Saturday, October 12, 2019

Metformin (11) a SHORT paradox

I'll just throw this one out there as I found it while looking for something else:

Metformin paradoxically worsens insulin resistance in SHORT syndrome

SHORT syndrome is a (very, very rare) genetic failure of insulin signalling at the PIK3 regulatory subunit 1 level. Insulin binds to its receptor but signalling fails due to a single downstream gene defect giving severe insulin resistance. People with this syndrome are, needless to say, very thin. They maintain normoglycaemia using a very high level of insulin which does, given a high enough concentration, produce normoglycaemia. There doesn't appear to be any problem with secreting insulin from the pancreas. In fact, to overcome the failure of insulin signalling during her OGTT the patient's pancreas produced a plasma insulin of 688mIU/l*. In new money that is just under 5000pmol. As in roughly ten times what you might expect. Severe, but not quite insuperable, insulin resistance.

*The paper specifies insulin in mIU/ml. I'm assuming this is a typo or a font failure because clinical insulin concentrations are usually expressed as microIU/ml or mIU/l. Obviously if it really is 688mIU/ml the concentrations will be 1000 times those quoted. Gulp. People really should use the SI system.

Back to the patient. The obvious thing to do is to give an insulin sensitising agent, number one in popularity nowadays being metformin.

This turned out to be a bit of a boo boo.

During an OGTT under metformin the patient's insulin resistance worsened and mild hyperglycaemia ensured but this was despite a plasma insulin concentration which was simply too high to measure. The lab could measure up to around 7000pmol (pax typos) and it looks like the curve went MUCH higher than that.

That is despite metformin's predictable and recently found ability to suppress insulin release from mouse islets.

From the Protons perspective metformin blunts insulin signalling via blockade of mitochondrial glycerol-3-phosphate dehydrogenase. Its beneficial effects to increase insulin sensitivity come from reduced exposure to insulin signalling in peripheral cells. The peripheral cells of a person with SHORT syndrome barely see insulin signalling at all even without the metformin. You would hardly expect further blocking any residual insulin signalling to help matters. It doesn't.

It's the sort of paradox which only happens when you are in the wrong paradigm of metformin's mechanism of action. Might have been a chance to make progress...


Addendum: The lady in question did not seem to enjoy her experience with the medics too much:

"As we intended to check the effects of this approach, an extended 75 g OGTT was performed on metformin 4 days later. This showed dramatic and paradoxical worsening of insulin tolerance with insulin concentrations above the upper assay detection limit (Fig. 1b). Metformin treatment was discontinued. She was discharged home on Dydrogesterone and vitamin D supplementation. We planned to perform investigations on other family members, and particularly on her younger brother, but despite several reminders they failed to attend clinic appointments as well as declined admission to the hospital".


Passthecream said...

Peter, is it possible to drive a functional complex 1 hard enough s.t. it would reduce q sufficiently to be able to generate reverse electron flow or are the redox potentials wrong from C1 to QH? I have been wondering for a while if the other electron transferring complexes (mtg3pdh, etfdh, sdh) also have different reaction potentials wrt Q such that one might pre-empt the others and all might pre-empt C1?

I was imagining a different, less horrible paradox eg what if diet was exclusively carbs (Kempner for instance, with the whip) but at the same time as taking metformin?

I wonder what these SHORT people end up eating? What carries the most calories across cell walls without insulin? Depends on which cells I guess. They must be a lot like full blown T1Ds but without the glucagon unless that is not sensitive to insulin for them either.

We won't know until they return their questionaire!

Alex said...

"We planned to perform investigations on other family members, and particularly on her younger brother, but despite several reminders they failed to attend clinic appointments as well as declined admission to the hospital."

What an arrogant tone!

Peter said...

Alex, Yep!

