Mike Lean & Roy Taylor on improving T2D classification

[Eddy Edson]

Determination of autoantibodies in type 2 diabetes: one simple way to improve classification. Reply by Lean et al to Ludvigsson J [letter] - Diabetologia

link.springer.com

We identified and interviewed six participants [in the DiRECT trial] who had lost >10 kg at 12 months but whose HbA1c level did not improve by at least 10 mmol/mol (1.13%). This is the subgroup that might include individuals with LADA, but none were positive for anti-GAD antibodies.

What we did find, on more detailed interviews with these participants, was that some had concealed rather longer durations of diabetes than the maximum of 6 years required for recruitment: two had a past history of recurrent severe abdominal pains requiring hospitalisation, one was previously diagnosed with pancreatitis, one gave a history of previous alcoholism and one revealed a history of severe childhood malnutrition in Bosnia, during the war with Serbia.

These insights cannot necessarily be translated more widely, but they do suggest that other factors may conspire to damage the pancreas and produce diabetes, which would be labelled as type 2 diabetes. The small numbers included in randomised trials such as DiRECT, which randomised 302 participants, are insufficient to quantify these categories; large observational studies are a better study design.

................

We agree with Ludvigsson [1] that a more clinically relevant classification of diabetes is needed, and suggest that this should include the large category of overweight, or ‘over-fat’-induced diabetes, that is, diabetes that is reversible into a non-diabetic state by substantial weight loss (perhaps, specifically, loss of ectopic fat in vital organs, although no current measurement method for liver or pancreatic fat is reliable enough for use in individuals).

An inexpensive autoantibody test with high sensitivity and specificity for LADA would allow us to advise overweight patients with diabetes who test positive that their benefits from weight loss are less likely to include remission, and also allow the earlier introduction of insulin or potentially, in the future, immunomodulatory therapy.

Applying the technologies developed during the COVID-19 pandemic might decrease the cost and difficulty of autoantibody testing.

For the time being, we do need to be aware of other causes of pancreatic injury and make clear that remission is likely but not guaranteed when recommending major weight loss. It should also be remembered that sustained intentional weight loss will bring many other health benefits.

 

[Eddy Edson]

One thing which has grated on me is the too-common implication or even assertion from Roy Taylor that T2D is always due to exceeding the "personal fat threshold". This latest from Lean & Taylor is a welcome correction!

As an example of what I mean, this is an otherwise useful overview from Taylor last year: https://scholar.google.com.au/scholar?oi=bibs&cluster=158954665592395934&btnI=1&hl=en

Summary
The problem of what causes T2DM is resolved and the simplicity
of the aetiology is clear. If a person exceeds their personal fat
threshold, liver fat will increase with increased fat export to the
rest of the body. That sets in motion all the problems of ectopic
fat and increases cardiovascular risk. Only in those people with
beta cells susceptible to fat excess does T2DM develop, and the
Twin Cycle Hypothesis explains why. There is a simple bottom
line: if a person has T2DM, they have become too heavy for their
own body – nothing to do with the population science concept
of obesity. The solution is at hand.

The lack of nuance seems both simply wrong and not very scientific.

 

[AndBreathe]

Determination of autoantibodies in type 2 diabetes: one simple way to improve classification. Reply by Lean et al to Ludvigsson J [letter] - Diabetologia

link.springer.com

We identified and interviewed six participants [in the DiRECT trial] who had lost >10 kg at 12 months but whose HbA1c level did not improve by at least 10 mmol/mol (1.13%). This is the subgroup that might include individuals with LADA, but none were positive for anti-GAD antibodies.

What we did find, on more detailed interviews with these participants, was that some had concealed rather longer durations of diabetes than the maximum of 6 years required for recruitment: two had a past history of recurrent severe abdominal pains requiring hospitalisation, one was previously diagnosed with pancreatitis, one gave a history of previous alcoholism and one revealed a history of severe childhood malnutrition in Bosnia, during the war with Serbia.

These insights cannot necessarily be translated more widely, but they do suggest that other factors may conspire to damage the pancreas and produce diabetes, which would be labelled as type 2 diabetes. The small numbers included in randomised trials such as DiRECT, which randomised 302 participants, are insufficient to quantify these categories; large observational studies are a better study design.

................

We agree with Ludvigsson [1] that a more clinically relevant classification of diabetes is needed, and suggest that this should include the large category of overweight, or ‘over-fat’-induced diabetes, that is, diabetes that is reversible into a non-diabetic state by substantial weight loss (perhaps, specifically, loss of ectopic fat in vital organs, although no current measurement method for liver or pancreatic fat is reliable enough for use in individuals).

