Tuesday, October 30, 2018

Selenium induced glutathione peroxidase generation

TLDR: excess selenium induces excess glutathione peroxidase which blunts physiological superoxide/H2O2 signalling within a cell. This, as you might expect, is a Bad Thing.

I stumbled across this paper quite by accident. It has a number of problems, not least of which is that none of the authors appears to be a native english speaker and this tends to show through. It also carries a rather catastrophic typo/brain fart in the abstract, where TCA, as in tricarboxylic acid cycle, was written out in full as trichloroacetic acid cycle. Ouch. Never the less, they don't seem to like antioxidants.

High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS

Over all they don't seem to like suppressing the physiological levels of ROS needed for insulin signalling, certainly while feeding their rats a high carbohydrate diet. Not that they tell us what they fed the rats on!

This is the intraperitoneal glucose tolerance test result, look at "control" and "Se" for the effect of the high selenium diet:

Among many of the problems with the paper another is the difficulty distinguishing which line is which on the graphs. I think we can say the top line is clearly the selenium supplemented group and the bottom line is probably the control group. The main effect is at the 30 minute mark. This suggests to me that there is an inadequate first phase insulin response (needing ROS from RET induced by mtG3Pdh) to overcome the systemic failure of insulin action (also needing ROS from RET via mtG3Pdh to diffuse as far as the insulin receptor). By 60 minutes the difference is negligible. Had they measured insulin I'd bet the second phase response was exaggerated.

Here is the intraperitoneal insulin tolerance test result:

This time the bottom line is clearly the control group, top line the selenium treated group. From the control group I see no suggestion that this particular dose of insulin is inducing insulin-induced insulin resistance, so all we see is the failure of the insulin signalling activating action of ROS at the two hour mark. Note the lines are all parallel until the one hour mark. This is what suggests that there is nothing wrong with insulin action per se at the 30 minute mark and is another factor which makes me suspect that there is a failure to secrete insulin during the early stages of the IPGTT. The normal response to exogenous insulin, up until one hour mark, occurs while ever the exogenous insulin can overcome the loss of ROS caused by the glutathione peroxidase excess induced by the high selenium diet.

As humans we deal with huge numbers of xenobiotic antioxidants, mostly from plants. For the vast majority we can simply use our liver and/or kidneys to dump them to where they can do us no harm. Just occasionally we fail, as with selenium. The end result is not pretty.


There are some more interesting finings in the paper which might be worth chatting about. Maybe another day.

Random throw-away thought: Is this how uric acid induces insulin resistance? By being too good an antioxidant???? Hmmmmmm.


raphi said...

talking about uric acid, Bryan Walsh's concern about it on keto diet is as follows http://www.nourishbalancethrive.com/blog/2018/10/23/mitochondria-more-powerhouse/

- go keto, uric acid goes up (maybe because of more purines from increased protein intake), but then it goes down longer-term. But urinary excretion of uric acid doesn't increase - so where does it go?

==> maybe keto is increasing oxidative stress and thus more uric acid is being used up
==> maybe uric acid is being used to mitigate the lowered PH from the ketogenic diet
==> ketones may be competing with uric acid for urinary excretion, and ketones win

"My concern is either the body is not making as much [uric acid], maybe as a protective mechanism and that's cool, but it is an antioxidant. Maybe it's being used up as an antioxidant and that's indicating that ketogenic diet is increasing oxidative stress"

I'm all for speculating about the significance of uric acid changes on ketogenic diets, but why do these concerns never come with 'due diligence'? meaning, why not challenge the assumptions of uric acid levels or its functions on non-ketogenic diets? are those normal? after all, we're concerned about uric acid on non-keto diets when their increase is associated with gout...so having an increasing on a totally different diet should cast shadows over what we think about how it usually works.

Peter said...

Hi raphi,

I’ve thought about uric acid on and off for years. As you well know the association of gout with purine intake is observational and potentially highly confounded.

