Monday, April 25, 2011

Diabetic nephropathy and the lost Swede

Chris over at Conditioning Research forwarded me the link to the PLoS paper demonstrating partial reversal of diabetic nephropathy in a couple of mouse models. This isn't exactly a world shattering finding as anyone with diabetes who is not eating a mildly ketogenic diet probably has shares in dialysis machines or is being grossly mismanaged.

Anyway, the first thing to do with a paper like this is to check whether the authors cited Nielsen's 2006 case report of a human being having their diabetic renal failure halted and partially reversed. I mean, this might be relevant...

They didn't.

The Swedish group simply fixed a patient without a mouse model in sight. They got ignored for their temerity. Shocking to fix a human without the death of a single leptin deficient mouse, but there you go. And it's not so hard to do either............


As a complete aside:

It turned out to be interesting to go back and see where the mouse folks were coming from. They cited this paper.


Here is part of figure 6, the line to follow is the open triangles.





Up to day 84 a high fat diet was fed. As happens so often, the high fat diet is 31.7% sucrose/maltodextrin by weight and (gasp) 20.7% lard.

From day 84 onwards these lazy, greedy porkers of mice were switched to a diet which was 47.5% lard and, utter horror, 19.95% butter. Of course this is not really a high fat diet as it has no sucrose or maltodextrin...

Look at the weight drop to below (ns) that of the mice fed crapinabag throughout........

Obviously this must be the satiating effect of protein, so often cited by idiots as the reason for weight loss of LC diets. Except it's not, the ketogenic mice had the lowest protein intake, 9.5% by weight cf 24% in the crapinabag and HF diets. That is very low in protein.

Here are the actual diets in Table 1:



A far more plausible explanation is that ketosis induces dissatisfaction in these mice concerning their body image due to their obese state so they then started to cut calories and go to the gym every night. Duh.

Now please don't make me put up the fasting insulin levels. Aw, okay, you twisted my arm.

Edit: I noticed that these are the FED insulin levels, we don't get fasting levels in the paper...



No comment.

Peter

34 comments:

Dr. N said...

And here is a paper (http://ncp.sagepub.com/content/22/1/16.short) on reversal of chronic renal failure with gastric bypass.

Many of these patients were already on dialysis. 5 of 41 had stablization or reversal of renal failure (not just your lightweight renal insufficiency with proteinuria).

Can't see behind the payment firewall but nutirtional details on the reversal patients could be very interesting too.

Stuart said...

The following just left me rolling on the floor:

Dr Iain Frame, director of research at Diabetes UK, said: "This research was carried out in mice so it is difficult to see how these results would translate into any real benefits for people with diabetes at this stage.

"It is too simple to say that kidney failure could be prevented by diet alone and it is also questionable whether the diet used in this model would be sustainable for humans, even in the short term."

Much better to end up on dialysis than to eat a ketogenic diet. We wouldn't want to inconvenience the doctor by requiring him to change how he thinks about the world.

john said...

Is the low protein intake perhaps the reason of higher liver trigs and higher proportional fat mass? It doesn't really follow along with low leptin and insulin.

Peter said...

Hi John,

http://www.ncbi.nlm.nih.gov/pubmed/20807839

is probably the next post

Peter

Peter said...

Dr N, the gastric bypass survivors tend to eat very restricted carbohydrate diets and frequently normalise glycaemia and insulin. There does seem to be a bit more to it than just carbs but these clearly are markedly restricted post surgery.

Stuart, well we can guess which direction he will direct research in to then... The dialysis ward I guess! Blood on his hands.

Peter

kulimai said...

Could this be relevant also for cystic kidneys (insulin, IGF-1 mTor, chloride channels...)?

annefromorry said...

I wish I'd known about a ketogenic diet when I had kidney failure. It's a million times better than dialysis which used to destroy me for the rest of the day. A ketogenic diet is also great for counteracting the obesogenic effects of immunosuppressant drugs post transplant.

majkinetor said...

Isn't 0.76% CHO on KD diet too low, its basically not possible unless you are on some sort of powder ?

Wizzu said...

Dear Peter, you had me rolling on the floor as usual... actually, efven a little more than the usual, with the following:

Quote:
A far more plausible explanation is that ketosis induces dissatisfaction in these mice concerning their body image due to their obese state so they then started to cut calories and go to the gym every night. Duh.

Thanks for the insight AND good spirit!

Wizzu

Brad Reid said...

Peter,

http://www.sciencedaily.com/releases/2011/04/110425135643.htm?

