Reactive Oxygen causes Insulin Resistance

One of the major health crises the world arguably faces is the threat from diabetes; this is intrinsically linked to obesity; but why should weight gain lead to an individual becoming insensitive to their own insulin? Speaking with Chris Smith, David James and Daniel Fazakerley at the University of Sydney suspect that when a person becomes overweight they end up in a metabolic vicious cycle whereby high energy intake provokes the production of reactive oxygen species in their mitochondria. This depletes the metabolic factor coenzyme Q, leading to even more free radicals and even poorer insulin sensitivity…

David - Insulin resistance is referred to as prediabetes and it's a very important condition now because it's one of the major risk factors, not just for type 2 diabetes, but a whole host of diseases including many forms of cancer. Quite frighteningly, in Australia there are probably 3 million people with insulin resistance but they don't know that they've got it. Our research is focused on trying to understand how people acquire insulin resistance and, of course, we're hoping that that will lead us to develop better therapies that could be used to prevent it.

Chris - And Daniel what tack did you take?

Daniel - We have access to a number of experimental model systems where we can study insulin resistance. And because we have access to so many, we took the idea that if we could look in a lot of different models and find common features across these models we might be able to find a mechanism that may explain insulin resistance. So what we actually did is we took a range of cell culture models, tissues from animal models, and human tissue too. And what we found is that enzymes when a a particular biochemical pathway were expressed at a lower level in insulin resistance, and this led us down the path of looked for a specific molecule called coenzyme Q which is involved in how the cell produces energy was decreased in all of the models. And the exciting thing was that when we replenished the levels of that molecule in these model systems we could restore the cells response to insulin, so they were no longer insulin resistant.

Chris - David, do you think this is chicken or egg? Is the coenzyme Q level low because of the insulin resistance or does the coenzyme Q level end up low and then cause insulin resistance and it becomes almost like a vicious cycle?

David - That's the big question and I'll draw upon some new findings that we have to best answer that. This is a new paper that we're just about to publish with Dr Mike Murphy from Cambridge University. Mike has developed these chemicals that very rapidly induce production of these things called reactive oxygen species. This is one of the molecules in this energy producing organelle of the cell called mitochondria that we believe is at the heart of insulin resistance. And our hypothesis in our eLife paper is that what happens first is that there is a lowering of the coenzyme Q levels, and that then somehow leads to an increased production of reactive oxygen species, and that subsequently leads to insulin resistance. So that's sort of our working model. So in this new study with Mike, we can show now that we can get rapid induction of reactive oxygen species, no change in coenzyme Q, but we see an induction of insulin resistance. Now if we zoom back to the eLife paper, we were able to show that when we genetically modulate the cells by perturbing their production of coenzyme Q that led to an increase reactive oxygen species production. Then again, when we replenish the coenzyme Q, the reactive oxygen species returned to normal. So putting all of this together, we're pretty confident that we've mapped a linear pathway whereby first you've got the lowering of coenzyme Q; that leads to an increase in reactive oxygen species, and in turn that leads to insulin resistance.

Chris - Daniel, where does the coenzyme Q go? Is it because it's not being expressed, is the gene not sufficiently active, or is the protein being consumed too quickly?

Daniel - So in some models it appears that the biosynthetic machinery to make the molecule coenzyme Q is downregulated, but in other models that doesn't seem to be the case. And it may be actually that the turnover of the molecule, so how well the cells can hold on to the molecule, is actually changed. So it may not be that in all these different systems it's the same process leading to a decreased level of co Q and it might be different, but it's the change in CoQ levels that are a common factor.

Chris - Now you said that you can supplement CoQ in cells and this appears to mitigate the effect? People have been trying to dose themselves with things like coQ for a long time. There's no evidence that it really makes a dent in diabetes though is there?

David - No that's right. And, in fact, this is a really important point that you've raised. It's probably going to be impossible to replenish the levels of coenzyme Q using oral supplementation. It's the coenzyme Q inside the mitochondria that is specifically lowered. You can't just get more coenzyme Q into the body or even into cells, you've got to get it into mitochondria. And we suspect, ultimately, we have to develop compounds that stimulate the actual synthesis of coenzyme Q and that could actually be a very fruitful path to therapy.

Chris - Statins are associated with diabetes aren't they? It's one possible reported side effects. Do they have any role in this process?

David - This is actually a very significant question. And we're quite careful about how we answer this because the coenzyme Q pathway is downstream of the actual enzyme that is hit by statins. And in fact we've shown in our eLife paper that if you incubate cells, and I have to preface this by saying it's a fairly high dose of statins, but nevertheless we have shown you get a reduction in the levels of coenzyme Q, and you also get insulin resistance.

Chris - But owing to the dyslipidaemia that goes along with diabetes, most people with diabetes are on statins. So actually, aren't we making their problem worse in some respects?

David - Again, let me just preface this by saying this is pure speculation, but I absolutely agree. And it's probably also the case that the link between statins and insulin resistance went undiagnosed for a long time because it stands to reason that most individuals that are taking statins have dyslipidemia and they probably also have some resistance. And I think it's only very recently that people have recognised that the statins may actually be worsening their insulin resistance, we could be worsening their dyslipidaemia.

Chris - So Daniel, not withstanding any of that, what sort of avenues does this open for us to explore now you've done this and shown this association?

Daniel - Yes. So we're really excited about our work because we think we've now provided some evidence for a linear pathway between the models of insulin resistance we've used which include things like diet in mice, a loss of coenzyme Q from a specific site within the cells - it's the mitochondria, the production of chemical reactive species in the mitochondria as a result of loss of coQ, and the induction of insulin resistance. Now our current work is working on okay, so how can we target this pathway we've identified to try and provide some therapeutic benefit? So as David said earlier, one of the things we've really interested in is understanding how we can potentially increase coQ levels in these models, so that's understanding why they're depleted in the first place. And the other arm of our research is understanding the link between mitochondria and the reactive option species and why insulin doesn't work so well in these cells anymore? And if we can identify those links, I think will have a much better chance of developing a therapy.