ReTUNE (ie remission via weight loss for normal weight T2D's) final results.

[Eddy Edson]

Presented at EASD conference in Stockholm yesterday.

Confirming the prelim results from earlier this year: normal-weight T2D's achieve weight-loss driven remission at about the same rate as overweight/obese T2D's. (But the avg amount of weight loss required is lower: ~8% of body weight vs ~15%.)

Slides:

https://twitter.com/x/status/1573248577777942529

DUK story: https://www.diabetes.org.uk/about_us/news/our-research-easd

After 12 months, the findings showed that:
Participants’ BMI averaged 22.4 kg/m² at the end of the study (reduced from an average of 24.8 kg/m²).
About three quarters (70%) of participants went into remission from type 2 diabetes during the study, with 50% of these going into remission after the first weight loss cycle.
People needed to lose on average 8% of their body weight to go into remission.
In the 14 out of 20 people who went into remission, their average HbA1c fell from 53mmol/mol at the start of the study to 45mmol/mol. Their blood pressure dropped despite taking less medication to treat this.
The participants’ liver and pancreas fat levels were higher than expected at the start of the trial but then decreased to normal levels after weight loss.


Chris Askew, Chief Executive of Diabetes UK, said:

“Building on the pioneering DiRECT trial, this game-changing study from Professor Taylor and his team advances our understanding of why type 2 diabetes develops, and what can be done to treat it.

“Our ambition is for as many people as possible to have the chance to put their type 2 diabetes into remission and live well for longer. The findings of the ReTUNE study potentially take us a significant step closer to achieving this goal by showing that remission isn’t only possible for people of certain body weights.

“It is our hope that ReTUNE – as DiRECT did before it – will inform the development of services and support so that many more people with type 2 diabetes will have the possibility of remission open to them."

 

[Deleted member 21371]

That seems to be amazing result.

 

[Chris Hobson]

I've just had Roy Taylor's book Life Without Diabetes given to me as a birthday present. I haven't had time to read it yet though. I'm currently doing reasonably well and am off medication. My weight was stable at about 75 kilos until I got to around 50 years old. At that point I ballooned slightly and went up to around 88 kilos. After diagnosis in 2013 at the age of 54, I started exercising more and got back down to 75 kilos. My current weight is 69 kilos, another review is approaching so we will see if that has helped.

 

[Eddy Edson]

Some more details from the presentation: https://www.medwirenews.com/diabetes/retune-personal-fat-threshold-reverse-type-2-diabetes/23530666

 

[Rabidlamb]

In the 14 out of 20 people who went into remission, their average HbA1c fell from 53mmol/mol at the start of the study to 45mmol/mol.

So they went from low diagnostic diabetic to pre-diabetic.
To remain in that state they need to maintain calorie restriction for the rest of their lives.
I would like to see the risk hazard ratio of complications of 53 vs 45, especially for someone in their 70s.
Nice to see his PFT theory confirmed though, The TOFIs are really unlucky, their genetic disfunction is to deposit fat on the organs long before subcutaneous stores are tapped.

 

[Eddy Edson]

To remain in that state they need to maintain calorie restriction for the rest of their lives.
I would like to see the risk hazard ratio of complications of 53 vs 45, especially for someone in their 70s.
Nice to see his PFT theory confirmed though, The TOFIs are really unlucky, their genetic disfunction is to deposit fat on the organs long before subcutaneous stores are tapped.

"To remain in that state they need to maintain calorie restriction for the rest of their lives." Calorie balance, not "restriction". Like everybody else, if they eat more than they burn, they'll put on weight. In their case, this will result in going over the T2D line at a lower weight than many others would. But there's nothing fundamentally different. (I assume that you don't actually think they have to restrict to 800 kcal/day forever?)

Anyway, I'm more-or-less one of "them". Starting at a BMI of 25 point something I reversed my T2D by losing ~10kg. But just in the "classical" way of setting a moderate calorie deficit for a few months, grinding off half a kilo or so per week. (Then I lost another ~10 kg for a safety margin, because I could & because it's fun being skinny.)

For the last 4 years I've been normoglycemic, eat lots & lots of carbs and these days about 2,600 - 2,700 kcal/day, like anybody else maintaining body weight at my age, weight, activity level & sex. It's just normal, not a special thing.

The improvements in this study are pretty modest, I agree, but the endpoint of the study was just "remission", in the now-accepted sense of below 48 / 6.5% for 3 months off meds. It wasn't designed to examine dose-response relationships or how low you could drive HbA1c with further weight loss. I bet that they would have found further HbA1c reduction with more weight loss, if that had been part of the design.

Anyway, I got my HbA1c down to 40 with the initial ~10kg weight loss and then mid 30's after an additional ~5kg, so I'm pretty comfortable with the dose-response story in my case.

