Roy Taylor on causes of T2D (Lancet podcast)

[PerSpinasAdAstra]

In the 1990s there was a big fuss about Amylin in Type 2 with the suggestion that a significant proportion of Type 2s were victims of over production of Amylin and should be reclassified as 'Amylinotics'. Not heard much about that since.

In the early 2000s a researcher using powerful microscopes discovered that the Insulin Resistance in at least 20% of Type 2s was caused by stubby or nonexistent tethers on their Insulin. Meaning the Insulin could deliver Glucose to the Glucose Receptor ( a Clathryn coated pit on the cell wall ) but couldn't tether itself to the Insulin Receptor Port to signal a delivery. The Glucose eventually freed itself and was eventually stored as fat. We have not heard any follow -ups on that research either. It might entail the quality of the insulin of each new Type 2 being examined with up to 20% being possibly better off with exogenous insulin from the kick-off instead of the usual ham-fisted palliatives.

Even when I was dxed in 1992 it was generally said that Type 2 Diabetes was a bunch of conditions with a common main symptom. Now Taylor seems to be claiming it's all one thing ( without much evidence, only unproven hypotheses) and Your Mileage May NOT Vary.

If you have a link to some further information on this I would very much like to read it. When I was diagnosed my GP said (paraphrasing) - I'm not producing enough insulin, that my insulin wasn't working properly (insulin resistance), or that I was producing the 'wrong type' of insulin, which I assume is the stubby tether kind. I haven't yet found the language to search for the research about the 'bad insulin' situation. If you have the links I'd love to read more on the subject. My GP had clearly read more on the subject than I have and I want to know how that works - some people, apparently, produce ineffective insulin? I'd genuinely love to know more on this subject if you have links to the research or have the language they used in the title or the research paper.

 

[Foz556]

I think my beta cells are in a bad state, diet and exercise keep it under control.

Hi @harbottle can I ask how you got into remission without medication? I am getting there but need a final push to get below HBA1c of 50 and then onwards! I am diet and exercise only. Last HBa1C was 53 but I have had it under 50 but never below the without meds.

 

[JITR]

Hi @harbottle can I ask how you got into remission without medication? I am getting there but need a final push to get below HBA1c of 50 and then onwards! I am diet and exercise only. Last HBa1C was 53 but I have had it under 50 but never below the without meds.

Hi Jane,
I will tell you what I did later to get into remission without medication. Meanwhile would you be able give a snapshot of your diet and eating patterns?
TIA

 

[Foz556]

Hi Jane,
I will tell you what I did later to get into remission without medication. Meanwhile would you be able give a snapshot of your diet and eating patterns?
TIA

Thank you. I was on a low carb diet which, as a vegetarian, I found very boring and kept my HbA1c around 50. I have since gone calorie controlled (around 1500kcal a day) and I've not quite got to the point of it reducing my blood sugar levels. For context I am just over 7 stone (I'm 5ft 2ins) and was about 8 1/2 stone when diagnosed so always been at the lower end of BMI. I much prefer calorie controlled as there is more choice. And I eat three regualr meals a day. I don't exercise that much but I am active (eg park with my 7 year old, walking an hour back from work a couple of times a week). I do like to have 2 pieces of 90% dark chocolate a day and milk seems to add most of the sugar to my diet at 9.6g for 200 ml.

Example meals:
Breakfast - 2 x weetabix with 200ml semi skimmed milk
Snack - small pack hula hoops
Lunch - open sandwich eg. one piece of brown bread, egg, light mayo, cucumber on the side
Tea - Quorn 'chicken' burger, mushrooms and salad (lettuce, spring onions, vinegar)
Snack - 2 peices 90% Lindt dark chocolate

🙂

 

[louisew]

I think you will find a more accurate statement is something like this:

There is a large group whose diabetes is due to fat build up in the liver and pancreas. Irrespective of weight, losing around 8-15 kg will restore normal liver function in most cases. Many of these will also restore normal glucose control, dependent on the state of the beta cells in their pancreas.