Pass, I did find support for the concept that the drive to provide electrons to CoQ was higher from sites other than Complex I but I can't find it off hand. Just logically looking at the glycerophosphate shuttle a molecule of NADH is providing two electrons, via FADH2, to CoQ. There is enough energy in NADH to do this AND pump four protons against the delta psi. Pushing one or more electrons back through complex I looks easy by comparison, especially if the electron(s) abort on to oxygen at FeS N1-a...

BTW will eventually reply to the other comment I'm not ignoring!


Beth said...

>> despite several reminders they failed to attend clinic appointments as well as declined admission to the hospital

That's the way I felt about going to the lipid docs. The one I saw was clueless, why go back? My experience wasn't as horrible as hers seemed to have been, but I do get her response.

Medicine is a sharp knife, mho, & should be used carefully.


Afifah said...

Hi Peter, I had a quick look to see if you have written much on glycine, and I don't see anything focused on it. I published this literature review yesterday and would appreciate your thoughts on it. Thanks so much!

karl said...

Still thinking about the lead poisoning pandemic - we are the lead generation (insert Led zeppelin joke).

I'm thinking that the Lancet paper is probably correct - low level lead exposure is a bigger deal than I was thinking. If I have thought through this correctly, it explains something that was stuck in my head - polyphenols in particular - but other anti-oxidants as well have been demonstrated to have small health benefits - but - are really poorly absorbed - those that get in - get out rapidly. What I had not considered is they are chelators - apparently acting in the intestinal chyme - likely attaching to heavy metals and keeping them from being absorbed.

It looks like all the chelators, vit-C, polyphenols, vitamin E,even EDTA all have anti-ox properties.

If I look at the protons->ROS picture and see that having this stuff go into your bloodstream might not be such a good idea - if you could be sure that they stay in the intestines - might be a good thing.

There was also the troubling chelation paper - showed a benefit - but only in the diabetic group. Could be that the sugar keeps the ROS from going to low?

Anyway, I might be wrong, but this could explain why the research that appears to be in conflict with Protons->ROS .

Peter said...

karl, here's another idea. ROS are insulin mimetics at low levels (intimal hyperplasia anyone?). At high levels they generate insulin resistance. That is Protons in a nutshell. So small amounts of lead make you fat. High amounts of lead stop you getting fatter but make you hyperinsulinaemic. Choose your poison!

Hi Afifah, no, I've never written about it but am aware that it has all sorts of benefits. Pig skin for breakfast this morning.

Beth, medicine certainly is. Dying of fulminating pancreatitis in the ITU is probably mot much fun. Good old cardiologists. For them pancreatitis is an SEP (Douglas Adams, Hitchhikers Guide to the Galaxy: SEP-> Somebody Else's Problem). It's not.


cavenewt said...

+10 for the HTTG reference

Passthecream said...

Peter is a guy who really knows where his towell is at.

Peter said...

cave, clinically I LOVE SEPs!


Steve said...

Subscribing just to get comments. Couldn't find an option without leaving a comment. Did I miss something?

Peter said...

I think that's just the mediocre software...


Olga said...

Hi Peter. Did you see this paper? Of course intermittent fasting would probably work even better and with no side effects.

cavenewt said...

Steve: I use Blogtrottr to subscribe to the RSS comments via email. Works great. Just have to subscribe to each post's comments feed as Peter put up new posts. They have a bookmarklet that makes it real easy.

There's a separate RSS feed for new posts, as opposed to comments; you only have to subscribe to Peter's main page once in order to get that.

Clear as mud?

Peter said...

Olga, I think I might have seen it on social media. I guess you could rephrase it, if you understood metformin, as "Decreased insulin signalling abrogates age-associated ovarian fibrosis". Interesting to try explain that by complex I blockade!


Dave Lull said...

If Blogtrottr can work with the same URLs as an RSS feed reader then I suspect it should be able to provide all comments on all posts using this URL:

cavenewt said...

Awesome, Dave, thanks! I have been wishing for a way to find out about comments on older posts.