Thursday, March 22, 2018

What has Dr Faustman been up to so far?

Now and then, I review the literature and check if some progress has been made towards a T1D cure or, less ambitiously, towards the understanding of T1D pathogenesis. (spoiler: not much). While I try stay away from controversial topics, in the “cure” field, Dr DL Faustman is hard to avoid.

The Faustman saga for dummies.

A long, long time ago, Dr Faustman revisited the even older topic of the BCG/Diabetes relationship. While she did find some interesting stuff, she over extended herself with claims that proved to be wrong. The erroneous claims (nothing wrong with being wrong, this is how science works) and partial replication of her results by another team (same remark) led to a conflictual situation that created difficulties for her to get funding but also contributed to the emergence of a fan base that supported her. That fan base consists of a mix of conspiracy theorists who think she has a cure but that it is being suppressed and very rational and generous people who support her as they would support any other group working towards the “cure” moonshot. On the other hand, Dr Faustman’s communication style, her bold claims, especially in the fundraising effort directed towards her base, has irritated a lot of people. She’s a White Knight to some, a Dark Lord to others.
Link: the “permanent disease reversal” paper that started the controversy: in a nutshell, the splenocyte role could not be replicated.

Restarting the saga.

In 2012, a publication titled Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes restarted the fireworks. Without diving into the details of what this paper shows or doesn’t show, something that would be out of my league as far as the finer points are concerned anyway, one can risk a few comments.
  • the title of the article is extremely bold: treatment of long-term type 1 diabetes would be a major breakthrough, worthy of a Nobel prize.
  • the use of BCG, basically a common vaccine, opens the door to catchy headlines such as “could a simple vaccine cure type 1 diabetes?”
  • the number of patients involved in the clinical trial (n=85, but only n=6 actual) can be seen as insufficient. Additionally, the 6 patients were initially split in 2 groups of 3 (control/intervention), but were then reshuffled as a 3-1+1 as an EBV infection occurred. Obtaining statistically significant results, at least at the patient level, is just black magic. Yes, formulas will provide an answer, they always do but…
  • the methods are extremely well documented and the trial seems to have been conducted according to the highest standard (double checked with actual researchers who stated “if all papers were like this, that would be good”).

Typical reactions to the paper.

The non scientifically educated patient will start looking for places where he can purchase the BCG vaccine and expect a full recovery whereas the physicist will trash the paper as bogus research and a shameful misapplication of statistics to massage the data into the desired results. Bottom line: there we go again! White Knight or Dark Lord?
That being said, if one looks beyond the catchy, almost dishonest, title, if one ignores the patient outcome and statistical massaging, one could focus on the flow cytometry results (essentially counting cells) and see an interesting effect. Had the paper been titled something like “BCG vaccination increases apoptosis in Insulin reactive T cells”, I believe it wouldn’t have generated as many negative reactions or false hopes.

So what’s going on here?

The BCG vaccine is used as a TNF proxy. TNF (Tumor Necrosis Factor) has been shown to play a role in the evolution of Type 1 Diabetes, a “paradoxical role” as researchers say since it has been shown to be both protective and harmful. The problem is that you can’t just go around and inject Type 1 Diabetics with TNF: TNF is usually bad for you, one is unlikely to obtain approval for a clinical trial involving TNF injections. (anti-TNF of all kinds have revolutionized the treatment of many auto-immune arthritis). Therefore, BCG – a known to be safe vaccine and known  TNF trigger as most mycobacterium are – is used as a relatively mild shot at the insulin reactive T cells which are known to play a role in the T1D auto-immune reaction.

One additional interesting point is that there are, at least, two different TNF Receptors that are unequally distributed in different cell populations and that trigger different responses. TNFR2 is the receptor Dr Kaufman is interested in, as it is shown in this 2016 paper Treg activation defect in type 1 diabetes: correction with TNFR2 agonism.
A small explainer may be needed here:
  • cytotoxic T cells are involved in the auto-immune reaction that kills healthy cells (for example insulin reactive T cells).
  • regulatory T cells (rTregs) when activated (aTregs) may prevent or stop auto-immune diseases by keeping cytotoxic T cells in check (preventing them from activating or triggering their death).
  • Type 1 Diabetics seem to have a defect in Treg activation (they end up with less aTregs).
  • that defect seems to be significant because the number of aTregs seems to be inversely correlated with residual C-Peptide secretion and control.
  • TNFR2 agonism (that means stimulating the TNFR2 receptor instead of blocking it as an antagonist would) leads to more aTregs which could be good.
Once again, the title of the paper is a bit ambiguous, the aTregs “defect” mechanism of action isn’t that clear and its clinical impact is only inferred through association and correlation. The snapshot fits in the current movie of our immune system understanding but isn’t definitely proven to be the root cause of all ills.