 

[Deleted member 21371]

So they went from low diagnostic diabetic to pre-diabetic.
To remain in that state they need to maintain calorie restriction for the rest of their lives.
I would like to see the risk hazard ratio of complications of 53 vs 45, especially for someone in their 70s.
Nice to see his PFT theory confirmed though, The TOFIs are really unlucky, their genetic disfunction is to deposit fat on the organs long before subcutaneous stores are tapped.

Well, if you can show me a diet where I can swim in unlimited food all day, and not gain weight, you'd be making millions.

 

[Rabidlamb]

Anyway, I'm more-or-less one of "them". Starting at a BMI of 25 point something I reversed my T2D by losing ~10kg. But just in the "classical" way of setting a moderate calorie deficit for a few months, grinding off half a kilo or so per week. (Then I lost another ~10 kg for a safety margin, because I could & because it's fun being skinny.)

This is where I see us T2 fattys as far luckier.
I went from a BMI of 42 @ 19.5st to a BMI of 30 @ 14st, so from mobidly obese to obese/overweight.
That was more than enough to reverse my T2, eat a moderate carb diet nowadays.
I like to know I have future wiggle room too should I need it in the future.
TOFIs that reverse are a tough bunch.

 

[Deleted member 21371]

This is where I see us T2 fattys as far luckier.
I went from a BMI of 42 @ 19.5st to a BMI of 30 @ 14st, so from mobidly obese to obese/overweight.
That was more than enough to reverse my T2, eat a moderate carb diet nowadays.
I like to know I have future wiggle room too should I need it in the future.
TOFIs that reverse are a tough bunch.

I don't know.
I was morbidly obese, I dieted to lose weight.
I lost enough to be a TOFI by a good margin, but I still had to mop up the internal fat with the Newcastle diet.
I suspect for some, like me, it's the last fat to go, but possibly the first to be put on for some.

 

[Eddy Edson]

This is where I see us T2 fattys as far luckier.
I went from a BMI of 42 @ 19.5st to a BMI of 30 @ 14st, so from mobidly obese to obese/overweight.
That was more than enough to reverse my T2, eat a moderate carb diet nowadays.
I like to know I have future wiggle room too should I need it in the future.
TOFIs that reverse are a tough bunch.

Losing 5.5 st seems tough enough!

 

[Rabidlamb]

Losing 5.5 st seems tough enough!

Not recommended, I did it far too rapidly, losing >10lbs some weeks.
Body went into shutdown mode, huge anxiety, insomnia, frozen cold.
Took months to reboot, don't do what I did, slow & steady only way to go.

 

[harbottle]

Not recommended, I did it far too rapidly, losing >10lbs some weeks.
Body went into shutdown mode, huge anxiety, insomnia, frozen cold.
Took months to reboot, don't do what I did, slow & steady only way to go.

I lost weight rapidly as well and it was... an interesting time. I did get very cold, but found sleeping improved. I suspect a lot of people who take Metformin and change diet blame these changes on the drug when it might be the change of diet.

Although recently I have started to gain weight without a change in diet.

 

[Deleted member 21371]

Not recommended, I did it far too rapidly, losing >10lbs some weeks.
Body went into shutdown mode, huge anxiety, insomnia, frozen cold.
Took months to reboot, don't do what I did, slow & steady only way to go.

Does that work out at around two months?

 

[Rabidlamb]

Does that work out at around two months?

Weight loss was weird, for me anyway.
So, the first week you'll lose 9lbs, then the body goes into starvation protection mode so the following week you'll only be down a pound or 2 despite eating less than 1,000 cals a day.
Then the levy breaks again & you'll be down half a stone the following week.
To lose 73lbs took me about 3 months

 

[Deleted member 21371]

Weight loss was weird, for me anyway.
So, the first week you'll lose 9lbs, then the body goes into starvation protection mode so the following week you'll only be down a pound or 2 despite eating less than 1,000 cals a day.
Then the levy breaks again & you'll be down half a stone the following week.
To lose 73lbs took me about 3 months

Quite normal, and not "starvation mode"
The first weight loss is from easily convertible stores, mostly glucose stored in water.
Lots of trips to the loo as well, as you're burning the glucose, and disposing of the water.
Hence the high weight loss.
Then you move onto fat burning, fat is twice as calorific as carbs and proteins, and no water storage, so yes, probably a quarter of the original weight loss to free the same calories required.
It'll step up again, as it takes more energy to convert the fat longterm.

 

[Eddy Edson]

Quite normal, and not "starvation mode"
The first weight loss is from easily convertible stores, mostly glucose stored in water.
Lots of trips to the loo as well, as you're burning the glucose, and disposing of the water.
Hence the high weight loss.
Then you move onto fat burning, fat is twice as calorific as carbs and proteins, and no water storage, so yes, probably a quarter of the original weight loss to free the same calories required.
It'll step up again, as it takes more energy to convert the fat longterm.

