Modelling energy intake: Canagliflozin

It is quite possible to make a very reasonable estimate of how many calories a given person has consumed over the previous few weeks by estimating their total energy expenditure (TEE) using doubly labelled water (DLW), estimating the calories supplied from fat in adipose stores using the changes measured by DEXA scanning and applying a little arithmetic:

TEE (by DLW) - Fat mass change (by DEXA) = Food derived calories

Nice and simple. And very, very expensive.

Quite a few years ago Kevin Hall's group had the idea that you might be able to reverse engineer the intake of food calories simply from the change in weight over time using a mathematical model. They validated this against a two year conventional diet study where weight, TEE by DLW and fat mass changes by DEXA were repeatedly measured. They produced this paper:

Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake

Their model is pretty good within certain limits. You could trip it flat on its face pretty easily but that's not today's post. Just assume it works in the above study and also in this one:

How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake

The second study piggybacked on a diabetes study using canagliflozin, a sodium glucose co-transporter inhibitor which increases urinary glucose excretion. Canagliflozin produces the loss of around 90g/d of glucose, ie around 400kcal/d. This loss is insensible, other than via counting the number of trips to the bathroom. There was no specification within the study protocol to lose weight or to restrict calories.

Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study

The interesting questions are whether this silent caloric loss produces weight reduction, what does it do to caloric intake and what mechanisms might be at work.

Here are the weight changes:

So. Obviously losing 400kcal/day does produce weight loss. Or is that genuinely obvious? Surely, if the hypothalamus wants to "see" a certain number of calories to run metabolism, shouldn't it immediately increase calories eaten to counter that 400kcal deficit? Yes, it should. Immediately. Except...

Here is what happened to the energy intake. The solid black line is Hall's model which does not include the starting point at time zero with weight change zero. I've added the red curve to include this and roughed in the rest of the data points as well as a curve in powerpoint can manage:

It's quite clear from the data points that there was an initial drop in total energy intake to a nadir, somewhere within the first three weeks. DLW is an averaging technique so the location of the nadir is an unknown but it must have happened, to explain the data points generated where week three is below time zero.  The effect is more marked in the placebo group and probably represents simply being in the trial and tidying up, in both groups, the worst of the normally execrable diabetic diet prior to starting the study.

The effect is blunted in the canagliflozin group, presumably because of those 400kcal/d down from day one and their hypothalamus will have noticed this and have kicked their cortex in to doing something about it (hunger). By 15 weeks the extra calorie intake estimate (around +350kcal/d) is getting pretty close to the urinary calorie loss estimate (around -400kcal/d). 

But for the first 15 weeks calorie intake was estimated to be well below urinary calorie loss. Food was ad libitum. Why any weight loss?

That's interesting.

Also, despite increasing food calories to match urinary losses, weight remained stable at over three kilograms below baseline, with no suggestion of weight regain at the end of a year.

That's interesting too.

Hall goes on to treat the changes in weight as an engineering control system, a bit like a black box, without any attempt at integrating any basic physiology. A quick search of the text shows no mention of insulin in the whole paper. Not surprising, given the stance taken by Hall over the CIM of obesity.

But even the most basic, strawman-facilitating version of the CIM of obesity has no problem explaining the results in some depth. It takes about 30 seconds on PubMed to ascertain what canagliflozin does to the insulin requirement of people with DMT2.

It drops the requirement.

Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial

For patients still using their own pancreas for insulin this seems very likely to simply be reflected in a spontaneous fall in plasma insulin, triggered by the loss of 90g/d of glucose which exits through the bladder rather than requiring insulin to stuff it in to storage within the body.

If we assume insulin drops by a fixed amount in proportion to 90g less of glucose, and stays at this reduced level for as long the canagliflozin is given, there will be an acute rise in lipolysis which will supply adipocyte derived calories to partially make up for the urinary loss.

As the hypothalamus monitors energy status it will see 90g/d of glucose as absent but being replaced by, initially, roughly a kilo of fat from adipocytes over three weeks. More arithmetic:

400kcal glucose x 21 days = 8400kcal deficit from glycosuria.

Weight loss of 1kg over three weeks = 9000kcal of fat from adipocytes.

I would suggest that fat loss comes as a direct response to lowered insulin levels and will easily at least partially replace the glucose loss, certainly initially. The fat loss can be described as "calories-in" without actually eating them. So people with an acutely lowered insulin level eat less than you would expect.

Let's look at this the correct way round. An all-glucose caloric deficit of 400kcal/d was acutely established which directly resulted in rapid drop in plasma insulin levels. Lipolysis was acutely increased which largely offset the glycosuric calorie deficit. Because over several weeks lipolysis gradually slowed to an appropriate level determined by the the new insulin levels, food calories had to increase in proportion, to maintain an adequate energy flux to keep the hypothalamus happy. Eventually extra food-in will equal urinary glucose-out giving stable weight. But with lower insulin levels this will occur at a lower total fat mass.

The weight loss/calorie intake deficit were both caused, directly, by a fall in insulin levels. Utterly simplistic CIM.

Kevin Hall is a great source of data. Of insight?

Not so much.

Peter