Thursday, December 20, 2018

Urinary c-peptide

It's the Winter Solstice tomorrow, greetings to all! My favourite astronomical event of the year, even though we do the major feasting on Christmas day in our house. Anyway, here's a fairytale for the depths of Winter (in the northern hemisphere anyway). Happy Solstice!

                                            *********

Here we go: Just occasionally you come across a statement like this:

"(B) Insulin secretion throughout the day was assessed by 24-hr urinary c-peptide excretion and was significantly reduced only following the RC diet".

Okay, what does it suggest to us when the reduced 24-hr urinary c-peptide group lost less fat  than the higher c-peptide group? Less insulin but less fat loss??? Perhaps it suggests that the insulin hypothesis of obesity is incorrect?

C-peptide is part of pro-insulin. Each molecule of insulin produced provides one molecule of c-peptide within the pancreas. Assuming (not completely accurately) that c-peptide is not consumed within the body we can use its 24-hr average urinary excretion as a surrogate for overall insulin production. With an awful lot of caveats, this seems fair to me. I think statement B is correct.

So 24-hr urinary c-peptide gives us an idea of how many molecules of insulin are being manufactured per day by the islets within the pancreas. Insulin is broken down by insulin degrading enzyme as part of its signalling process, not exactly proportionally, but as a general principle this is correct. I went through it in some detail when thinking about the Potato Diet, a sub-category of carbosis. The more signalling, the more degradation.

On average around 50% of secreted insulin (in dogs on a mixed diet) is removed by the liver on first passage from the portal vein through to the hepatic vein (termed first past extraction, FPE). Humans are very similar. None of this hepatic first pass extracted insulin ever arrives in the general circulation. The rate of extraction varied from as low as just over 20% up to almost 80% in the dog study. If you have 100 molecules of c-peptide produced, somewhere between 20 and 80 of the associated molecules of insulin will never arrive in the systemic circulation.

Does anything specific alter the FPE? Well, yes, of course. Does anyone think it might be free fatty acid delivery to the liver? Much as this paper tells us

Free Fatty Acids Impair Hepatic Insulin Extraction in Vivo

So under a weight stable modest LC diet (or more accurately; under whole body adipose tissue mass stability) the reduction of insulin secretion from the pancreas under that modestly reduced carbohydrate intake will undoubtedly occur, but would be offset by reduced hepatic FPE and enough insulin will penetrate to adipocytes to keep them full. In the real world this is extremely difficult to make happen, people just want to eat less on a LC diet because as insulin falls more fat exits adipocytes and hunger diminishes. As in Aberdeen. But you can approximate it by artificially controlling (increasing) food intake, ie you pay people to eat more dietary fat than they would like to (which keeps insulin secretion unchanged but increases fatty acid delivery to the liver), hepatic FPE falls and more insulin reaches adipocytes to keep them full.

Under ketosis (let's say with carbs less than 20g/d) there is so little insulin secretion that having an FPE which is probably approaching zero doesn't matter much. Near basal physiological insulin is secreted, almost none is FPE-ed by the liver but there is still minimal exposure of adipocytes to insulin because almost none is being secreted in the first place. So appetite plummets as FFAs rise as they pour out from the adipocytes, despite a minimal hepatic FPE. This should make it even harder to overeat. However, if you do manage it, minimal hepatic FPE by the liver is one of your methods to maintain fat stores under ketosis!

Conversely you can achieve low FFA delivery to the liver by using acipimox. People do not necessarily gain weight with this lipolysis inhibiting drug because it decreases hepatic FFA delivery, so increases hepatic insulin signalling and so increases hepatic insulin metabolism. I assume this increased insulin metabolism will increase FPE and this will decrease insulin delivery to the systemic circulation. I also think this is also how carbosis works, hence the need for very low fat provision in any carbosis inducing diet.

Anyway, here's a thought experiment using made-up numbers. Any resemblance to real life is totally accidental. If a moderate carb diet (say 140g/d) allows a 22% fall in 24-hr urinary c-peptide, does this mean there is a 22% fall in 24h exposure of adipocytes to systemic insulin? Well no...

Say 100 molecules of insulin are secreted and FPE pre-study is 50% then 50 molecules of insulin survive passage through the liver to suppress systemic lipolysis. If only 78 molecules of insulin are secreted under mild carbohydrate restriction but FPE falls to 20% (exaggeration to make the point!) due to increased lipolysis delivering extra FFAs to the liver, then 62 molecules of insulin will make it through FPE and as far as the adipocytes. This insulin could conceivably allow less lipolysis when compared to a carbosis inducing diet, despite reducing insulin secretion.

On a diet in which fat is so restricted as to allow almost none to be spared for oxidation so that FFA delivery to the liver falls precipitously, we can suggest an 80% FPE might be the result. This would be the situation under carbosis, say with a human eating 7.7% fat as part of a severely calorie restricted diet. So of the 100 molecules of insulin still being produced under these circumstances (typified by no fall in 24-hr urinary c-peptide) with an 80% FPE only 20 of those molecules of insulin will eventually hit the adipocytes and so lipolysis would then be greater than under the modest LC diet.

Please bear in mind that these numbers are a reductio ad absurdum example, but they do make a point about what is possible. There are other effects which would kick in but that's not my point here.

My grossly biased opinion is that any study which shows an intervention with superiority in fat loss will be associated with either lower insulin exposure of adipocytes or with an induced failure of insulin to act on those adipocytes (ie by metformin, alcohol, fructose or of course palmitic acid, plus a few others) than is achieved by any comparison diet.

But then I would say that..........

Peter

9 comments:

Gretchen said...

What's the RC diet?

Peter said...

Kevin Hall's trial from the last posts. So is the 7.7% fat diet....... An exercise in incomplete information!

Peter

Peter said...

There, I've put a link in...

All the best

Peter

cavenewt said...

This is fascinating and makes my brain hurt.

Yet another example of the wondrous complexity of biological systems, and the hubris of thinking humans can manipulate things based on incomplete understanding.

Merry Solstice!

Passthecream said...

It was a rather cool 24C for the mid-summer here today but it will be 40 for Xmas! A solstice seems like the proper time to end one year and start the next trip around the Sun and to thank you for another year's worth of interesting thoughts.


Thanks Peter!

karl said...

OT - but could be important - did you ever have a Wikipedia page?

Thinking about this:

https://drmalcolmkendrick.org/2018/12/18/wikipedia-a-parable-for-our-times/

I have a hunch that some of the twisted science is due to vegan activism (i.g. high fat diets without fat in them).

( Some of the stories our host students have told me about suppressing non-PC results - or even results that might embarrass others in the field are staggering. )

Peter said...

Happy Solstice, Christmas and New Year all.

Hi Karl, I've followed the saga via Malcolm Kendrick and Tom Naughton mostly. I've no idea if I have a wikipedia page but no one has suggested it's going to be deleted if I did! PC-ness, bleaugh...

All the best and have a happy Christmas

Peter

Bob said...

Karl said,"( Some of the stories our host students have told me about suppressing non-PC results - or even results that might embarrass others in the field are staggering. )"

Karl, you really ought to blog about that one. Too many people (and I know one of them) worship Science and believe that if a Scientist Says So, it must be so. Unless of course it's a dissenting scientist who must be shilling for some Bad Guys.

Amazing how easily science can become like the religion it replaced. Meet the new dogma, same as the old dogma.

cavenewt said...

There's a recent discussion in the Facebook group Gary Taubes Fan Club about difficulties editing Wikipedia articles with any positive comments about low-carb. While it's true the formatting and sourcing requirements can be stringent, it still appears some of the editors/admins have sort of a power thing going on.