This inspired me to write up some notes/paraphrases on Kevin Hall's reintepration last year of his classic "Biggest Loser" study, as he discusses in this thread:

https://twitter.com/x/status/1463548802103590914

Biggest Loser involved savage calorie reductions (~65%) and a huge amount of exercise in a tightly supervised environment, resulting in lots of weight loss:



Briefly: "metabolic adapation"/"adaptive thermogenesis"/"starvation mode" is reduction in RMR (resting metabolic rate) with calorie restriction beyond what would be expected from changes to body weight and composition. It's a thing but not as big a thing or as long-lasting as lots of the Internet etc commentary suggests, in the absence of exercise, and not enough to cause "plateaus", usually. The Biggest Loser contestants had lots of metabolic adaption but on average they lost weight steadily, as you can see from the chart above. Hall & others would suggest that "plateaus" are more likely due to lapses in diet adherence.

The chart below sketches energy changes over the same timeframe. RMR decreased due to a combination of changes to body weight and composition, and metabolic adaption. The fairly sharp drop right at the beginning of the contest was mainly the metabolic adaption piece; it's not very significant compared to the changes to energy intake and exercise.


Up until recently, the model Hall & others developed based on studies and mechanisms has the kind of behaviour seen in this chart: When energy intake is changed you get a short term metabolic adaption, which stabilises over a couple of weeks resulting in an avg RMR (resting metabolic rate) change of 0.14 X (Change in daily kcal) beyond what you'd expect from changes to body weight and composition. The "0.14" factor is an empirical average derived from studies.

So if you reduce intake by say 1,000 kcal/day then on average you'll take a "metabolic hit" of 140 kcal/day to your base energy expenditure beyond any changes due to weight loss etc.

This is part of the overall model Hall's group developed for the NIDDK's body weight planning tool: https://www.niddk.nih.gov/bwp You can nerd out with the underlying maths here: https://www.niddk.nih.gov/-/media/Files/BWP/Hall_Lancet_Web_Appendix.pdf

If you increase energy intake again, this metabolic adaption will reduce or disappear. Because in the real world energy intake does usually revert to something close to baseline after about 6 months or so, you expect the metabolic adaption to disappear or become small on this kind of timeframe. And in fact, most studies and trials show just that.

But with Hall's reinterpretation, the model now changes to also recognise the impact of exercise on metabolic adaption, adopting the constrained energy expenditure model of Herman Pontzner et al as described in the twitter thread above.

Briefly: the hunter gatherers studied by Pontzner et al are much more active than sedentary Western office workers but burn the same amount of energy overall, when adjusted for body size etc. The key insight is that with prolonged regular exercise, RMR reduces. There's an obvious evolutionary rationale for why body systems might have developed in this way. Reduction in chronic inflammation, sex drive, other things have been proposed as mechanisms.

With these insights, Hall revisits the classic "Biggest Loser" studies. Back in the day, a surprising finding at year 6 follow-up was that out-sized reductions in RMR persisted despite subjects reverting to pre-contest energy intake levels and regaining two-thirds of the weight they lost. So there was a large and persistent metabolic adaption, against expectations and in contrast to most other weight-loss studies.

(Various grifters, click-bait merchants and wellness gurus jumped on this to make bogus claims about weight loss "destroying" the metabolism.)

"Biggest Loser" involved a very large amount of physical exercise and contestants on average persisted with elevated exercise levels through the 6 year follow-up period. This distinguishes it from most other programs and studies. With the Pontzner model in hand, Hall now proposes that this is the reason for the large & persistent metabolic adapation: it's the exercise, not metabolism-destroying calorie restriction!

Indeed, there was a good correlation between exercise changes and RMR reduction. And contestants who stopped exercising a lot would likely see the metabolic adaption disappear and their RMR changes from baseline reduce to match their changes in body weight & composition.

However, they would also likely put on weight. This is the other key insight from the reinterpretation. Despite the metabolic adaption increases with exercise, weight regain was less for the more-exercise group. The reduction in RMR was outweighed by the increase in energy expenditure from exercise. In fact, at year 6 both the more- and less-exercise groups ate about the same amount as they did before the contest started. You might expect the more-exercise group to eat more, but something about exercise appears to weaken the nexus between energy expenditure and appetite.

I can believe it. I burn 500+ kcal/day from walking. Walking gives me a real buzz and I'm pretty sure that buzz means I have less food craving. On the other hand, my energy expenditure seems to be a bit less than the estimate from pre-constrained energy models, suggesting a degree of persistent metabolic adaption. Also, my CRP and other inflammation markers are apparently too low to measure, which also fits. No comment on sex drive!

 

[Eddy Edson]

The peer-reviewd ReTUNE paper finally published: https://portlandpress.com/clinsci/a...Aetiology-of-Type-2-diabetes-in-people-with-a