Insulin resistance (05) Spanish butter in Noddy numbers.

Let's go back to butter vs PUFA as in the last post. I'm going to use reductio ad absurdum to try make it absolutely clear why a failure of insulin resistance is catastrophic and obesogenic. I'll use stearate and linoleate to simplify matters further, ignoring the other fatty acids in butter and soybean oil.

Let's say a cell needs to generate 100 ATP/min. When it has that 100 ATP/min, it doesn't need any more. If the cell is oxidising 100% glucose there will be low levels of ROS generated, insulin will signal and more glucose will eneter the cell until ATP generation settles at that preferred 100 ATP/min level. Trying to go above 100 ATP/min will raise delta psi and so raise ROS generation which, as it reaches 100 ROS/min, will reduce insulin signalling to a level which will allow just enough glucose to enter to maintain that 100 ATP/min generation. Excess ROS/min above this 100 ROS/min level will signal that the cell is "full" and must resist insulin's signal so no extra enters.

With fat it is different. Oxidising fat will always generate ROS, irrespective of delta psi and this ROS/min signal will act as a base-load of ROS on to which extra ROS from glucose, derived from raising delta psi, are added to generate the "full" signal, which I'll still consider to be 100 ROS/min.



Let's imagine stearate oxidation is generating 60 ROS/min out of the 100 ROS/min needed for "fullness" while generating 60 ATP/min out of the 100 ATP/min needed to run the cell. Generating 40 more ATP using glucose will generate the extra 40 ROS/min when delta psi rises enough to generate them to give the essential 100 ROS/min needed to signal "full". We end up with the necessary 100 ATP/min, a perfectly filled cell and 100 ROS/min "fullness" signal which limits excess caloric ingress by resisting insulin. All is stable.

Now let's oxidise linoleate to generate the same 60 ATP/min. It will take a smidge more than stearate because linoleate oxidation lacks the energy from 2 FADH2s. So linoleate generates its 60 ATP/min, as needed by the cell. But it doesn't generate the correct number of ROS (due to the lower FADH2 input) for the ATP it provides. Let's say it generates 55 ROS/min instead of 60 ROS/min.

As glucose tops up the ATP supply to 100 ATP/min it will generate its own delta psi dependent ROS/min signal, exactly as it did with stearate, ie 40 ROS/min. This 40 ROS/min from glucose will be added to the 55 ROS/min being provided by linoleate.

That gives 95 ROS/min. This is too low to adequately limit insulin signalling. But the cell is already ATP replete and *needs* to limit insulin signalling. Three things happen. Calories enter the cell in excess. They go in to storage. Rising delta psi, to pathological levels, adds the final 5 ROS/min to shut down insulin signalling.

ATP levels are very, very tightly controlled in a healthy cell. Calories in excess of cellular needs have entered the cell under linoleate oxidation because, despite there being the perfect 100 ATP/min, the cell was still signalling at only 95 ROS/min, ie giving a "still hungry" signal.

What happens to the excess calories which have entered the cell because insulin was allowed to signal for five extra ROS/min before the correct 100 ROS/min "fullness" signal was achieved? 

They get stored (if you are lucky, other things can happen). You get fat.

That's it.

Peter

PS obviously it's just a tiny step to transfer this concept to the brain. Maybe another post.