Scopinaro and biliarypancreatic diversion

The late Nicola Scopinaro was an interesting chap. I came across him while reading about the use of the biliarypancreatic diversion (BPD) operation for the management of obesity and diabetes. He developed the operation in the 1970s and produced a string of publications about it over around 40 years. He died in 2020.

I can appreciate his practical abilities. In an obituary a friend describes how, during a parachute malfunction in the 1970s, Scopinaro spent his time during the descent in working out how to best position himself on impact to minimise the probability of any of the 13 fractures he sustained leading to a penetrating injury of his abdominal or thoracic viscera, or brain. He survived, hitting the ground at ~100kph. So he can work things out. An impressively pragmatic person.

His operation works.

If anyone wants the details there is always Scopinaro's comprehensive (and possibly mildly biased) review from the early days here:

Biliopancreatic diversion

but the core is that it pretty well always works and while there can be catastrophic problems these can be relatively simply managed. Inject B vitamins sooner rather than later if your patient's brain malfunctions and perform revision surgery to increase the protein absorption section if they develop protein malnutrition. And a few others. All in the paper.

Here's what the operation does.

If that's not clear we can analyse it in a little more detail. Most of the small intestine is separated from the stomach and is simply left in place to act as a conduit for bile salts and pancreatic juices to be transferred to the far end of the small intestine. We can remove this conduit from the diagram and replace it with the large red arrow like this:

The last 250cm of the small intestine is plumbed directly to a truncated stomach and functions to absorb glucose and sucrose (using the brush border sucrase enzyme), highlighted in blue below:

The conduit provided by the rest of the small intestine delivers the bile salts and pancreatic secretions to the last 50cm of small intestine. This 50cm section is the only section of the gut which is able to digest starch, fat and protein, that's the region highlighted in red:

Under these condition it is impossible to overfeed using anything containing starch, fat or protein. People with this alteration to their digestive system usually eat around 3000kcal/d, with just under half of the food eaten going down the loo.

If you make them over-eat to a total of ~5000kcal/d by adding an extra 2000kcal of fat/starch there is absolutely no change to their weight over 15 days. I prefer not to think about the resulting changes to their already execrable lower bowel function during this period.

Here are the weight loss data from a case series who had a milder version of the above procedure. Roughly 70% loss initial excess weight (IEW) maintained for longer than 18 years:

The full operation as described above gives more like an 80% permanent loss of IEW.

You can develop all sorts of ideas about how this operation works physiologically, what bypassing the bulk of the small intestine does to GPL-1, GIP, vagal sectioning, endocananbinoids etc etc but the bottom line is that Scopinaro was a pragmatic surgeon and what he means by satiety and appetite may not be quite the same as I do.

Which puts us in a position to think about Tataranni's paper comparing BPD patients with normal weight people as regards insulin sensitivity and RQ. And maybe basal metabolic rate.

Peter

Synchronicity and the origins of Protons (2)

This is the paper which Amber mentioned in her podcast conversation, primarily in the context that low carbohydrate, high fat diets markedly reduce hunger in diabetic rats. I wasn't looking at that aspect, what had caught my attention was the caloric intakes of the non diabetic rats on different levels of linoleic acid inatke and I had this post pretty well complete. Which looked pretty uninteresting unless you have a Protons perspective. Here's the post very much as was:

                                        *****************

I happened on this paper by Edens and Friedman many years ago:

Response of Normal and Diabetic Rats to Increasing Dietary Medium-Chain Triglyceride Content

and this is the core quote:

"On the other hand, LCT-fed [corn oil, 55% linoleate] normal rats overate for several days when they were given the higher fat diet."

Notice the word "overate" and that this was transient, then look at Figure 5, from which I've removed section B because that is just about the diabetic rats which are irrelevant to the current discussion:

I think it is not unreasonable to draw a straight line through the calorie intakes, provided we ignore the upper trace of the corn oil fed rats (filled dots) in the section circled in blue, which are the ones we are interested in:

NB the line trends downwards because the rats are slowing their growth rate so need fewer calories per day as the weeks go by.

Next we can look at the blue circled area and add in, by eye on Powerpoint, a smoothed line for the calorie intake during this period. Which looks like this, again in blue:

The 25% fat by weight diet supplied around 43% of calories as corn oil which gives around 24% of calories as linoleic acid.

We've seen something similar before of course, from the Schwartz lab:

on to which we can draw a similar set of lines:

I think exactly the same phenomenon is happening in both diets, one from 1984, the other from modern day D12942. The effect is much smaller and goes on for half the time period but it's there. These differences give us some insight in to what has been tweaked over the decades to improve the obesogneic nature of diets leading to the development D12942 and D12451.

Aside: The reason why the effect is small and the effect of MCT oils is minimal is another whole discussion. On the to-do list. End aside.

Is the 25% fat diet from 1984 going to be obesogenic when the rats only "overate" for a few days? Of course it is. Rats on D12942 only over eat for seven days before food intake drops to statistically indistinguishable from chow fed rats, but they still get slowly fatter over the weeks. So too would the rats in this venerable study, had they eaten it for long enough. IMNSVHO.

The discussion section is interesting because the authors are continuously trying to tease metabolic effects apart from "palatability" effects. That's good but the lack of concepts that insulin signalling is a redox based system and that the generation of superoxide/H2O2 is controlled by the relative proportion of FADH2 and NADH produced by a given metabolic substrate means that the conclusions must, necessarily, be far from complete.