Off topic here a bit, but posting for you and others to take a look and comment on what is at work here. Brad

Paul Jaminet said...

Peter, great post as usual.

Looking forward to your next one - should have comedic potential. I've only looked at the abstract but liked this line: "Food intake was 56% (P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase (P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations."

If food intake is lower with same calorie intake, doesn't that mean the food has more calories per gram, ie is fattier? Was it plasma N-acylphosphatidylethanolamine or the scientists who caused these mice to eat a ketogenic diet?

John Speno said...

I recognized that those graphs! I saw one of the authors (Maratos-Flier E.) presenting about those mice and the FGF21 gene a few weeks ago.

She started the presentation by lightly bashing low-fat, high carb diets. Said she was a non-conformist. I was pleased.

Hilary said...

Hi Peter,
Thanks for this excellent post! Here's a better link to the Nielsen paper, as it gives the complete text for free:
http://www.nutritionandmetabolism.com/content/3/1/23

Hilary said...

Looks like it might have truncated the URL, so here it is again, shorter:
http://bit.ly/hmCjiX

-Hilary McClure

David Isaak said...

As an economist friend is fond of saying, That may be fine in practice--but can't you see it doesn't work out in theory?

First we have people telling us that low-carb diets don't cause bone loss. Now we have people claimimg low-carb diets don't cause kidney damage.

There's a simple solution to these seeming contradictions: ignore the experimental results.

Now excuse me--I have a dish of phlogiston on the stove.

Peter said...

Hi kulimai, I have wondered whether PCKD in cats might reflect chronic carbohydrate ingestion, it is certainly an interesting idea but I've never chased to look it up.

Annefromorry, yes, on pred you are insulin resistant, the only solution is not to use insulin for your caloric supply...

majkinetor, you can't really get rodents in to ketosis without extreme diets. If we extrapolate from epilepsy comparisons then Atkins induction or OGWL would be as effective and much more palatable and safe than a traditional extreme ketogenic diet.

You're welcome Wizzu

Brad, metabolic syndrome with obesity produces elevated oestrogen levels, so chemically castrates blokes who go there (40 over 40 etc...). So you can hypothesise, as others have done, that anything which reduces oestrogenisation might worsen high grade prostate cancers where as more effective castration with trans fats ameliorates them... Just speculation as the study is just observational.

Paul, I'll see how it shells out...

Hi John, nice to see non conformists can still get funding! It's a rather nice paper for a rodentophile like myself.

Thanks Hillary

David, "There's a simple solution to these seeming contradictions: ignore the experimental results" That's certainly the way we go today...

Peter

Lucas Tafur said...

"Obviously this must be the satiating effect of protein, so often cited by idiots as the reason for weight loss of LC diets."

This statement made my day. Thank you!

blogblog said...

A far more plausible explanation is that ketosis induces dissatisfaction in these mice concerning their body image due to their obese state so they then started to cut calories and go to the gym every night. Duh.

Mice are natural exercise fanatics. They will happily run for a couple of hours every night if they have suitable facilities such as a treadmill or a very large cage with ramps etc.

Mice have a staggering aerobic exercise capacity - 2-3x as high as any human. They can easily run for up to two hours at 20m/min (1.2km/h) pace after a few months training. This roughly equivalent to a human running 100km in two hours.

Mice and rats - unlike humans- must exercise vigorously to stay healthy.

john said...

blogblog,

...especially these mice, and the extended longevity is a nice bonus:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491496/?tool=pmcentrez

Stan (Heretic) said...

Charles Mobb, one of the study author is talking about it on Jimmy Moore's:

Dr. Charles Mobbs: Diabetic Kidney Damage Can Actually Be Reversed...

Well worth listening, (esp. the second part)

Indcidentally he appears not to have heard of the Nielsen's 2006 study (I also forgot about it when writing my recent post), but he does mention Eric Westman and others. Interestingly he talks that they have had problems in getting it published because peer reviewers demanding explanations why does it work, not just describing how does it work. That's why they put a lot of discussion and tests on activation of certain cellullar repair mechanisms by ketone bodies directly regardless of the glucose and insulin issue. They have done it specifically to get published but I personally found that part of their paper the most valuable!

Stan

CarbSane said...

Perhaps for the edification of us idjuts in the audience you can explain how the mice lost weight, reversed diabetic nephropathy and even partially reversed the damaged morphology while more than tripling the neolithic agent of disease content of their diet.

antispirit said...

Blogblog- Are you sure that it's not "healthy mice exercise vigorously"

Peter said...

@CarbSane,

No. The edification of idjuts is, in general, unrewarding.