See: https://www.ncl.ac.uk/media/wwwnclacuk/newcastlemagneticresonancecentre/files/Publications 2.pdf



See

Blimey if I lost 8 kg, I’d only weigh 6 stone 8, with a BMI of under 20. At my age 59, with my body shape curvy with boobs, I wouldn’t consider that a healthy weight atall. I haven’t weighed that since I was about 16

 

[JITR]

What rarely gets mentioned at the same time Taylor was introducing his research, Exter introduced that they had identified many distinct variations of Diabetes. I have forgotten the exact number they found but it was many, and the treatments were different.
I suspect unless we get some sort of genetic tests, the exact tye for some won't be known.

@grovesy

Is this the research you had in mind?

2008 Apr;4(4):200-13.
doi: 10.1038/ncpendmet0778. Epub 2008 Feb 26.

Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes​

Rinki Murphy <a title="Peninsula Medical School, Exeter, UK." href="https://pubmed.ncbi.nlm.nih.gov/18301398/#full-view-affiliation-1">1</a>, Sian Ellard, Andrew T Hattersley
Affiliations Collapse

Affiliation​

• 1Peninsula Medical School, Exeter, UK.

• PMID: 18301398
• DOI: 10.1038/ncpendmet0778

Abstract​

Monogenic diabetes resulting from mutations that primarily reduce beta-cell function accounts for 1-2% of diabetes cases, although it is often misdiagnosed as either type 1 or type 2 diabetes. Knowledge of the genetic etiology of diabetes enables more-appropriate treatment, better prediction of disease progression, screening of family members and genetic counseling. We propose that the old clinical classifications of maturity-onset diabetes of the young and neonatal diabetes are obsolete and that specific genetic etiologies should be sought in four broad clinical situations because of their specific treatment implications....

 

[Foz556]

Blimey if I lost 8 kg, I’d only weigh 6 stone 8, with a BMI of under 20. At my age 59, with my body shape curvy with boobs, I wouldn’t consider that a healthy weight atall. I haven’t weighed that since I was about 16

I'm the same - if I lost 8kg of my body weight I would be considered very underweight. I've read Prof. Roy Taylor's book and the science is really interesting so I emailed him to find out about people who have low BMIs. Unfortunately there is no research yet to support the science for this demographic yet. The ReTUNE study is for people with 'healthy' BMIs but they are at the top of the range. As a guide he said to consider your weight aged 20 and aim for that. However I have gone around this weight now (as much as I can remember being 20!) and not seeing my HBA1c come down yet.....

 

[louisew]

ml.

Example meals:
Breakfast - 2 x weetabix with

I'm the same - if I lost 8kg of my body weight I would be considered very underweight. I've read Prof. Roy Taylor's book and the science is really interesting so I emailed him to find out about people who have low BMIs. Unfortunately there is no research yet to support the science for this demographic yet. The ReTUNE study is for people with 'healthy' BMIs but they are at the top of the range. As a guide he said to consider your weight aged 20 and aim for that. However I have gone around this weight now (as much as I can remember being 20!) and not seeing my HBA1c come down yet.....

Well that’s more realistic, although I’m only a few pounds off that. My hbac1 is only 5.4 but i’m on insulin (not much since I started metformin) and 1000mg metformin. But I’m kind of resigned to being one of those who can’t put it into remission. It really has to be a percentage of your weight surely. So a six foot man with a Bmi of around 24 could lose 8 kg safely, because it would be around 10% of their weight. But for someone who weighs 50kg, it’s around 16%, which is just too much.

 

[Eddy Edson]

Well that’s more realistic, although I’m only a few pounds off that. My hbac1 is only 5.4 but i’m on insulin (not much since I started metformin) and 1000mg metformin. But I’m kind of resigned to being one of those who can’t put it into remission. It really has to be a percentage of your weight surely. So a six foot man with a Bmi of around 24 could lose 8 kg safely, because it would be around 10% of their weight. But for someone who weighs 50kg, it’s around 16%, which is just too much.

The range of weight loss for remission from Taylor's studies is approx 10% - 15%. Lower end for people with normal-ish BMI, higher end for people with obesity.

For me, starting at BMI ~25, the magic number was around 10%.

