Insulin and the Rewards of overfeeding

I've been tempted away from the electron transport chain, origins of life and the suspected paleo prompt nuclear criticality on Mars by a neat paper from Liz.

This is what they did in the study: Over-fed 9 slim, young, fit, healthy blokes for two weeks while limiting their exercise. They establish an energy surplus of about 2000kcal/d. Here we go:




Needless to say, they gained weight. Here we go again, Table 3:



A total of about 1.5kg in two weeks.

Now, all you have to do is to go and ask any cutting edge, state of the art obesity researcher and you can be told that hyperinsulinaemia is a consequence of obesity, not a cause, and that carbohydrates are the worlds greatest slimming aid because insulin is a satiety hormone and, oh, did I fall asleep there?????? Sorry.

Back to the paper. The overfeeding was with utter crap



and produced a rise in fasting insulin from 35pmol/l to 74pmol/l in 3 days.

Personally, I found this quite amusing.

Aside: What would have happened if they had overfed with lard? That's another post, it has been done, rather badly, in Schwartz's lab using dogs. They gained weight. End aside.

By 3 days the fat mass had increase by an average of 100g. My, that is potent fat! Here's the table, day nought vs day three is the place to look:



We could leave it at that and just go away scratching our heads about what goes on in the minds of obesity researchers, but it does get quite interesting. Obviously, as obesity progressed the level of insulin should increase if insulin resistance is caused by fat mass. It doesn't. Fasting insulin falls progressively after the initial spike, and in a fairly linear manner, through days 3, 7 and 14, while weight (and especially visceral fat) actually increases over this time period.

So the idea that fasting insulin rises as a consequence of rising fat mass is, well, you know what it is.

Ah, but if insulin stores fat, why should the level of insulin fall progressively during a sustained hypercaloric eating episode? Surely you must need insulin to store those extra calories? In fact, as insulin levels fall, so does the rate of fat storage. The chaps gained, from Table 3, 1kg of fat mass in the first week and only 0.5kg of fat in the second week... Oh, I guess this must be because the subjects either (a) sneaked off to the gym in the second week or (b) flushed their Snicker Bars down the loo in the second week, without passing them through their gastro intestinal tract first (good idea!) or (c) got bored with Snickers and stopped finding them rewarding. And of course they disconnected their Actiheart monitors at the gym.

Otherwise how you can eat 2000kcal over your energy expenditure, equivalent to nearly 200g of fat gain per day, and gain a kilo of fat in the first week, then continue to eat an excess 2000kcal/d for a second week and only gain half a kilo of fat? Calories in, calories out, you know the rules. Hmmm, in the second week there are 14,000 excess calories-in, 5,000 stored, very interesting.

We all know the obese lie about calories. It seems probable that so too must experimental subjects, in direct proportion to the duration of their over eating! Now we know. Bit of a milestone paper this one.

So what is really going on? What appears to be happening is the insulin system working exactly as it should do. Insulin resistance protects cells from caloric excess, when forced in to the body by a study protocol. Think of it in these terms, with thanks to Dr Guyenet from back when I used to read him. The vast majority of free radicals will be generated at complex I.

The mitochondria say they have too many calories. It's easy for mitochondria to refuse calories from glucose by using insulin resistance, working at the whole cell level. In the presence of massive oral doses of glucose this must elevate insulin to maintain normoglycaemia. The elevated insulin diverts calories from dietary fat in to adipocytes, away from muscle cells. And inhibits lipolysis at the same time, look at the FFA levels in Table 3 on days 7 and 14, waaaay down from pre and post study values. I wonder why they didn't measure FFAs on day 3? So insulin goes up to maintain normal blood sugar levels, overcomes insulin resistance to run cells on a reasonable amount of glucose and shuts down FFA release to counterbalance its action in facilitating the entry of glucose in to cells.

Core to this is (a) there is no hyperglycaemia, insulin still successfully controls glucose flux and (b) insulin inhibits lipolysis. So you store fat. These subjects are both young and healthy. They do not have insulin resistant adipocytes, mitochondrial damage or a fatty liver. The system works as it should.

As time goes by fasting insulin levels fall and weight gain slows. Calorie intake doesn't drop. The only plausible explanation is that the subjects generate more heat and radiate that heat during the second week of the study. Total energy expenditure was estimated using the Actiheart device. You have to wonder how well its computer algorithms coped with the massive overfeeding. It looks like the weakest link in the protocol, assuming the the subjects really ate their muffins and Snicker bars. The device is supposed to be very good but where else did those calories-in go? So let's consider uncoupling proteins. These decrease the inner mitochondrial membrane potential and so decrease free radical production, which decreases insulin resistance. You can afford to allow more glucose in to cells when the UCPs are in place and working. More posts on this to come when we get back to the electron transport chain and free radicals. Free radical generation at complex I is VERY dependent on the inner mitochondrial membrane voltage.

Unfortunately the clamp studies were only performed on days 0 and 14, so all we can say about the insulin sensitivity by clamp (gold standard) is that it was worse on day 14 than day 0. Who knows what the results would have been on days 3 and 7? This protocol is understandable as clamps are a pain to do, but there is no way of ascertaining what glucose disposal per unit insulin was through the body of the study.

So forced weight gain fits quite nicely with the role of insulin in fat storage. It's a nice study because it looked at insulin before fat gain had occurred, and kept on looking too. But how much does forcing people to overeat tell us about "accidental" weight gain in people who have spent good money on some slimming plan to lose weight temporarily with enormous difficulty? Under these circumstances calories are offered to cells at very reasonable levels, mitochondria are already dysfunctional and signal (using free radicals) excess calorie warnings (free radical leakage) and so induce insulin resistance inappropriately. So calories, especially those from dietary fat, get diverted to adipocytes through the subsequent hyperinsulinaemia. And are kept there due to fasting hyperinsulinaemia.

The situations are quite different, I'm not sure that overfeeding healthy subjects tells us too much about accidental obesity, except that they both seem to work through insulin and mitochondria. But this study does tell us a great deal about the idea of reward.

This study is the ultimate affirmation of the Reward Hypothesis of obesity:

If you reward people with enough Danish Krone for over eating, they gain weight.

Peter