Well, it's quite easy. You just rearrange their digestive system to virtually join their stomach to their colon. Tatarinni wrote the paper. Eat, have a bowel movement, eat some more, poo some more. Maybe you have to eat sitting on the loo. Once patients have "adapted" to their bilio-pancreatic diversion they can get down to as few as 3-5 bowel movements a day, allowing them to leave the bathroom occasionally.
This is what you do (I added the red arrow for clarity):
Total remaining absorptive gut is about 250cm long. This works for weight loss. Tataranni's paper is fascinating as it gives us a picture of the metabolism of eight post-morbidly-obese women who are close to an ideal BMI and who have been that way for over two years.
You need the caveat that these people have a markedly maligned digestive system, so may not represent their metabolic state pre-obesity, but they are very interesting never the less. You also could make an argument that these people, given a normal digestive system, would rapidly become obese again. So perhaps they may really tell us something about people who are pre-obese.
The most striking aspect is that they are NOT insulin resistant. Fasting insulin and fasting glucose are quite, quite normal. Their resting metabolic rate is indistinguishable from that of control women.
But they are not quite normal. The response to a 75g oral glucose load shows markedly increased insulin sensitivity.
Let's just emphasise: Post-obese women with long term sustained normal bodyweight have a significantly increased sensitivity to insulin during an OGTT compared with never-obese women.
Fasting free fatty acids are lower, as you might expect, albeit ns in a group size of eight.
Obviously, with limited access to FFAs, the control of metabolic substrate supply at the cell surface must be managed by manipulating GLUT4s using a glycolysis derived input, which of course means mtG3Pdh as the CoQ input to resist insulin's action. This means there must be enhanced glucose (or insulin) induced thermogenesis to achieve this insulin resistance. Here it is in the aftermath of an OGTT:
The excess energy expenditure is, in part, heat generated by the in-putting of high energy NADH electrons to the CoQ couple without pumping protons.
I floated the concept that glycerol-3-phosphate might be a core protectant against caloric overload on an individual cell basis in the last post, by inducing insulin resistance. I also suggested that the other related function might be the diversion of excess calories to lipid storage, phosphorylated glycerol being essential for intracellular triglyceride formation.
So here we have another interesting set of graphs from Fig 5:
The first striking thing is that in post-obese people an oral load of 75g of glucose induces a respiratory quotient of greater than one. Second is that, during this time, lipid oxidation becomes negative. It was only ever half that of the never obese controls to begin with. As the authors comment:
"After the oral glucose load, the RQ increased more in P0 [post-obese] than in C [control] subjects, reaching values > 1. Thus, lipid synthesis exceeded lipid oxidation in P0 subjects 45 min after the oral glucose load and continued to do so for 40 more min".
What is happening is that these women accept glucose in to their cells very easily. The glucose is converted to pyruvate, this is decarboxylated via the pyruvate dehydrogenase complex to yield CO2 which increases the RQ. The acetyl CoA formed is exported to the cytoplasm as citrate. Obviously the citrate is formed by combining acetyl CoA with oxaloacetate, the latter can also be derived from pyruvate but this time via carboxylation, and hence the TCA never turns. Oxygen is never consumed. RQ >1.0.
So these post-obese women are exquisitely sensitive to insulin, in particular they are remarkably efficient at de novo lipogenesis and at the inhibition of lipolysis.
Were they like this before becoming obese? I think so. Why they might be like this is interesting to think about from the mitochondrial point of view.
Might there be any way of controling their weigh gain without the need for gross malabsorption secondary to removing most of their gut?
Well, you could take insulin out of the equation by simple ketogenic eating and see what happens...
I was going to leave this as an interesting snippet but there are a few add-ons to these ideas.
Some artificial models of this effect are available from various "pre-obese" rodent models. I had a think about them here.
Edward emailed me a link to this paper about a post-obese case report from Dundee. This man has a normal digestive system, he simply didn't use it for 382 days.
Look at the glucose levels in Table 1:
NB, these glucose levels are all very, very low. The authors feel that these values are real. Perhaps he may have been morbidly obese, yet still insulin sensitive. You need to have retained some insulin sensitivity to attain massive obesity without limiting weight gain by the transition to diabetes. But anyhoo, the trends are what interested me.
What we need to look at is the first column, fasting glucose levels. If we ignore day 355, where there was some sort of a hiccup, FBG was around 35mg/dl. This is quite low but the chap was in extended starvation so this might not be surprising. This is the level of glucose under deep, deep physiological insulin resistance. Ignore day seven value of re-feeding because metabolism will, in all probability, still be far from normal and the chap was only consuming liquid glucose at this time.
Instead I looked at day 55 of re-feeding, while he was on 1000kcal of a mixed diet. His FBG was very low, about two thirds of what it was during fasting. This chap, like the Italian enterectomy women, was very, very insulin sensitive. Insulin drives fat storage as well as hypoglycaemia.
He kept the weight off for at least 5 years. Two points: This chap was a psychological outlier! Second is that 1000kcal/d, if it is Food based, is a LC diet even if it is also a low-everything-else diet too.
Enjoy the winter festivities!
Peter