An inexpensive autoantibody test with high sensitivity and specificity for LADA would allow us to advise overweight patients with diabetes who test positive that their benefits from weight loss are less likely to include remission, and also allow the earlier introduction of insulin or potentially, in the future, immunomodulatory therapy.

Applying the technologies developed during the COVID-19 pandemic might decrease the cost and difficulty of autoantibody testing.

For the time being, we do need to be aware of other causes of pancreatic injury and make clear that remission is likely but not guaranteed when recommending major weight loss. It should also be remembered that sustained intentional weight loss will bring many other health benefits.

Without detailing how they know the pancreas is damaged, I wish they had left those words out.

I'd have been interested to know what further information might have been gathered at the 12 month point relating to the ongoing ways of eating, and whether that >10kg loss was at the end of the 12 week programme or at the 12 month point, and what if any differences there were.

 

[Deleted member 21371]

I guess it depends on how you view the findings.
I took what he said at face value, from someone who wasn't selling a snake oil cure.
If I lost weight, some other people who had done the same reversed their diabetes.
No guarantees.
It cost me nothing, I wasn't locked in for life, if it didn't work, what had I lost?

 

[Burylancs]

Oops ... At least one false statement DiRECt ' 'randomised 302 participants'. No it didn't it randomised 50 or 60 Medical Practices and then incompetently analysed the results as though the individual participants had been randomised.

 

[Deleted member 21371]

Oops ... At least one false statement DiRECt ' 'randomised 302 participants'. No it didn't it randomised 50 or 60 Medical Practices and then incompetently analysed the results as though the individual participants had been randomised.

Who cares?
It works, or it doesn't, with no need to buy the book of the diet.
If you want guarantees, there is always someone who can sell you them.

 

[AndBreathe]

Who cares?
It works, or it doesn't, with no need to buy the book of the diet.
If you want guarantees, there is always someone who can sell you them.

Me. That'd be me. I care. I care about reading accurate information.

As you say, in life there are no guarantees, except for 20 years on a Samsung washing machine, but even then I reckon there will be caveats.

 

[Eddy Edson]

Oops ... At least one false statement DiRECt ' 'randomised 302 participants'. No it didn't it randomised 50 or 60 Medical Practices and then incompetently analysed the results as though the individual participants had been randomised.

It'd be great if you had a reference for the "incompetence" thing. I mean a reference to the piece in which the guy made the "incompetent" comment about cluster studies, not just the name of the guy (which I can't remember from when you made this point previously).

 

[Burylancs]

It'd be great if you had a reference for the "incompetence" thing. I mean a reference to the piece in which the guy made the "incompetent" comment about cluster studies, not just the name of the guy (which I can't remember from when you made this point previously).

Yup I'll rake out the exact quotes of Prof David Spieglehalter in his 'The Art of Statistics' and he also wrote an article about cluster studies of which the abstract or article might be illuminating. In the meantine do you accept that Taylor's claim about randomising 302 participants is untrue ? The unwary might get the impression that DiRECT was an RCT - it wasn't.

 

[Deleted member 21371]

Me. That'd be me. I care. I care about reading accurate information.

As you say, in life there are no guarantees, except for 20 years on a Samsung washing machine, but even then I reckon there will be caveats.

Well, if you care, show us the proof it's inaccurate.
Already been here in other threads, it's just a random opinion you are repeating to try to discredit a study that goes against the bias that doesn't seem to sell your books.

As to the Samsung guarantee, a perfect example of selling the punters the words they want to hear to part them from more of their money each time.

 

[Eddy Edson]

Yup I'll rake out the exact quotes of Prof David Spieglehalter in his 'The Art of Statistics' and he also wrote an article about cluster studies of which the abstract or article might be illuminating. In the meantine do you accept that Taylor's claim about randomising 302 participants is untrue ? The unwary might get the impression that DiRECT was an RCT - it wasn't.

Well no, because I don't think cluster RCT's are inherently "incompetent".

Obviously Spiegelhalter's opinion about this is worth a zillion times more than mine, but my guess is that he was talking about cluster trials where correlation effects haven't been properly dealt with. The DiRECT study design addressed this issue.

I also don't really see how you'd do a good RCT for something like this without clustering. You'd have to have people assigned to different treatment regimes delivered by the same people within the same practice. How would you control for leakage?

 

[AndBreathe]

Well, if you care, show us the proof it's inaccurate.
Already been here in other threads, it's just a random opinion you are repeating to try to discredit a study that goes against the bias that doesn't seem to sell your books.

As to the Samsung guarantee, a perfect example of selling the punters the words they want to hear to part them from more of their money each time.

I can't say it is inaccurate any more than you can say it is accurate. It just seems a shame (at least to me) to make unnecessary claims.

I am not trying to discredit anything. ND is an option. It is not an option I chose, but that doesn't affect that it is an option.

