Insulin Resistance Starts In The Mitochondria

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Often diabetes is associated with the loss of insulin, however, long before the onset of type 2 diabetes the person at risk is suffering from a condition called “insulin resistance”. Insulin resistance is a big deal because it means that you are now “pre-diabetic” and are on the way to full blown diabetes. The consequences of insulin resistance are first; that your blood sugar is elevated leading to tissue damage and second; that your pancreas is working overtime to make more insulin and will eventually poop out. By the time this happens the patient is in full blown diabetes and is taking insulin.

We are extraordinarily interested in insulin resistance because it precedes type 2 diabetes onset by perhaps a decade. Detect it and you have a chance to modify your life style and perhaps head off this disease. It can be modulated both in the bad direction and in the good direction. Inactivity, overeating, pregnancy, corticosteroid treatment, and hepatitis C infections (for example) all increase insulin resistance while exercise and diet decreases insulin resistance (which means increasing insulin sensitivity).

Since there are so many ways that we can increase insulin resistance we can ask the question: where do these processes converge within the cell? Do they all meet at some major nexus of insulin signaling or do they meet at some earlier point which then feeds into the insulin signaling pathway? This question was recently addressed by an Australian group led by David James and just published in the Oct 20 issue of the Proceedings of the National Academy of Sciences. Intriguingly they found that many different inducers of insulin resistance met in a single place: the mitochondria.

The mitochondria, as we learned in high school, are the power house of the cell. The energy rich compound ATP is synthesized there from the Krebs cycle leading to the electron transport chain (here’s a link in lieu of your high school biology book). With all of those electrons getting passed around, one might imagine trouble brewing if things are not regulated in a careful manner. It turns out that a surprisingly large number of different things which induce insulin resistance in a model system (in this case isolated muscle cells grown in culture) also cause the mitochondria in those cells to get very messy with their electrons. The authors mimicked overeating by putting excess fat into the culture medium and in separate experiments excess insulin. They mimicked inflammation by adding a protein signal that macrophages release during inflammation. Interestingly, they also looked at a common drug that blocks inflammation, a corticosteroid. All of these additives caused the muscle cells to become insulin resistant and also caused the mitochondria to start producing compounds that contained those pesky electrons. We call them reactive oxygen intermediates (ROIs).

Perhaps the most striking observation was that by using highly toxic drugs that target the mitochondria, uncoupling different parts of the electron transport chain (and testing the cells quickly before they died) they were able to completely block the development of insulin resistance. The cell has a more natural way of dealing with oxidative stress (what happens when mitochondria leak these ROIs). One enzyme that it makes has the ability to chemically modify those compounds making them safe again. The enzyme is called superoxide dismutase (SOD). When the gene for this enzyme was introduced into mice such that the mice would now make more of it, the researchers found that these mice became at least partially resistant to a high fat diet. Their insulin resistance was blunted.

This paper is really part of a much larger emerging story. If one does a search at the national library of medicine using the terms diabetes, mitochondria, and oxidative stress one gets over 300 hits (although half are reviews). This would suggest that you will be seeing a lot more on this topic in this blog.

What is interesting here is that so many different pathways seem to converge on the mitochondria. Over eating makes sense. Too much nutrients and not enough factory capacity to convert it to ATP leads to partially processed intermediates that are dangerously reactive. What about some of these other signals? We know that oxidative stress can cause an inflammatory response but these data suggest that an inflammatory response can cause oxidative stress. And what about corticosteroids? These are anti-inflammatory drugs and yet they are doing the same thing to the mitochondria as inflammatory signaling molecules! What a mystery. This is what makes biology so fun.

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