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Comment by diminoten | Hacker News Reader

From that article:

> The dose of sweetener was the equivalent to the maximum acceptable daily intake in humans, as set by the FDA.

Now I realize that I, random commenter from the Internet, am unlikely to find a fatal flaw in an experiment designed and carried out by folks who do this professionally, but can someone explain to me why it's okay to give mice a human-amount of sweetener, and not a mice-amount?

It just seems to me that our larger bodies are probably better capable of handling... well, most everything, and to start dosing mice with human levels of sweetener is actually going to cause a much worse reaction than if humans were to consume that amount.

Edit: Also, it looks like the effects are reversible by "wiping" gut bacteria via antibiotics. If mice can survive the process of "wiping" gut bacteria, can humans? Is there a cure for this pre-diabetic state?

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can someone explain to me why it's okay to give mice a human-amount of sweetener, and not a mice-amount?

This means that the mice got a dose per unit of body weight like what humans would get if they ate that FDA-defined maximum. That's what equivalent doses are taken to mean in animal models of human nutrition or medicine. When there is known to be a different bioavailability or digestive response in animals from humans, then the dose is adjusted with that in mind before the experiment begins.

So, no, the tiny bodies of mice were not subjected to the large servings that much bigger human beings eat. They got a dose adjusted for the body weight of mice.

Okay that makes a ton of sense, and I figured it was my own lack of understanding here. Thanks. :D

it's more than just a "per kg" dosing as well. Rats/mice have a very different level of metabolism than humans do just because of scale.

Basically there's a fudge factor of 0.75. Of course, the following article goes on to explain that it's actually drug mechanism dependent as well. Very complicated stuff!

"The value of the exponent for whole body metabolic rate was originally calculated by Max Kleiber in 1932 to be 0.74 (Kleiber, 1932). A few years later, Brody et al. published their famous mouse to elephant curve and calculated the exponent to be 0.734 (Brody, 1945). A value of 0.75 is now accepted because it is easier to use, and the difference from 0.734 is considered to be statistically negligible (Schmidt-Nielsen, 1984). However, it should be noted that exponents in the range 0.6–0.8 have been reported for metabolic rate (Agutter and Wheatley, 2004). A value of 0.75 means that the whole body metabolic rate increases as body weight increases, but to a lesser extent than would be expected of a simple proportional relationship. It follows on from this that the specific metabolic rate (the metabolic rate per unit mass) decreases as animals get larger (the exponent is −0.25); the metabolic rate of 1 g blue whale tissue is 1000 times less than that of 1 g shrew tissue (Kirkwood, 1983)."

from:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737649/

The paper contains some preliminary human data as well. From the New Scientist writeup:

But can the results in mice be extrapolated to humans? To find out, the team examined data from 381 people. They found an association between glucose intolerance and general sweetener use.

and:

To explore this, the team asked seven healthy people who don't normally consume sweeteners to eat the FDA's maximum daily allowance of saccharin. ... By day five, four of the seven people had a significant decrease in their glucose tolerance, while three saw no change. Sequencing showed that those who responded to the sweetener started out with different gut bacteria to those who didn't respond. What's more, the gut bacteria of the four responders changed significantly after consuming sweeteners, while the non-responders' barely changed.

Doesn't "equivalent to" in this case mean "the mice equivalent to the maximum accetptable in humans"?

It does.

I'm no experimentalist, but my naive assumption (gut feeling, heh) would be that the way to do this is to scale by body mass.

That's a really charming synonym for 'scientist'

The theorists disagree with you, and I'm sure they have a long paper with lots of equations explaining why.

(it's a joke)

What, "experimentalist"? That's not a synonym for "scientist", it's a subset.

At least in physics, the main categories are "experimentalist" and "theorist". You'll sometimes find intermediate categories like "phenomenologist" (people who apply basic theory to make detailed predictions for experimental measurements) or "computational(-ist?)" (people who measure experimental-style results from simulations of basic theory).

I think we should add a third category, 'modeller', as in someone who runs experiments in silica. It's not really an experiment, and it's not really just theory.

Assuming I understand you, that's what I was getting at with "computational" scientists as a separate or intermediate category.

Not quite. Scientists also come in the Theoretician variety.

Almost, you scale by their metabolic weight. It's about 7 times higher for mice than for humans.

I'm not a scientist (heh) so the best explanation a quick google search gave was an article on CLA from the jn - journal of nutrition:

"The relationship between basal metabolic rate or energy expenditure and body weight in different size mammals is described by the function Y = aX0.75, where Y is basal metabolic rate (kJ/d), X is body weight (kg) and a is basal metabolic rate per kg0.75 per day, which is ∼300 kJ/ (kg0.75 · d). Thus, the basal metabolic rate in different size species is proportional to the body weight raised to the 0.75 power, the so called metabolic weight."

http://jn.nutrition.org/content/131/7/2067.full

From the paper:

"To examine the effects of pure saccharin on glucose intolerance, we followed a cohort of 10-week-old C57Bl/6 mice fed on HFD and supplemented with 0.1 mg ml 21 of pure saccharin added to their drinking water (Extended Data Fig. 1c). This dose corresponds to the FDA acceptable daily intake (ADI) in humans (5 mg per kg (body weight), adjusted to mouse weights, see Methods)."

I read "was the equivalent" to mean "Is the same ratio of grams of sweetner to pounds of mouse-flesh as the maximum ratio set by the FDA," not "is the same numeric amount."

A cure is clearly fairly likely for this particular pre-diabetic state. It does cure the problem, but the exact effects wiping out gut bacteria is not terribly well understood. In fact, this is one of the more interesting areas of research... beyond just the direct applicability to human problems, this provides a very interesting data point about how exactly gut bacteria coexist with us.

Whenever you take antibiotics, you typically 'wipe' gut bacteria. Maybe not to the same degree as in a clinical trial, but you certainly kill a lot -- healthy and unhealthy alike. Which is why several medical practitioners will prescribe/advise you take probiotics alongside the anti-, to promote good health.

There is colon hydrotherapy when the doctors fill your intestines with water. They use it for several reasons including candida elimination. So humans can survive "wiping".

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