Aetiology of type 2 diabetes: an experimental medicine odyssey

[Eddy Edson]

Just-published Roy Taylor review of the "prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice."

A great resource!

Aetiology of type 2 diabetes: an experimental medicine odyssey - Diabetologia

This review describes a prolonged research endeavour to test the twin cycle hypothesis that type 2 diabetes is caused by fat-induced dysfunction of the liver and pancreas, guided by the happenstance of clinical practice. Testing of the personal fat threshold hypothesis, that individuals exhibit...

link.springer.com

 

[JITR]

Bravo!

Note from the paper: 'This review was invited based on the Claude Bernard Lecture at the EASD, September 2024'

Link: Claude Bernard Lecture at the EASD, September 2024'.

 

[beating_my_betes]

Thanks for this! Quite a lot to get though, here.

One of my biggest worries is that due to having higher levels for quite a while, I would've lost enough beta cell function to never be able to be fully cured. And while that is still a major concern, I am somewhat buoyed by this section:

 

[silver minion]

An interesting if very long read. It certainly gives hope for remission for a lot of type 2s.

Unfortunately I don't seem to fit the profile. I was overweight post covid and led a mostly sedentary lifestyle so I did diet and increased exercise, and BMI dropped from 29 to 26. Stopped dieting over Christmas and noticed in Feb that I was still losing weight although my calorie intake was back to around 2000 per day. Over the next 12 months with undiagnosed diabetes my BMI had dropped to 18 without dieting. I had little if any visceral fat by then and still have a slim waist/tummy now. Prior to diagnosis I had gradually increased my calorie intake to over 4000 per day and I felt permanently hungry and thirsty and was still losing weight.
Since diagnosis and medication plus a reduced carb diet of 2000 calorie per day I have slowly regained weight and muscle mass to a healthy BMI of 21 as my blood glucose has reduced. I am now struggling to continue reducing my BG and keep my weight at its current level.

 

[Drummer]

The low level of carbs I need to keep my numbers normal has been remarked on, but for decades I was protesting about how carbs made me feel so ill, but I was still encouraged to eat high carb foods, low fat - and ten years before diagnosis I had a flagged high glucose level in some tests - that was dealt with by not repeating the test or letting me know about it - I still feel betrayed by the very people who should have been paying attention and helping me deal with my inability to cope with carbs - many others in my family had the same problem, but I am now the oldest survivor.

 

[Eddy Edson]

An interesting if very long read. It certainly gives hope for remission for a lot of type 2s.

Unfortunately I don't seem to fit the profile. I was overweight post covid and led a mostly sedentary lifestyle so I did diet and increased exercise, and BMI dropped from 29 to 26. Stopped dieting over Christmas and noticed in Feb that I was still losing weight although my calorie intake was back to around 2000 per day. Over the next 12 months with undiagnosed diabetes my BMI had dropped to 18 without dieting. I had little if any visceral fat by then and still have a slim waist/tummy now. Prior to diagnosis I had gradually increased my calorie intake to over 4000 per day and I felt permanently hungry and thirsty and was still losing weight.
Since diagnosis and medication plus a reduced carb diet of 2000 calorie per day I have slowly regained weight and muscle mass to a healthy BMI of 21 as my blood glucose has reduced. I am now struggling to continue reducing my BG and keep my weight at its current level.

Just checking that you & yr doc are sure you're T2? From your profile, I might have guessed at something T1-ish - FWIW.

Anyway, one of the things I don't like about Taylor's messaging is the implication that *every* T2 case is explained by the twin cycles model. I'm pretty sure it's true in most cases, but also pretty sure not every case.

(On the other hand, I don't believe in the usefulness of the common story you see about dozens or whatever of different species of T2. It's like hypertension - lots & lots of genetic combinations which can lead to it but that doesn't translate into lots & lots of different types from a clinical perspective.)

 

[silver minion]

Just checking that you & yr doc are sure you're T2? From your profile, I might have guessed at something T1-ish - FWIW.

Anyway, one of the things I don't like about Taylor's messaging is the implication that *every* T2 case is explained by the twin cycles model. I'm pretty sure it's true in most cases, but also pretty sure not every case.

(On the other hand, I don't believe in the usefulness of the common story you see about dozens or whatever of different species of T2. It's like hypertension - lots & lots of genetic combinations which can lead to it but that doesn't translate into lots & lots of different types from a clinical perspective.)

I have queried it but they seem to think I am T2 although AFAIK I haven't had any T1 blood tests. As my BG has dropped from 165 to low 70s they say I am still producing insulin.
On max dose of metformin and gliclazide now so keen to find out what my HbA1c will be this month. Hard to predict from FP testing as the results are still quite variable.

 

[Docb]

Anyway, one of the things I don't like about Taylor's messaging is the implication that *every* T2 case is explained by the twin cycles model. I'm pretty sure it's true in most cases, but also pretty sure not every case.

Agree wholeheartedly with you there.

 

[JITR]

Agree wholeheartedly with you there.

Obviously, some cases of T2 as diagnosed by doctors are (wholly or partially) caused by disease, drugs and who knows what else. ICD-11 provides a way of qualifying the diagnoses with 'stem codes' and 'extension codes', see link below. That approach should help to clarify the messaging between senders and receivers.

https://libmaneducation.com/icd-11-coding-of-diabetes

 

[Eddy Edson]

I've been testing out ChatGPT for various things. Have to say it's not bad at medical stuff,as far as I can tell - quite a lot better than Grok, FWIW. Anyway, here's what it gives me for applicability of the twin cycles model as an explanation of initially diagnosed T2D, by final diagnosis subtype:



So about 80%. FWIW, that's consistent with the view I had put together from reading a bunch of studies.

Of course most of the "misses" here are simply misdiagnoses, except for that top category where things are murky. So if you restrict the discussion to validated T2D diagnoses, the twin cycles proportion would be well above 80%, according to ChatGPT.

Note this does't speak to reversability/remission potential. Just because the twin cycles model explains the origin of the diabetes it doesn't mean that weight loss will necessarily reverse it - eg the "Advanced t2d with beta-cell failure" group, where the beta cells are toasted beyond recovery. And obviously nothing guarantees weight loss sustainability!

It also doesn't necessarily fit with people's views of themselves. Eg the common situation of people saying they don't fit this model because they are "not overweight" and "healthy", and then when you dig they have a waist-to-height ratio >0.50 (which is the important metric for predicting excess visceral fat, much more so than BMI), and signs of insulin resistance as suggested by a simple tool like the Triglyceride Glucose (TyG) Index.

Even though the numbers here are just ChatGPT's estimates, IMO it's fair to say that the actual number of cases of T2D not amenable to a twin cycles explanation is quite small, in relative terms.