Misconduct at Oxford prompts retraction of insulin paper

cellmetabcoverCell Metabolism has retracted a 2006 article by a group of researchers at Oxford in England after an investigation concluded that the first author had committed misconduct.

The paper, “Nicotinamide nucleotide transhydrogenase: A key role in insulin secretion,” came from the lab of Frances Ashcroft, a world-renowned expert on ion channels. (We’ve written about Ashcroft’s lab before.)

According to the abstract:

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. QTL mapping identified Nicotinamide Nucleotide Transhydrogenase (Nnt), a nuclear-encoded mitochondrial protein thought to be involved in free radical detoxification, as a candidate gene. To investigate its functional role, we used siRNA to knock down Nnt in insulin-secreting MIN6 cells. This produced a dramatic reduction in insulin secretion and the rise in [Ca2+]i evoked by glucose, but not tolbutamide. We identified two ENU-induced point mutations in Nnt (N68K, G745D). Nnt mutant mice were glucose intolerant and secreted less insulin during a glucose tolerance test. Isolated islets showed impaired insulin secretion in response to glucose, but not to tolbutamide, and glucose failed to enhance ATP levels. Glucose utilization and production of reactive oxygen species were increased in Nnt β cells. We hypothesize that Nnt mutations/deletion uncouple β cell mitochondrial metabolism leading to less ATP production, enhanced KATP channel activity, and consequently impaired insulin secretion.

The paper has been cited 95 times, according to Thomson Scientific’s Web of Knowledge. But as the retraction notice states:

This paper is being retracted because of concerns with Figures 2B and S3. In Figure S3, the SDS-PAGE gel image had molecular weight markers added from another autoradiograph and additional nonspecific bands obscured or removed. In the top panel of Figure 2, an actin Western blot was used instead of a GCK Western blot. This matter was investigated by the Medical Research Council (UK) under their Scientific Misconduct Policy and Procedures, and scientific misconduct pertaining to the issues described here against the first author Helen Freeman was found. Repetition of these experiments by other group members gave identical results to those shown in the paper. Nevertheless, although we feel that the scientific conclusions of the paper (that loss of NNT impairs insulin secretion and impairs glucose tolerance in C57BL/6J mice) still stand, given the conclusion of scientific misconduct against the first author, the authors think the most responsible course is to retract the paper. The authors sincerely apologize for the inconvenience caused by this retraction.

We note that Freeman’s name does not appear on the earlier retraction from Ashcroft’s team. Could it be a second lightning strike?

Meanwhile, there’s a bit more to this story. The group narrowly escaped (we’re not quite sure how) the retraction of a similar 2006 paper, this one in the journal Diabetes. Here’s the correction notice for “Deletion of Nicotinamide Nucleotide Transhydrogenase: A New Quantitive Trait Locus Accounting for Glucose Intolerance in C57BL/6J Mice:”

In the article listed above, it was discovered that the Western blot in Fig. 1C was inappropriately manipulated. It appears that a protein band labeled C3H/HeH, which was a control sample, was added to the figure in its preparation. A Medical Research Council investigation found that there had been scientific misconduct by the first author, Dr. Helen Freeman, and that none of the other authors were involved. The other authors sincerely apologize for this having occurred, and wish to correct the published record. The authors have replicated the results of the original figure using their remaining bacterial artificial chromosome (BAC) mouse line (see Fig. 1C replacement below) and have also previously replicated the rescue of the glucose tolerance phenotype in this line, thus showing that the original conclusions of the article are not compromised.


New Fig. 1C legend: BAC transgenic expression of wild-type NNT protein in male C57BL/6J mice.Top panel: Expression of NNT protein in C3H/HeH (lane 1), C57BL/6J (lane 2), C57BL/6NTac (lane 3), and BAC transgenic C57BL/6J (lanes 4 and 5) mouse liver. Bottom panel: Reprobing of the same blot with an anti–α-tubulin antibody as a loading control. Protein was separated on a 4–12% gradient polyacrylamide gel (Invitrogen) and electrophoresed in MOPS SDS running buffer (NuPage, Invitrogen). The NNT antibody was our own custom affinity purified rabbit polyclonal. The anti–α-tubulin monoclonal antibody was 12G10. The 12G10 anti–α-tubulin antibody developed by Joseph Frankel and E. Marlo Nelsen was obtained from the Developmental Studies Hybridoma Bank, was developed under the auspices of the National Institute of Child Health and Human Development, and maintained by The University of Iowa, Department of Biology, Iowa City, IA. The Western blotting was carried out by Dr. Michelle Goldsworthy.

That paper has been cited 66 times, according to Thomson Scientific’s Web of Knowledge.

We also note that Freeman and Ashcroft appear on a patent application for “Methods and compositions for the diagnosis of treatment of type 2 diabetes.”

11 thoughts on “Misconduct at Oxford prompts retraction of insulin paper”

  1. That’s three (by my count) fairly high impact retractions (J Neurosci, PNAS and Cell Metab.), and the only common denominator is the PI.

    1. That raises a question: Does the PI reads the manuscripts sent out from his group? Or, is he/she too busy managing an empire?

      1. For the paper under discussion, the problems were in figures 2B and S3.

        For 2B the notice states: “In the top panel of Figure 2, an actin Western blot was used instead of a GCK Western blot.”

        This could only have been detected from within the lab by someone with access to notebooks and original files. It would count to their credit if this retraction originated with their own investigation.

        Figure S3, however, is very crudely manipulated. If you look at the supplementary information you can see immediately that S2 and S3 have identical markers. The bands in S3 also have obvious rectangles around them. It seems doubtful that any of the other authors looked at the supplemental information. I would have a fit if any of my coauthors sent an equivalent figure in a manuscript.

  2. In the UK institutions reap rewards for publications through the Research Excellence Framework (used to be RAE). The retracted paper was part of the University’s submission and would be worth £5000 to £15,000 per year to the University (depends on how the funding was worked out for the area of assessment, termed UoA 15 in 2008). This highlights yet another reason why institutions do not want to push investigations into papers – they have far too much at stake in terms of income, from grants to research support funding. Journals are similarly tied, though I do not see how their inaction actually ties in with maintaining their reputation.

  3. Does this count as a third retraction?
    Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9811-6. doi: 10.1073/pnas.0800952105. Epub 2008 Jul 3.
    Glucose regulates the effects of leptin on hypothalamic POMC neurons.

    Ma X1, Zubcevic L, Ashcroft FM.
    Author information
    Henry Wellcome Center for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.

    2009 retraction notice.

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