My point is, why claim to appear to know something without saying how they know it. That statement of other factors conspiring to deliver diabetes would be equally strong without stating they had damaged pancreases.

You know, even a gas bag like me knows that sometimes less is more in communications.

 

[Burylancs]

Well no, because I don't think cluster RCT's are inherently "incompetent".

Nobody has suggested they are 'inherently incompetent'. They are useful in certain contexts. You're missing the point - the results have to be analysed in a certain way, with the clusters as the unit of comparison not the individuals within them.

 

[Eddy Edson]

Nobody has suggested they are 'inherently incompetent'. They are useful in certain contexts. You're missing the point - the results have to be analysed in a certain way, with the clusters as the unit of comparison not the individuals within them.

I disagree with that, but very willing to be corrected by Spiegelhalter if he has a relevant contrary position.

 

[Deleted member 21371]

I can't say it is inaccurate any more than you can say it is accurate. It just seems a shame (at least to me) to make unnecessary claims.

I am not trying to discredit anything. ND is an option. It is not an option I chose, but that doesn't affect that it is an option.

My point is, why claim to appear to know something without saying how they know it. That statement of other factors conspiring to deliver diabetes would be equally strong without stating they had damaged pancreases.

You know, even a gas bag like me knows that sometimes less is more in communications.

No one appears to be claiming anything contentious?
Well, unless now the trial subjects are taking to lying twice about their previous medical history?

Or is the claim that others factors may damage the pancreas one you actually disagree with?

Mine seems to have been damaged by being overweight, probably in the style that was suggested by the Newcastle Study, now I'm not, it seems to be undamaged again?

That's definitely good enough for me.

 

[AndBreathe]

No one appears to be claiming anything contentious?
Well, unless now the trial subjects are taking to lying twice about their previous medical history?

Or is the claim that others factors may damage the pancreas one you actually disagree with?

Mine seems to have been damaged by being overweight, probably in the style that was suggested by the Newcastle Study, now I'm not, it seems to be undamaged again?

That's definitely good enough for me.

Yes, the claim their pancreases have become damaged.

Unfortunately, some people fib, and embellish the truth, where it serves their agenda. Medical research is not isolated in that.

I'm not discouraging you from believing in anything. I'm still living in hope Santa will bring me a unicorn.

 

[Deleted member 21371]

Yes, the claim their pancreases have become damaged.

Unfortunately, some people fib, and embellish the truth, where it serves their agenda. Medical research is not isolated in that.

I'm not discouraging you from believing in anything. I'm still living in hope Santa will bring me a unicorn.

I guess you truly believe in that, if you truly believe a medical research into diabetes would have no way of checking a pancreas as a follow up in research into diabetes, when speaking to people admitting to having fibbed to them before.
Good luck with your unicorn.

 

[Burylancs]

. You'd have to have people assigned to different treatment regimes delivered by the same people within the same practice. How would you control for leakage?

Yup, that's how virtually all medical trials are conducted - the same people run both control group and intervention group.
But there seems to have been no 'control' over the intervention group in DiRECT. The participants were given the elements of the Cambridge Diet, bars and shakes, and told to get on with it. And then it was anecdotal self-reporting of what they had eaten.. There was no actual control by Taylor of the participants shopping trolleys, fridge or freezer doors. And his Lancet article of 2018 makes it plain that some of the 'self-reporting' by participants was actually third party hearsay with talk of Carers reporting what the participants had eaten. The lack of real control in DiRECT may be one reason for its failure with the majority, 53%, failing to achieve so-called remission even on Taylor's limited definition.

 

[bulkbiker]

the trial subjects are taking to lying twice about their previous medical history

Wasn't that in fact the case as was revealed in their recent LADA letter.

" What we did find, on more detailed interviews with these participants, was that some had concealed rather longer durations of diabetes than the maximum of 6 years required for recruitment"...

Determination of autoantibodies in type 2 diabetes: one simple way to improve classification. Reply by Lean et al to Ludvigsson J [letter] - Diabetologia

link.springer.com

 

[harbottle]

Yes, the claim their pancreases have become damaged.

Unfortunately, some people fib, and embellish the truth, where it serves their agenda. Medical research is not isolated in that.

I'm not discouraging you from believing in anything. I'm still living in hope Santa will bring me a unicorn.

It's more a hypothetical statement than a claim:

"but they do suggest that other factors may conspire to damage the pancreas"

I have no idea why there is so much objection to this statement. It's fairly well known that the pancreas has been damaged in some way in T2 diabetics from scans that that show a decreased mass and also tests that show blunted insulin response and also markers that show cell apoptosis. As some people don't respond to weight loss and see improvements, there are other factors at play - I know someone who has had T2 since their 30s and has never been overweight. No antibodies or any markers for T1. All they know is that insulin production is low and something has caused that.