These percentages are averages - so for example some people with obesity in the DiRECT trial got to remission with less than 15% weight loss. It's interesting to note that at the 5 year mark, it seems like the only people who maintained weight loss sufficient to maintain remission were these 10-percenters.

 

[louisew]

Thank you. I was on a low carb diet which, as a vegetarian, I found very boring and kept my HbA1c around 50. I have since gone calorie controlled (around 1500kcal a day) and I've not quite got to the point of it reducing my blood sugar levels. For context I am just over 7 stone (I'm 5ft 2ins) and was about 8 1/2 stone when diagnosed so always been at the lower end of BMI. I much prefer calorie controlled as there is more choice. And I eat three regualr meals a day. I don't exercise that much but I am active (eg park with my 7 year old, walking an hour back from work a couple of times a week). I do like to have 2 pieces of 90% dark chocolate a day and milk seems to add most of the sugar to my diet at 9.6g for 200 ml.

Example meals:
Breakfast - 2 x weetabix with 200ml semi skimmed milk
Snack - small pack hula hoops
Lunch - open sandwich eg. one piece of brown bread, egg, light mayo, cucumber on the side
Tea - Quorn 'chicken' burger, mushrooms and salad (lettuce, spring onions, vinegar)
Snack - 2 peices 90% Lindt dark chocolate

🙂

You’re quite similar to me, although I was under 8 stone when diagnosed with an hbac1 of 143. I was on insulin only , for a year, but was putting on weight, so asked to be prescribed Metformin, which has been amazing for me. Down from around 24 units of insulin to less than 10, no morning liver dump and able to eat more carbs. And nearly back to my original weight.

 

[louisew]

The range of weight loss for remission from Taylor's studies is approx 10% - 15%. Lower end for people with normal-ish BMI, higher end for people with obesity.

For me, starting at BMI ~25, the magic number was around 10%.

These percentages are averages - so for example some people with obesity in the DiRECT trial got to remission with less than 15% weight loss. It's interesting to note that at the 5 year mark, it seems like the only people who maintained weight loss sufficient to maintain remission were these 10-percenters.

I’m literally 2 pounds off that. Not going to be holding my breath. It is what is it. I was very active, ate healthily, (same as my husband who isn’t diabetic) ate very few unhealthy takeaways and was a healthy BMI. my dad was also an active healthy eating type 2 diabetic. Sir Steve Redgrave, when competing was diagnosed with type 2 and I shouldn’t think he’s got a fatty liver

 

[JITR]

As a reminder, the aim of weight loss is to eliminate relatively small amounts of excess fat from the liver and the pancreas. The ReTUNE study showed this can be tricky for those of normal BMI. Two or three rounds of weight loss were necessary for some, and from memory some did not achieve it.

Presumably it may be even more difficult for those of you with low BMI. Speculatively, a 5:2 or (6:1) dietary regime of some kind might do the trick - without having to lose much if any weight. This is based on Roy Taylor's observation that fat comes out of the liver first. The 'fat burning' during each intermittent fasting period might therefore take a peck at the excess fat and gradually reduce it over the weeks and months. This idea is supported by a recent paper from China which found that a 5:2 diet was at least as effective as Metformin at reducing blood sugar levels over a few months.

Although Roy Taylor mentioned weight as 20 year old in his letter to Jane, he often says the $64 question is the waist size of your jeans. In any case he always says the only way to find out how well your beta cells will recover is to try.

 

[Foz556]

As a reminder, the aim of weight loss to eliminate relatively small amounts of excess fat from the liver and the pancreas. The ReTUNE study showed this can be tricky for those of normal BMI. Two or three rounds of weight loss were necessary for some, and from memory some did not achieve it.

Presumably it may be even more difficult for those of you with low BMI. Speculatively, a 5:2 or (6:1) dietary regime of some kind might do the trick. This is based on Roy Taylor's observation that fat comes out of the liver first. The 'fat burning' during each intermittent fasting period might therefore take a peck at the excess fat and gradually reduce it over the weeks and months. This idea is supported by a recent paper from China which found that a 5:2 diet was at least as effective as Metformin at reducing blood sugar levels over a few months.