So it lacks the Protons hypothesis and cannot tease out why a jump in linoleic acid intake causes a brief period of "overeating". And, of course, if you considered these few days of significantly increased caloric intake to be the only effect of the high fat corn oil diet you might be forgiven for concluding that polyunsaturated fats are non obesogenic The authors published in 1984 so cannot be criticised for being unaware that the redox state controls caloric ingress in to individual cells, as falls out from the appreciation of the ratio of FADH2 to NADH from fats vs carbohydrate as they affect the function of the ETC, RET and superoxide generation. Especially the effect of sub-physiological production of FADH2 per unit NADH as it features in the beta oxidation of linoleic acid.

Where as the difference in redox signalling generated by linoleate vs stearate (and to a lesser extent palmitate) has good explanatory power.

Peter

Synchronicity and the origins of Protons

Amber O'Hearn has a podcast conversation up on Spotify with LowCarbLogic here. Very early on in the discussion she mentions this particular study from Mark Friedman. He has championed the concept that obesity is a result of the sequestration of lipid in to adipocytes, fat trapping. This is mediated by insulin, hence the role of low carbohydrate diets, ie low insulin diets, in the management of obesity.

This idea, promoted by Gary Taubes, has profoundly shaped my thoughts on obesity, in common with those of Amber. It is difficult to over emphasise how important this is to any sort of understanding. It's that mind-bending concept that obesity is *causal* to over eating.

Your adipocytes steal your calories, so you have to eat extra calories to have adequate substrate for energy generation to run your metabolism. 

Getting fat makes you hungry.

Of course there are a number of major problems with this simple but incomplete hypothesis. The two most spectacular of which are the observation that countries such as Japan and China, whose populations ate the vast majority of their caloric intake as rice, historically had no obesity and, conversely, that of rodents fed on an high fat, low carbohydrate diet become grossly, grossly obese. D12942 supplies only 20% of calories as carbohydrate but is the gold standard for generating diet induced obesity in rats and mice.

What separates fat trapping from obesity is the failure to limit insulin signalling to the appropriate physiological level. Correctly functioning insulin signalling does not cause obesity.

You cannot talk about what controls obesity without talking about what controls insulin signalling. Oddly enough there is more to insulin signalling than the level of insulin in the plasma.

Understanding insulin signalling is impossible without appreciating that the system is intrinsically related to the actions of reactive oxygen species, as elegantly demonstrated by Czech back in 1974. You can activate all of the functions of insulin on adipocytes in cell culture by exposure to hydrogen peroxide. Low concentrations activate the insulin signalling cascade, higher concentrations inhibit it.

Of course there is no point in talking about the generation of ROS without understanding the work of David Speijer. There is a comprehensive description of his ideas, from 2019, and his thinking goes back to 2011. Probably further. I would also say that Skulachev's work on ROS and membrane potential is fairly essential too.

All I have done in the Protons thread is to throw together the ideas from Czech and Speijer and spend nearly 14 years thinking about them. With a few other inputs from evolutionary biology and the origin of life, largely from Nick Lane. And especially thinking about the paradoxes.

Oh, the trigger for this post was that I have already written a separate post about that study published by Mark Friedman in his early days, back in 1984. It's the same study which Amber cited at the start of the podcast. Having her discuss the same study which I'd already written about but not quite published struck me as profound synchronicity. Got me thinking. Anyway, this post is too long and philosophical to go on to doodle lines all over graphs so I'll update the original post to include Amber's mention and get it published separately fairly soon.

Peter

Addendum. There has been some posting recently on X about the role of the Randle cycle by which the conversion of glucose to malonyl-CoA inhibits the uptake of long chain fatty acids in to mitochondria, leading to failure of fatty acid oxidation and preferential oxidation of glucose derivatives. This is absolutely correct. The massive hole in citing the "Randle cycle" to explain obesity is in failing to ask what limits this from happening. Obviously it is limited by limiting insulin signalling. What limits insulin signalling? Well duh, ROS limit insulin signalling. Presenting a cell with a mix of glucose and long chain saturated fats means that the oxidation of these fatty acids correctly limits insulin's ability to activate both the PDH complex and the ACC complex. So the concentration of malonyl-CoA is kept at a functional level.

Saturated fats limit insulin signalling to allow co-oxidation, in the same cell, of both glucose and lipid substrates. Hence the generation of whole organism respiratory exchange ratios that indicate both fatty acid and glucose oxidation are occurring concurrently. As they do.

Unless that fatty acid FAILS to generate adequate ROS to apply this essential limitation system.

Linoleic acid's low ROS signal (compared to stearate) allows excess insulin signalling to facilitate malonyl-CoA generation and the immediate inhibition of fat oxidation, even within the first hour of ingestion of D12451 (kid brother of D12942). I hope you have all read Matsui et al's paper where an oral dose of metformin 300mg/kg, 30 minutes before food access after an overnight fast, completely normalised caloric intake of D12451 when it is eventually re-supplied. And Chung et al's paper where they tracked the RER daily during the three day transition from low fat to D12451. This 45% fat diet *raises* the RER, despite increasing fat provision and decreasing carbohydrate provision. All just Protons.

It's quite straight forward.

Of course, without Protons, you're lost.

I'll stop now.

P.