So What Causes Insulin Resistance?

Hey, guys!  Today we're going to get back to the topic of ectopic fat.  For those of you who don't remember, ectopic fat is fat that's stored in abnormal places.  The ectopic fat in muscle tissue, called "intramyocellular fat" by stuffy scientist-types, is one of the main causes of insulin resistance.

There's really not that much information out there about ectopic fat.  Its Wikipedia page is completely nonexistent, and if Wikipedia doesn't know about something, it's probably not important, right?

It's such a reliable source.

Well, actually, since it leads to insulin resistance, ectopic fat is probably one of the main causes of Type II Diabetes.  In order to show this, I will, again, use my wonderful scribbles.

We will, again, look at this chart:

Get used to seeing it.

We've talked about citrate leak, how insulin up-regulates the production of ACC, and how Malonyl-CoA shuts CPT1, which allows the cell to burn fat.  Now, the question is, where does that triglyceride molecule go?

Some of it is shipped off to regular fat cells, to be saved as extra energy if the body doesn't get enough glucose.  This is an evolutionary holdout--if early humans couldn't find enough food for the day, then extra energy is stored very efficiently as fat to be used as fuel.

The rest of it actually stays in the cell.  Since most ATP production happens in muscle tissue (because those are the cells that do the most work), a lot of that excess fat stays gooped up inside of the cell.

Gloop.

From now on, triglycerides will be abbreviated as TAG, because it is easier to type.

Now, TAG itself doesn't have any real problems.  It just kind of hangs out in the muscle cell waiting to be used.  Eventually, though, it turns from this

Friendly fat just waiting to be useful!

into this

The guy who hangs out in the bad part of town.

which is called DAG.

DAG, unlike TAG, doesn't just loiter around.  DAG interferes with certain metabolic pathways.

Glucose enters the cell from the bloodstream in a series of biochemical reactions.  In the presence of insulin, glucose can pass through the first gate.

DAG interacts with one of the steps of this reaction, specifically with an enzyme called GLUT4.

This doesn't let glucose into the cell.  The body will naturally try to neutralize the glucose within the blood, because high blood sugar causes other problems.  This means that the pancreas will have to produce more and more insulin to overcome DAG's influence on GLUT4.

Simplified, ectopic fat interferes with the body's ability to metabolize glucose.  In order to reduce blood sugar after eating large amounts of glucose, the body needs to secrete more insulin.  This insulin resistance can eventually lead to Type II Diabetes unless it's treated!

So, the answer to reducing insulin resistance?  Getting rid of ectopic fat.  If it's not there, DAG can't block the GLUT4 receptor, meaning glucose can enter the cell as per usual, so the pancreas will make less insulin.

Which makes your pancreas very happy.  Also, apparently they make pancreas plushies?

One simple way of removing ectopic fat is simply eating a low-glucose diet, which I'm currently doing.  If the body has no glucose to burn, then it will take it from ectopic fat stores in the muscle.  Once those are gone, then the body can mobilize fat from fat cells.

Another way is by using the drug Invokana.

Aw yeah.

While it won't do all the work on its own, Invokana is extremely useful for helping diabetics and pre-diabetics get rid of a bunch of glucose without keeping to such a strict diet.  Invokana is a sodium glucose transport inhibitor (SGTI).  What does this mean?

Well, in order to see that, we have to look at our kidneys.  Our kidneys are in charge of removing toxins from our bloodstream and getting rid of them through urine.  Kidneys have certain transport proteins that put glucose back into the bloodstream, which means that glucose stays in the blood until it is metabolized.  Invokana blocks that transport protein, so that glucose is secreted from the body in urine.  How much sugar is gotten rid of?

Seventy to one hundred grams of sugar.  That's a lot.

In order to illustrate, here's the amount of sugar that ends up getting flushed down the toilet.  Let's be cautious and say 85 grams.

Mmm, pure sugar...

So, Invokana is really useful in reducing the amount of glucose and, by extension, ectopic fat, which is the problem in the first place.

Thanks for reading!