Dr Faustman could indeed very well be on an interesting track, as she recently stated in this opinion piece TNF, TNF inducers, and TNFR2 agonists: A new path to type 1 diabetes treatment but one can’t help being a bit annoyed by the boldness of her claims compared the current level of evidence.

Some of her detractors could joke: “What next? Will she also treat cancer?”

Ugh, well, yeah, she could…  TNFR2: A Novel Target for Cancer Immunotherapy.

My own (worthless) opinion

Interesting research, despite the hype. This is an area that is definitely worth exploring and it is actively explored by many researchers in many different fields. A cure? Not within 5 years. Small steps in the correct direction? most probable.

Wednesday, March 21, 2018

Perception bias in T1D communities: late onset type 1 diabetes

T1D communities are often very vocal when it comes to the issue of initial Type 1 Diabetes. This is especially true when a case of late diagnosis leading to a fatal or debilitating DKA goes viral. At that point, prayers and thoughts (which are as effective in preventing diabetes or treating DKA as they are in school shootings and gun control) fly and the T1D community erupts in “know the signs” memes and aggressive comments about medical professional who, at best, are accused of not doing what they should be doing, namely finger pricking every case of stomach flu they encounter. That measure that would be expensive, hard to interpret, lead to a lot of even more expensive confirmation tests. While they would probably yield a few earlier diagnosis, even fewer early stage DKA detections, the benefits – in the current state of therapies – would be nil in terms of long term prognosis and minimal in terms of DKA complications (ease of access to quality health care matters much more in terms of initial DKA prognosis, initial DKA isn’t a major factor in morbidity/mortality).

One of the latest circulating memes, recycling the “know the signs” memes, is that you can catch T1D at any age (true, although the onset is definitely skewed towards the young) and that T1D is often misdiagnosed as T2D. That’s understandable given the fact that T1D communities will have their fair share of members who have been diagnosed T1D after a misdiagnosis of T2D.

However, the T1D communities perception of “misdiagnosed” T1D is the result of multiple biases.

- Adult T2Ds far outnumber T1Ds.
- T2Ds who were initially misdiagnosed as T1Ds are unlikely to hang around in T1D communities.
- T1Ds who were initially misdiagnosed as T2Ds are likely to join T1D communities and likely to be unhappy and vocal about their misdiagnosis.

What’s the reality?

In fact, the issue is well known and well recognized

Late-onset type 1 diabetes is difficult to diagnose in people aged 31–60 years because it represents only a small minority of patients diagnosed with diabetes; its misdiagnosis as type 2 diabetes results in inappropriate treatment. (quote from the paper below)

However, given the huge discrepancy in the size of the respective populations, what actually happens in terms of diagnosis mistakes is the exact opposite of what the T1D communities are worried about.

Errors are often made when diagnosing type 1 diabetes later in life. For example, more than 50% of patients diagnosed with type 1 diabetes after age 35 years were shown to have type 2 diabetes in long-term follow-up. (quote from the paper below)

That issue is, for example, addressed in “Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank” (free full text).

One of the sensible ways to improve diagnosis accuracy as far as adult onset T1D and T2D is to take genetic predisposition factors into account.

Sunday, March 4, 2018

Another quick example of the main Libre problem: thermal compensation.

Apologies for not keeping up with the blog, real life has been interfering...

That being said, here is another example of the main drawback of the Libre: thermal compensation is really poor.

Have a look at the chart below and try to guess what it shows...

I am wearing the patch. I am a non diabetic person (neither Type 1, nor Type 2).

12:00: small meal

13:00: exercise (stationary bike starts)

14:00: bottle of sports drink as I start feeling the lack of supplies.

15:00: exercise stops, feeling really drained. My Garmin Fenix says I'll need 67 hours of recovery. My average heart rate was 142, with several spikes to my maximum FC. So far, so good, 61 might be a bit on the lowish side, but nothing incoherent.

15: 30: I do not eat or drink anything and decide to relax in a warm bath for a while...

My BG starts to climb steadily, first spot check is at 105 mg/dL, second spot check is at 157 mg/dL, around 250% of my actual value. As soon as I get out of my bath, my BG starts to drop precipitously (the reader refuses to provide values at that point) and then resumes cruising at the pre-bath value.

What if I had had to take an insulin dosing decision during that time? What if I had an AP running?

Abbott needs to fix this in the future. Fancy apps, not so much. Decent temperature compensation, yes, definitely.

On the "plus" side, at least for Abbott, the combined effect of the sub-optimal (cough, cough) temperature compensation and the delay compensation - the actual smoothed value never reached the projected high - is so bad that I stopped being motivated in reversing it long ago...