October 24, 2020

The Niche

Knoepfler lab stem cell blog

The Betatrophin Blues after Harvard Diabetes pub

All the recent high-profile papers that are having troubles are bumming me out, with the latest example being the “Betatrophin” Diabetes paper from Harvard last year.

Yesterday it was called into major doubt by a new Cell paper from a group led by Jesper Gromada at Regeneron.

The authors of the original 2013 Betatrophin paper–Doug Melton’s team at Harvard– indicated in their own accompanying, somber perspectives piece also in yesterday’s issue of Cell that they agree that their 2013 report was largely incorrect. This unfortunate turn of events is based on both the new Regeneron paper and the Melton lab’s own follow up work.

Rewind back to 2013 when the Betatrophin finding first came out and it was hard not to get into the story at that point given how it was being portrayed. A Harvard press release made little doubt that this was a seminal discovery for Diabetes research:

The hormone, called betatrophin, causes mice to produce insulin-secreting pancreatic beta cells up to thirty times the normal rate…it could eventually mean that instead of taking insulin injections three times a day, you might take an injection of this hormone once a week or once a month, or in the best case maybe even once a year.

The 2013 paper itself was also very bold with statements such as:

Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.

Betatrophin

They raised expectations sky high.

I blogged about that apparent blockbuster finding here back then in 2013 and I definitely was excited about it given how it sounded. Now there’s a major letdown. The new paper’s title alone pretty much says it all:

ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion

You can see the graphical abstract from this paper at left in which the authors report that Betatrophin, which now should probably go by the more objective name ANGPTL8, does not substantially impact beta cell growth, but rather seems to have a notable role in mouse triglyceride metabolism. ANGPTL8 is probably a very interesting molecule, but it is not what it seemed to be.

In the perspectives piece, the Betatrophin authors say that boosting their N of mice has led their main conclusion to come into doubt:

In Yi et al. we reported an average beta cell replication rate of ∼4% in betatrophin-injected mice (n = 7); with five additional experiments (n = 52 mice in total), the average beta cell replication rate in betatrophin-injected mice drops to 1.2%. While still significantly above control levels (p = 0.016 for all experiments) of beta cell replication (0.6%), the conclusion from Yi et al. must be corrected and modified with respect to the magnitude of the effect.

It’s now unclear what the fate of the 2013 Betatrophin paper will be moving forward given that its central argument is incorrect and even the naming of the molecule “Betatrophin” is indeed perhaps not appropriate any more.

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