Kurt G. Harris MD said...

Nice post , Peter

Your blog comments and Stephan's have been permanently infected by the same virus, I see.

What a shame.

Poisonguy said...

Maybe someone can explain how the ketogenic rat chow could have tripled the amount of neolithic agents of disease ingested in the diabetic neuropathy rat study when the control chow was composed of greater than 75% neolithic agents of disease (the AIN-93M control diet is—46.7 cornstarch, 15.5 dextrin, 10 granular sugar, 4 soy oil). Yesterday, I had to explain to my 6 year-old that proteins were not neolithic agents of disease. Today, I’m teaching her simple math.

FYI, the KD used is Bio-Serv Inc. F3666 chow, which was slightly modified by the authors is 0.76% carbohydrates, 8% protein, 79% fat, 12% water, fiber, and ash. F3666 is a ketogenic chow composed of lard, butter fat, dextrose, casein, fiber, corn oil, mineral mix, and a vitamin mix. F3666 is rich in saturated fats. Greater than 29% of the F3666 chow is composed of saturated fats by weight: 2.4% myristic acid (C14:0), 18.9% palmitic acid (C16:0), and 8.4% stearic (C18:0).

CarbSane said...

@Poisonguy: I was talking about the veggie oil O6 PUFA. Peter frequently points to the fatty acid contents of various chows to debunk certain studies. In many cases I think he presents a strong case the types of fat being as important if not more than the amount of fat. But this study wouldn't support such a contention as the veggie oil content was more than tripled.

Poisonguy said...

I think you are mixing things up. I've noticed this happens quite regularly when you try to juggle more than one variable at a time. Kurt Harris is the NAD guy (no offence meant) and he specifically has sugars, and likely cornstarch, as NADs. Peter is another guy--the owner of this blog, so why you are addressing him about NADs, especially when he was talking about the "satiating" effect of proteins, is beyond me and my six year old daughter (please don't try to explain).

But why would you give a rat's ass about fatty acid compositions of various diets as far as weight loss is concerned? Isn't a calorie a calorie?

CarbSane said...

Yes, I know Kurt is the NAD guy. But Peter's Axen posts, for example, finger fat type. My general feeling is that much of the bad associated with PUFA is due to other things about the fatty acids such as processing/heating, and not the FA's themselves. I recently took a look at Mark Sisson's PUFA intake if you're interested.

~ virus signing off LOL

gunther gatherer said...

Hi Peter, given the impressive results of the KD, wouldn't it be better for you to be running on ketones instead of subbing in glucose powder, dark chocolate or potatoes?

Do you have any evidence that KD would actually be bad for us long term?

To experiment, I got rid of all the sugar, went zero carb just to see what it feels like, and found hunger went even lower than on OD. Energy level was the same (pretty high), sleep good as ever, concentration great, muscular output the same (mountain climbing), etc. And I lost ten more pounds (going below my goal weight on OD for the last 2 years). Don't miss the sugar at all, actually.

Lucas Tafur said...

@gunther:

I think most ODers are in ketosis despite their 50-60g carbohydrate intake. Research has shown that this is somewhat the threshold for being ketotic, but there are many factors to take account (specially if you exercise). You can eat an only protein diet and be in ketosis (we are not rats!). Your experience might have been due to increased levels of ketones, as you have been using them for a while now.

Peter said...

Hi Poisonguy and others so inclined,

Could I politely ask that you do not engage CarbSane on my blog. As I say, the edification of idjuts is unrewarding and both you and I can see the gaping holes in this current dose of twaddle which she has posted. But please do not engage.

Thanks

Peter

Peter said...

Gunther and Lucas,

I think we just don't know. We have to work with limited information from appallingly poorly conducted studies, certainly in humans. It is worth pointing out that these mice are in very extreme states of physiology and, as far as I know, no one has looked at murine duration of life under these conditions. You easily get in to discussions of the role of insulin in longevity. This is interesting but I'm not sure you could start to understand dietary effects to the level where you might bet your life....

Peter

Chris Masterjohn said...

I also blogged about this study:

When Fat Burns in the Flame of Lean Muscle Mass

http://blog.cholesterol-and-health.com/2011/05/when-fat-burns-in-flame-of-lean-muscle.html

Not sure I would want to emulate these mice.

Chris

Peter said...

Hi Chris,

I would concur. Fortunately it's a great deal easier to generate a few ketone bodies in humans... I'd guess that our big brain demands glucose sparing ketones at much higher carbohydrate and protein intakes than a mouse brain does.

Peter