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Pancreatic alpha cells retain considerable plasticity and can – under the right circumstances – transdifferentiate into functionally mature beta cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used antimalarial drug artemether suppresses the alpha cell transcription factor Arx to promote transdifferentiation into beta cells. However, key initial experiments in this paper were carried out in islet cell lines and most subsequent validation experiments implied transdifferentiation without direct demonstration of alpha to beta cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary alpha cells into beta cells. Moreover, artemether reduces Ins2 expression in primary beta cells >100-fold, suppresses glucose uptake, and abrogates beta cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote alpha to beta cell transdifferentiation in treating diabetes.

“How do you deal with data manipulation and retractions?” Indicative of the nebulous nature of the issue, this is a question often posed to us in hushed tones, late at night at meetings or toward the end of a phone call. Though certainly not our favorite topic, due to the procedural complexities and inherent sadness involved, we would like to take a moment to shed some light on this type of retraction at Cell Metabolism.In simplified terms, retractions occur because the conclusions based on data presented in the paper cannot be relied upon anymore. Though still rare, the overall number of retractions has gone up in past years, contributing to the reproducibility concerns plaguing the biomedical community. However, it should be emphasized that not all retractions are due to data manipulation. At Cell Metabolism, papers are retracted if (1) there is proven scientific misconduct affecting the data presented, (2) the scope of corrections that would be needed is extensive, or (3) the changes needed would affect the conclusions of the paper. For the latter two retraction reasons, the mistakes might not be a consequence of fraud, falsification, or violation of ethical and publishing practices, but they are serious enough to shake the foundational conclusions.A common perception is that journals are reluctant to take action on reported concerns of data manipulation because months and sometimes years go by before anything happens. However, rather than being indicative of tergiversation on our part, the silence is due to the lengthy and confidential nature of the behind-the-scenes workings until the time we issue a retraction, if one is necessary. In order to start an investigation, we ask to be formally notified of concerns, usually in the form of an email, clearly detailing the issues at hand. Our current policy at Cell Metabolism is that the editors do not follow blog discussions on data manipulation because we cannot consistently and comprehensively monitor the ongoing discourse; also, our experience has been that it is difficult to ascertain the validity of many of the allegations—at face value, PowerPoint presentations showing blown-up images “with circles and arrows,” quoting Arlo Guthrie’s “Alice’s Restaurant,” invariably appear incriminating. In our opinion, to conclusively determine if there is an issue or not, one needs to see the raw data. Another point of contention that we wrestle with is that the majority of the notification emails are from anonymous “concerned readers.” We certainly understand the worry about backlash for a whistleblower, especially for a junior researcher, and have always respected the person’s wishes. However, there is a fine line between genuine reports and timewasters. Over the years, we have received our fair share of both serious and frivolous emails. Examples of the latter type include “Dr. X does not buffer their PBS appropriately; you can’t trust their data; you have to retract all their papers,” and “I saw Dr. Y present the data 4 years ago and they were different; clearly the authors are lying.” Our thought is that it is best to provide the journal with sufficient confidential information about the issue and context, and for the concerned reader to be available for follow-up questions from the editors.Fraudulent data fabrication and falsification can occur at various stages of the work—during data generation, analysis, and processing or during figure preparation. On the journal end, figures are usually the first problematic aspect that is detected. Is the western blot band A from Figure 1 the same as band B from Figure 6? Many bands look similar, but are they identical? We recently had a case at Cell Metabolism where the western blot bands in different experiments for different figures looked identical to all of us, including the authors, but after extensive analysis by a team of experts, the blots proved to be different. When a seemingly valid concern is raised, our first port of call is to ask the authors for the raw data, which raises another issue: how long can we reasonably expect authors to have access to the original data? Different institutions and funding bodies across the world have different statutes of limitations for data retention. Our current operating guideline at the journal is that, in most cases, 5–7 years is a reasonable time frame to expect authors to still have the data at hand. Based on the scope of the issues raised, we may also ask the authors to contact their institution’s office of research integrity, if they have not already done so, to review the concerns. Having the involvement of another reviewing body can add additional layers of complexity and delays, for example due to the type of confidentiality agreements that the institution may have. At the journal, we may wait to receive the official report of the investigation to alert the readers, although, depending on the circumstances, we may also proceed independently.In our experience, once it is determined that there are valid concerns surrounding a paper, most authors are willing to take the responsible course of action. Retractions are extremely distressing for all parties concerned—the authors, especially the ones who were not aware of the problem, the journal, and the community at large. They make us all pause and reflect. As scientists, we evaluate data with a skeptical eye, though our default is to trust that each other’s data have been generated in good faith. The underlying reasons for scientific misconduct are complex, and we all unwittingly play our part in the larger problem. At the journal, we are at the end of a chain of events, but we recognize that we can no longer just rely on the self-correcting nature of science and that effective collaboration with the community, funding bodies, and our publishing colleagues is needed to curb the real incidents of scientific misconduct.Our collective goal is to be more vigilant from submission to publication. At Cell Press, we screen the figures on accepted papers, although we fully appreciate that the lion’s share of scrutinizing the data falls on our reviewers, as experts in the field with first-hand knowledge of the type of data presented, to flag issues during peer review. We also often consult with statistical experts, especially for the Clinical and Translational Reports at Cell Metabolism. Reviewing is increasingly more challenging as science becomes more interdisciplinary and new technologies allow one to ask questions that we could not previously have tackled. As we approach “Reviewer Week,” we wanted to take this opportunity to recognize and thank our unsung heroes at Cell Metabolism, as well as at other journals, for the tremendous work they put in every day to ensure the rigor of published papers and maintain the credibility of the metabolism field. Every year we see thousands of papers, and we can honestly say that peer review works and that collaboration among authors, reviewers, and editors almost invariably results in stronger papers. Thank you, Reviewers, for the important work that you do.We hope that this Editorial has helped clarify what our current practices are regarding retractions at Cell Metabolism. As usual, please let us know if you have questions, feedback, or ideas for improving the journal and helping us better serve the community. We love hearing from you! Please continue to make the most of our monthly editorial office hours, email us, or catch us in person at meetings and lab visits.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).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.

