lean marathon runner and the obese type 2 diabetic.

When you start measuring levels of tissue ceramides or its precursor dihydroceramides, there's still some debate as which of the two matters most.

I'm very strongly just saying it's one of them.

And so I'll just say ceramides as a family.

you can, in any biological model, cause very strong, robust insulin resistance just by increasing the ceramides because ceramides will block the insulin signal.

When insulin binds to its receptor, then you have a series of phosphorylation events.

Ceramides block that very well.

It's a very well-defined pathway.

And if you can just do one thing and just resolve the ceramides, you correct the insulin signaling.

So when it comes to ectopic fat,

It's not a matter of how much triglycerides you're storing, but rather what is the entire metabolic milieu to be promoting ceramides in various tissues throughout the body.

Interestingly, all of those primary stimuli, the quick insulin resistance, all induce ceramide biosynthesis and accrual.

But with the slow insulin resistance...

I still think it's appropriate to invoke fat, but by that it's the fat tissue.

And I don't want to get ahead of us, but my view is that if you look at tissue level insulin resistance, is it starting in the muscle or the liver or the fat?

I'm very much an advocate of the fat first focus when it comes to insulin resistance from that slow progressive.

It settles in over years and it may take weeks to months in order to reverse.

Yeah, that's exactly.

And that's where that's where ceramides act.