Although Roy Taylor mentioned weight as 20 year old in his letter to Jane, he often says the $64 question is the waist size of your jeans. In any case he always says the only way to find out how well your beta cells will recover is to try.

That's really interesting about the IF as another way to tackle the liver fat. And yes the only way is to try it out - convincing the diabetes nurses was a whole other battle but I eventually met with one who was really open minded and could see what I was trying to do (and knew about Prof Taylor's work). A bit of experimentation ahead (and measuring of waistline 😉)
I'll look out for that paper from China as I'm currently a student so luckily can look at the research. If you remember the name of it that would be really helpful 🙂

 

[harbottle]

Hi @harbottle can I ask how you got into remission without medication? I am getting there but need a final push to get below HBA1c of 50 and then onwards! I am diet and exercise only. Last HBa1C was 53 but I have had it under 50 but never below the without meds.

I was on 1000mg of metformin initially.
I lost 3 stone in weight and cut the 'bulk' carbs (Still occasionally ate potatoes and oats.)
Metformin was cut after 3 months to 500mg as hba1c was 36
I kept the weight off and hb1ac remained in the 30s, even when I introduced more carbs to my diet.
So they stopped the last 500mg of metformin this year and the next blood test was lower than the previous one.

Meals consist of veg and meat (Chicken and fish mainly) but will small portions of things like chips and seem to be able to handle potato and oats without an issue now. Occasionally have a burger (With bun). If I go out I sometimes don't restrict myself at all, and in the two weeks before my last hba1c I ate normally (As I was on holiday!)

I also do a walk every day, but I was doing that already when I was diagnosed.

 

[harbottle]

I'm sure in Taylor's work he reported that although the beta cells started working again and first phase insulin response came back, there was no change in insulin sensitivity in skeletal muscles?

This paper is a review of the current knowledge of the molecular causes of IR:

Current Studies on Molecular Mechanisms of Insulin Resistance

Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor ...

www.ncbi.nlm.nih.gov

Free Fatty acids in the bloodstream are known to cause insulin resistance, but the mechanism isn't known - it's thought they might interfere with the signalled as part of the process.

Fasting levels being elevated are due to increased glucose production by the liver because insulin fails to suppress the production of enzymes that trigger glucose release.

 

[harbottle]

If you have a link to some further information on this I would very much like to read it. When I was diagnosed my GP said (paraphrasing) - I'm not producing enough insulin, that my insulin wasn't working properly (insulin resistance), or that I was producing the 'wrong type' of insulin, which I assume is the stubby tether kind. I haven't yet found the language to search for the research about the 'bad insulin' situation. If you have the links I'd love to read more on the subject. My GP had clearly read more on the subject than I have and I want to know how that works - some people, apparently, produce ineffective insulin? I'd genuinely love to know more on this subject if you have links to the research or have the language they used in the title or the research paper.

It could be this:

First image of insulin 'docking' could lead to better diabetes treatments

A landmark discovery about how insulin docks on cells could help in the development of improved types of insulin for treating both type 1 and type 2 diabetes. For the first time, researchers have captured the intricate way in which insulin uses the insulin receptor to bind to the surface of...

www.sciencedaily.com

They worked out how insulin interacts with receptors for the first time.

 

[JITR]

That's really interesting about the IF as another way to tackle the liver fat. And yes the only way is to try it out - convincing the diabetes nurses was a whole other battle but I eventually met with one who was really open minded and could see what I was trying to do (and knew about Prof Taylor's work). A bit of experimentation ahead (and measuring of waistline 😉)
I'll look out for that paper from China as I'm currently a student so luckily can look at the research. If you remember the name of it that would be really helpful 🙂

Intermittent Fasting for Glycemic Control Among Adults With Diabetes

This randomized clinical trial evaluates the effect of 16 weeks of intermittent fasting plus a meal replacement diet on glycemic control among patients with early type 2 diabetes compared with metformin and empagliflozin.

jamanetwork.com

Note: this research combined meal replacement with 5:2 for the clinical trial but my 'takeaway' from was the effect of 5:2 regime itself.