An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness.

Glycolysis supports effector T cell function but is detrimental to the immunosuppressive activity of regulatory T cells. In a recent issue of Nature, two papers address a role for glucose and lactate availability within the tumor microenvironment for the balance of pro- and anti-tumoral effects of T cells and the efficacy of neoadjuvant cancer immunotherapy.

Compelling evidence indicates that tumors may evade immunosurveillance by subverting the metabolism of immune cells. In a recent paper in Nature, Song et al. (2018) demonstrate that ovarian cancers activate IRE1α-XBP1 signaling within CD4+ T lymphocytes, thereby disrupting their bioenergetic function and contribution to anticancer immune responses.

Cancer cells frequently hijack normal metabolic pathways to promote their growth and metastasis. Two recent papers by Knott et al. (2018) and Pavlova et al. (2018) demonstrate that asparagine and glutamine work in concert to drive tumor growth and metastasis through modulation of cell survival, growth, and EMT regulatory pathways.

It has been more than a dozen years since FGF21 burst on the metabolism field in a paper showing that its pharmacologic administration caused weight loss and improved insulin sensitivity and lipoprotein profiles in obese rodents. Since then, FGF21 analogs have advanced all the way to clinical trials, and much progress has been made in understanding FGF21's pharmacology and physiology. In this Perspective, we highlight some of the interesting themes that have emerged from this first dozen years of FGF21 research, including its roles in autocrine/paracrine and endocrine responses to metabolic stress.

High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.

Glycolysis is prudently regulated and coupled to cell growth. Phosphofructokinase 2 controls glycolytic flux by generating fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase 1. In a recent paper in Nature, Dasgupta et al. address the novel role of PFKFB4, an isoform of phosphofructokinase 2, in regulating gene expression to promote tumor growth.

The pancreatic islet β cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in β cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.We, the authors, wish to retract “Decoupling Ferritin Synthesis from Free Cytosolic Iron Results in Ferritin Secretion” by De Domenico et al. (Cell Metab., 13 (2011) 57–67, http://dx.doi.org/10.1016/j.cmet.2010.12.003 and “The Role of Ubiquitination in Hepcidin-Independent and Hepcidin-Dependent Degradation of Ferroportin” by De Domenico et al. (Cell Metab., 14 (2011) 635–646, http://dx.doi.org/10.1016/j.cmet.2011.09.008) because a number of errors have been detected in the assembly of the figures, and some of the original data were inappropriately removed from the laboratory. We stand by the validity of our studies; the data are reproducible, and the conclusions were not affected by the errors. However, we believe that the most responsible course of action is to retract the paper. We are preparing a new expanded version of this study for future submission. We deeply apologize to the community for the inconvenience.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.We, the authors, wish to retract “Decoupling Ferritin Synthesis from Free Cytosolic Iron Results in Ferritin Secretion” by De Domenico et al. (Cell Metab., 13 (2011) 57–67, http://dx.doi.org/10.1016/j.cmet.2010.12.003 and “The Role of Ubiquitination in Hepcidin-Independent and Hepcidin-Dependent Degradation of Ferroportin” by De Domenico et al. (Cell Metab., 14 (2011) 635–646, http://dx.doi.org/10.1016/j.cmet.2011.09.008) because a number of errors have been detected in the assembly of the figures, and some of the original data were inappropriately removed from the laboratory. We stand by the validity of our studies; the data are reproducible, and the conclusions were not affected by the errors. However, we believe that the most responsible course of action is to retract the paper. We are preparing a new expanded version of this study for future submission. We deeply apologize to the community for the inconvenience.

SummaryThis paper describes a convergent mechanism for the feedback control of cholesterol synthesis and uptake mediated by SREBPs, membrane bound transcription factors. Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. In sterol-overloaded cells, Scap/SREBP binds to Insig-1, which retains the complex in the ER. Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes. Scap/SREBP moves to the Golgi, where SREBP is processed to liberate a nuclear fragment that activates genes for cholesterol synthesis and uptake and the gene for Insig-1. Ubiquitination is not necessary for release of Scap/SREBP from Insig-1, but it establishes a requirement for synthesis of new Insig-1 for feedback inhibition. When the new Insig-1 and cholesterol converge on Scap, Scap/SREBP binds to Insig-1, preventing ubiquitination. The Insig-1/Scap/SREBP complex accumulates in the ER, ready for liberation when the cell is again sterol deprived.

GDF11 was reported to decline with age and to have muscle and heart rejuvenating effects. These reports were disputed. A Cell Metabolism paper now shows that in human beings, GDF11 does not decline with age and is actually a risk factor for frailty and other morbidities (Schafer et al., 2016).

There is great interest in discovering targets for in vitro manipulation of autologous T cells that enhance their cytotoxicity against tumor targets as a potent cancer immunotherapy. In a recent Nature paper, Xu and colleagues reveal new insights into the link between cellular cholesterol metabolism and CD8 T cell functions.

Elevated levels of circulating lipids are the major cause of cardiovascular disease, but beneficial outcomes might be realized by targeting lipid carriers. Two papers in this issue of Cell Metabolism (So et al., 2012; Wang et al., 2012) demonstrate how modulation of one arm of the unfolded protein response can decrease plasma levels of VLDL particles and their associated lipids.