Sunday, October 21, 2018

Metformin (09) Islets

This is another very abstracted study using isolated mouse islets in cell culture to assess the effect of metformin on insulin secretion.

Metformin Inhibits Mouse Islet Insulin Secretion and Alters Intracellular Calcium in a Concentration-Dependent and Duration-Dependent Manner near the Circulating Range

From the Protons perspective the factors which drive insulin signalling are the same ones which drive insulin secretion, certainly at low physiological concentrations. The situation is different under post prandial conditions where, eventually, reverse electron transport increases from low, physiological activating levels of ROS to the high physiological levels which drive insulin resistance rather than activation. Recall this is what I consider to be the cellular repletion signal, the one so easily mistaken for insulin as an anorexic agent. Anyway, here we have metformin acting under 11mmol/l of glucose to suppress insulin secretion.

Just to recap; 20micromolar metformin is therapeutic, 200micromolar is life threatening lactic acidosis and 1mmolar (1000micromolar) is death:















Any findings in the paper using concentrations of 200micromolar or higher can safely be ignored for therapeutic relevance. Except for the confirmation that cells die rather well at 1.0mmol of metformin and are doing rather more apoptosis than you might like at 200micromolar (see Figure 3 in the paper). No surprises there.

Also consider that picking up subtleties of insulin secretion by measuring the concentration in a culture well is a very blunt instrument. But at least they are looking.

So why doesn't metformin cause diabetes on the sort of criminal (up until very recently) diet advised by any diabetologist?

This is partly because the redox changes in the liver suppress gluconeogenesis, though the exact mechanism by which blockade of mtG3Pdh suppresses hepatic glucose production is debatable.

It's also because, certainly in peripheral cells suffering from chronic hyperinsulinaemia-induced lipotoxicity, cessation or reduction of insulin signalling will allow release of fatty acids able to generate their own RET via the oxidation of beta oxidation derived electron transporting flavoprotein at mtETFdh of the electron transport chain and so restore insulin signalling. Or, if there is enough superoxide, insulin resistance. So cells suddenly realise they have a great supply of FFAs, adequate ATP generation and no need for any more caloric ingress. Which generalises to the whole organism as a "no need to eat" state, which might just give weight loss. As metformin does.

Kind of like LC eating in a pill.

Peter

Actually metformin might do the same to lipid in the pancreas as it does in peripheral tissues. Loss of accumulated pancreatic lipid is what people like Dr Roy Taylor consider the mechanism by which the hypoinsulinaemia of semi-starvation induces some degree of remission of diabetes, in a few patients, while they can stick to it.

14 comments:

Unknown said...

Peter, is it plausible that if you could bring glucose down to near zero for 1-2 days with drugs,(while consuming exogenous ketones) you could kill most if not all cancer in the host, animal or human?

Best Regards

cavenewt said...

@Unknown, I think that would be a death sentence for the host (and, thereby, the cancer).

Unknown said...

I saw that Dom D'agastino went to zero for 30 minutes while under ketosis and consuming exogenous ketones and felt no negative effects?

cavenewt said...

I guess so... Coincidentally, I just ran across this today:

"1. Blood glucose below about 60mg/dl must thus be risky only for people on high carb diet, not on ketogenic diet." by Stan Heretic). A hyperlipid post well worth revisiting.

http://high-fat-nutrition.blogspot.com/2014/07/in-comments-following-previous-post.html?showComment=1408227365748#c3822559219854812571

cavenewt said...

Sorry, I didn't finish my comment. To go back to your original question to Peter, I'm curious if eating a standard carb-rich diet, but bringing your glucose down to near zero with drugs while consuming exogenous ketones, would kill you or not.

Peter said...

Unkown and cave,

That needs a bit of thinking about. It seems pretty clear that a ketogenic diet might be an adjunct to cancer management in a significant number of cancers. Going to extremes might increase the proportion but I tend to look at ketone bodies from the ETC point of view and they look a bit like acetyl-CoA with a little NADH thrown in. Their only drive to generate ROS are from Complex II, whereas FFA metabolism has mtETFdh to fall back on for RET generation which might trigger apoptosis in a glucose adapted cancer cell. Hence the teasing data on stearic acid...

https://www.ncbi.nlm.nih.gov/pubmed/19267249
https://www.ncbi.nlm.nih.gov/pubmed/19838949

Peter

Galina L. said...

I am sorry that I am writing out of the post subject, however, in order to help to a friend, I decided to ask you, if you may give some suggestions how to make a supplemental liquid food for a baby who is 13 months old. He is undergoing a chemo now due to a bladder cancer, his mom doesn't have enough milk, and he is loosing weight fast.

Peter said...

Hi Galina,

That’s way outside any area I have any experience with and I’d expect one so young to be under medical supervision for the cancer management, which should include nutritional support. Once one is under medical support the options to go to something akin to the paleo ketogenic diet seem very limited. But I’d start by contacting the paleo group in Hungary, their technical papers are here and look reasonable to me

https://www.paleomedicina.com/en?page=tartalom&tipus=cikk

Peter

Galina L. said...

Тhank you, Peter. I passed the information to the parent. It is amazing, but one of Pateomedicina doctors happens to speak Russian language because he is a former student of the Military Medical Academy in Moscow. Sure, child is nutritional guidance, however, it is the usual kind. Sory to jerk you into an odd problem.

Peter said...

I hope they can help...

Peter

cavenewt said...

@Galina...wet nurse or donated pumped breast milk an option?

Bob said...

Metformin seems to be one busy drug! Among its other effects, it may even work against endometriosis.

https://www.sciencedirect.com/science/article/pii/S1110569012000957

Galina L. said...

cavenewt -they managed to obtain a ready-to use keto-mix and and thanks god it worked. Poor kid somehow vomits that mix less that a breast milk. We all keep fingers crossed for that family. Sorry to take attention to an unrelated problem.

Peter said...

Bob, yes, but if you view endometriosis as metabolic syndrome as expressed by the uterus it should come as no surprise that blocking mtG3Pdh should ameliorate it by attenuating insulin signalling....

Galina, glad they found something that helped a little

Peter