You might enjoy this one


Obviously the commonest trigger for a gout flare is either the initiation of or an increase in dose of allopurinol. That should make us think. It’s an interesting subject. Needless to say I’ve not reached any conclusion except most of what we think is probably wrong!

Interestingly diazoxide is a trigger drug too. Acute hypoinsulinaemia (diazoxide) or acutely increased insulin resistance (ethanol) may be potential common mechanism. Keto eating is protective provided the acute fall in insulin is mitigated by ketone induced suppression of the inflammatory process (inflammasomes etc) while the intra articular crystals dissolve.

Just occasionally folks do get caught out with keto triggering an acute flare (so I’ve heard).


cavenewt said...

I've run into many warnings not to eat too many Brazil nuts for fear of selenium poisoning. When I buckled down to find out more, turns out it's probably an overblown concern. Anybody know for sure?

Just to add (what I think) is an interesting aside, there was an episode of House M.D. that involved a suspected case of radiation poisoning which turned out to be overindulgence in Brazil nuts. It's always fun to watch House, the personification of iatrogenesis, try to kill his patients in various ways before finding the True Path. https://en.wikipedia.org/wiki/Whatever_It_Takes_(House)

Peter said...

I'm not sure how to convert the doses used in the rat studies in to brazil nuts for humans but they were only using adequate vs twice adequate for their in vivo studies. But the paper really is badly written so telling exactly what they really did is not easy and there is one utterly inexplicable result that they don't discuss in any way, so a bit cautious here. However excess selenium produces excess ROS scavenging which leads to marked mitochondrial derived ROS generation. Nick Lane in Oxygen emphasises the similarities between radiation injury and ROS generation from other causes... Some support there??????


Bob said...

Here's a 2015 Chinese study on selenium and diabetes in 5400 people. They concluded higher selenium intake was a progressive risk factor, although the highest odds ratio (about 2) occurred in subgroups with BMI over 25 versus odds ratio of 1.2 for BMI under 25.


WebMD also describes a study showing higher diabetes incidence in people taking 200mcg selenium vs placebo.


But the study participants were older people with skin cancer history, so "further studies are needed to see if selenium supplements truly raise diabetes risk, note the researchers".

I take a half tablet of a multivitamin which contains 55mcg selenium. This is the RDA. Average intake in the US is estimated to be 125mcg. I have no idea if the 28mcg added to whatever my dietary level is puts me at any risk. I'm also low carb with BMI under 25.

Peter said...

Hi Bob, ultimately these odds ratios are utterly ignorable, especially based around "completion of the Semi-Quantitative Food Frequency Questionnaire (SFFQ) about food and drink consumption over the past year". The rodent study gives me pause for thought even if appallingly written up. But my main interest is in the antioxidant delivered problems to metabolism. Every time I see some miracle food packed full of some antioxidant I think of how poorly marketing has to do with reality and what we need ROS for...


Peter said...

That will be "...how little marketing has to do with..."!


digital doctors.org said...

https://youtu.be/-ygExIZm7Wo has good info on this topic. Enjoy !

I thought selenium in mustard was good for me.

digital doctors.org said...

Does anyone think that using allopurinol in diabetics on keto would help with IR and fat loss ?

I recently read that renal function outcomes are improved when uric acid is lowered.

I think uric acid is harder on the body than currently known.... just not sure how to translate that to clinical practice.

Peter said...

The allopurinol in diabetics is interesting. I think it would be very context specific. After all, the role of insulin is the inhibition of lipolysis. If you make adipocytes more insulin sensitive you will undoubtedly inhibit lipolysis at a given level of insulin. You would only get weight loss if you dropped insulin enough to more than offset this. That implies LC eating. At which point there is no need to worry about insulin resistance as you're not using insulin to control caloric ingress in to cells....... Then there might be benefits from uric acid. As I mentioned to raphi, it's a subject with a lot of potential exploration and not in the least straightforward.


cavenewt said...

@digital doctors.org "I thought selenium in mustard was good for me."

I like mustard, but what about the general principle of avoiding seeds because of the toxins?