For weight loss I had followed a real food version of the Newcastle diet (protein and vegetables), and 16:8 IF which I have continued for weight maintenance. Latterly this has become 5 days lunch and dinner with 2 days dinner only. That's two 22 hour fasts allowing for fat burning to compensate for any weight gain during the other 5 days. See the Weight Loss section of this article for the general idea, 'What should we eat?'

 

[Leadinglights]

I reduced my HbA1C from 50mmol/mol to 42 in 3 months and to 36 in another 6 months by following a low carb approach having about 70g carbs per day, I did not look at calories but had meals based on meat, fish, eggs, cheese with plenty of vegetables. I don't normally have rice, normal pasta, potatoes, but do have a small amount of bread and low sugar/keto granola and normal fats rather than high fat, just not low fat.

 

[Eddy Edson]

Now the NHS T2 Remission programme is in full swing there should be plenty of data available, but has it been published?

The most current available data is for the period up to end 2022: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00194-3/fulltext

Findings​

Between Sept 1, 2020, and Dec 31, 2022, 7540 people were referred to the programme; of those, 1740 started TDR before January, 2022, and therefore had a full 12-month opportunity to undertake the programme by the time of data extraction at the end of December, 2022. Of those who started TDR before January, 2022, 960 (55%) completed the programme (defined as having a weight recorded at 12 months). The mean weight loss for the 1710 participants who started the programme before January, 2022 and had no missing data was 8·3% (95% CI 7·9–8·6) or 9·4 kg (8·9–9·8), and the mean weight loss for the 945 participants who completed the programme and had no missing data was 9·3% (8·8–9·8) or 10·3 kg (9·7–10·9). For the subgroup of 710 (42%) of 1710 participants who started the programme before January, 2022, and also had two HbA1c measurements recorded, 190 (27%) had remission, with mean weight loss of 13·4% (12·3–14·5) or 14·8 kg (13·4–16·3). Of the 945 participants who completed the programme, 450 (48%) had two HbA1c measurements recorded; of these, 145 (32%) had remission, with mean weight loss of 14·4% (13·2–15·5) or 15·9 kg (14·3–17·4).

Interpretation​

Findings from the NHS T2DR programme show that remission of type 2 diabetes is possible outside of research settings, through at-scale service delivery. However, the rate of remission achieved is lower and the ascertainment of data is more limited with implementation in the real world than in randomised controlled trial settings.

Lots of missing data, but short term adherence & therefore outcomes maybe a bit disappointing.

At five years, there's no reason to expect that it will be much different to any other lifestyle program (low carb, low fat, whatever: low long term adherence, maybe 5% remission rates?

 

[Eddy Edson]

What rarely gets mentioned at the same time Taylor was introducing his research, Exter introduced that they had identified many distinct variations of Diabetes. I have forgotten the exact number they found but it was many, and the treatments were different.
I suspect unless we get some sort of genetic tests, the exact tye for some won't be known.

This is a quote from Taylor's paper: Hence, genetic study of clustering of characteristics can provide useful insight into degrees of likelihood of expressing various clinical phenotypes, but not necessarily into causes.
I think this is part of a debate with groups like the Exeter precision health guys I think you're referring to: https://www.exeter.ac.uk/research/diabetes/

For any phenotype phenomenon there are a myriad of genetic influences all working in a messy mix of causes, suppressions, enhancers, bystanders ... The question is whether they just influence greater or lesser susceptability to what you identify as root "causes" at the phenotype level, or do they correspond to root causes themselves?

As I understand it, you find this kind of debate around all areas of proposed "precision" approaches. Sometimes you have things like Zoe, where the genetic elements identified so far have just about zero effect on optimal diet recommendations (it's always pretty much the standard guidelines). Maybe in some areas you actually do identify usefully differentiated "causes".

But at this case, I'm pretty sure Taylor would say that Exeter's claims are misleading. The genetics influence how susceptible the individual is to overloading ectopic fat storage and how susceptible he/she is to resulting liver & pancreas fat. But these differing susceptibilities do not constitute different "causes".

On the other hand, for the little it's worth I think it's probably overreach to say that the Twin Cycles mechanism is responsible for *all* cases of T2D-like diabetes, but from the studies I've looked at it seems like it is the major cause, maybe 75%+ of cases.