Insulin (part 4): The Science
I hope you have been wondering, after reading the previous articles, what in the heavens causes the body to turn a deaf ear or two to insulin? I’m sure you will agree that this question is fundamental to reversing metabolic syndrome (a nickname for insulin resistance), as otherwise we would be taking a shot in the dark. Most of the time, these shots end up in the calorie, sugar, and exercise bowls, whether they are actually the real culprits or not.
As with anything science, the reality of what is happening is much more complicated. My article today may not be everyone’s cup of tea, so don’t feel bad if this is not your thing. For those of you who have nothing else to do other than reading nerdy science, you may carry on. It is especially useful if you are a healthcare professional or someone who deals with clients with health needs. It may also benefit you if you have difficulty shaking a paradigm given to you years ago, and yet your health outcome has not improved. With that, let’s get going.
Insulin, upon its production, doesn’t just magically act on the cells around the body. Its signaling depends on how the hormone binds to the appropriate receptors present on the cell surface. The main receptor it binds to is IRS-1, which stands for Insulin Receptor Substrate-1. This action is indispensable for cells to ‘listen’ to insulin, without which they become stubborn or resistant to its signaling. If the IRS-1 is activated appropriately in the adipocytes, a downstream enzyme LPL (lipoprotein lipase) is successfully produced, which helps take triglycerides into cells. The same IRS-1 activation also allows for GLUT4 transporter expression, which makes it possible for glucose to move into cells.
In chemistry, the word phosphorylation replaces our lay term activation, simply because the body uses phosphate molecules to activate the system it encounters. But phosphorylation differs from activation as the act of adding a phosphate group to a protein causes a structural change to the protein—which then turns a process on or, in some cases, off. The phosphate comes from the ATP we generate in the mitochondria, as ATP stands for Adenosine Triphosphate (three phosphate molecules). Why are we talking about this again? Well, the IRS-1, which is key for insulin signaling to complete, gets phosphorylated in order for it to work. The problem is, there are multiple ways to phosphorylate IRS-1, and they don’t all end up making our cells insulin sensitive. The body needs to have these different phosphorylation pathways as we don’t always want to be insulin sensitive. Insulin resistance, in the right context, can be not just healthy but essential for life and survival. Pregnancy is a striking example of when insulin resistance is highly appropriate for the human body. Furthermore, our bodies are naturally insulin sensitive in the morning and resistant in the evening for the right circadian (body clock) reasons.
Back to the IRS-1. When it is phosphorylated on the tyrosine residue, LPL and GLUT4 end up being produced, making the host cell sensitive to insulin. If, however, it is phosphorylated on the serine or threonine residue, LPL and GLUT4 production is blunted, and the cell becomes insulin resistant. What decides which residue will the IRS-1 be phosphorylated on? Let’s first talk about ceramides and diacylglycerides (DAG).
Before we vilify them in their entirety, these two signaling switches are crucial for life. Without ceramides, our ability to get rid of older senescent (from the word senile) cells and younger misformed cells is critically compromised. In real life, that means we get older and sicker quicker. Without ceramides, we won’t be able to hold our keratin in place—say goodbye to waterproof skin. Without DAG, babies won’t grow inside the mother's wombs, there won’t be a circadian response to eating, all of our consumed energy will be stolen by the muscles leaving the other organs hungry, and so on and so forth. The problem is when ceramides and DAG constantly activate the IRS-1 or even simply if they are working on IRS-1 at the wrong time of the body clock. Therein lies the answer you are seeking.
The main over-activator of these two are oxidative stress / inflammation and a broken circadian rhythm. Oxidative stress at the level of mitochondria produces a surge of ROS (reactive oxygen species) and, together with inflammation from TNF-alpha and IL-6, promote over production of ceramides and DAG. These in turn activate the PKC pathway, which phosphorylates IRS-1 on serine or threonine but not tyrosine. The resultant cellular response precludes PI3K, which would have been necessary for LPL and GLUT4 production, assisting the cell's response to insulin. If you allow oxidative stress and inflammation to rampage the body, your cells hardly get a moment to listen to insulin.
In oversimplified terms, the main sources of oxidative stress and inflammation are excess dietary linoleic acid turning into OxLAM (oxidized linoleic acid metabolites), chronic caloric excess, environmental (mycotoxin, fumes, occupational hazards), recreational (cigarettes, alcohol, drugs), and medications (prescribed, over-the-counter supplements). Notice that sugar is not listed as a cause, and this is intentional, as it does not affect the IRS-1 so long as it is taken whilst maintaining a net neutral caloric balance. I will not promise to go into each one of these at a deeper level as I have a lot more other information to share with you at this stage which are more pressing (yes, more pressing than insulin resistance!). Perhaps they are good ‘rabbit holes’ for us to go into once the big players have been all covered.