Director's Breakfast Briefing

Event participants

James Bacchus, Chair, Global Agenda Council on Governance for Sustainability, World Economic Forum; Chair, Appellate Body, World Trade Organization (1995-2003); Chair, Global Practice, Greenberg Taurig LLP

Widely considered the ‘kings of comedy’ in Jamaica, Ity and Fancy Cat have been serving up laughter to audiences for years. Their comedy series, The Ity and Fancy Cat Show, ended in 2017 but the duo continued to deliver high-quality entertainment...

In this article, I share my two final case studies, which examine changing our cultural attitudes to enhance productivity. Case study #5 – The role of punctuality An entrepreneur named Michael Fairbanks, who specialises in developing...

Famous American poet and singer Maya Angelou shared this about matters pertaining to the heart: “Love recognises no barriers. It jumps hurdles, leaps fences, penetrates walls to arrive at its destination full of hope.” What started out as an...

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

Loss of functional β-cell mass is an essential feature of type 2 diabetes, and maintaining mature β-cell identity is important for preserving a functional β-cell mass. However, it is unclear how β-cells achieve and maintain their mature identity. Here we demonstrate a novel function of protein arginine methyltransferase 1 (PRMT1) in maintaining mature β-cell identity. Prmt1 knockout in fetal and adult β-cells induced diabetes, which was aggravated by high-fat diet–induced metabolic stress. Deletion of Prmt1 in adult β-cells resulted in the immediate loss of histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) and the subsequent loss of β-cell identity. The expression levels of genes involved in mature β-cell function and identity were robustly downregulated as soon as Prmt1 deletion was induced in adult β-cells. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing analyses revealed that PRMT1-dependent H4R3me2a increases chromatin accessibility at the binding sites for CCCTC-binding factor (CTCF) and β-cell transcription factors. In addition, PRMT1-dependent open chromatin regions may show an association with the risk of diabetes in humans. Together, our results indicate that PRMT1 plays an essential role in maintaining β-cell identity by regulating chromatin accessibility.

Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell–derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C only–expressing mice (Lmna^LCS/LCS) become obese but remain glucose tolerant due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that Lmna^LCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in Lmna^LCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a β-cell–adaptive transcriptional program during metabolic stresses, highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.

The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A⁺ NK6 homeobox 1⁺ cells and very few INS⁺ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.

The Orioles' restocked farm system might inject some excitement into the club's retooled roster.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Bone pain is the most common type of pain from cancer and is present in around one third of patients with bone metastases, currently, improvements in cancer treatments mean that many patients are living with metastatic cancer for several years. Christopher Kane, NIHR academic clinical fellow in palliative medicine at Leeds University School of...

In this podcast Alexandra Barratt, professor of public health at the University of Sydney, discusses how questions about overdiagnosis in breast cancer screening programmes were first raised 45 years ago, and why it has taken so long for the concept to become mainstream. Read her full analysis: http://www.bmj.com/content/350/bmj.h867

Abdominal aortic aneurysms (AAA) are usually asymptomatic until they rupture, which is fatal in more than 80% of cases. Screening aims to detect the aneurysm before it ruptures, enabling preventive surgery and hence reducing morbidity and mortality. However, preventive surgery has a mortality of 3.9-4.5%. As the prevalence of risk factors, ie...

Cervical screening programmes in many countries stop at around the age of 65 and much of the focus is often on younger women. However, comparatively little attention has been given to older women despite the fact that they account for about a fifth of cases each year and half of deaths. In this podcast Susan Sherman, a senior lecturer in...

The claim that cancer screening saves lives is based on fewer deaths due to the target cancer. Vinay Prasad, assistant professor at Oregon Health and Science University, joins us to argue that reductions in overall mortality should be the benchmark and call for higher standards of evidence for cancer screening. Read the full...

Lily was diagnosed at 14 years old with stage four Hodgkin's lymphoma and received six rounds of chemotherapy and two weeks of radiotherapy. She survived but now lives with the long term effects of that therapy - and joins us to discuss how it has impacted her quality of life. We're also joined by Saif Ahmad and Thankamma Ajithkumar, oncologists...

Viral exanthema can cause rash in a pregnant woman and should be considered even in countries that have comprehensive vaccination programmes. Measles and rubella can cause intrauterine death. Intrauterine infection with rubella can lead to congenital rubella syndrome in the liveborn baby. In this podcast, Jack Carruthers, honorary clinical...

The Alzheimer’s society, in the UK, predicts that if the rates of dementia remain constant there’ll be 1.7 million people in the country living with the condition by 2050. We also know that things like improvements in cardiovascular health are changing those rates. New research published on bmj.com attempts to model what the outcomes of those...

The increase in life expectancy in England has almost “ground to a halt” since 2010 and austerity measures are likely to be a significant contributor. In this podcast Michael Marmot, director at University College London’s Institute of Health Equity, joins us to discuss what might be causing that drop off, and why a decrease in early life chances...

The world bank was set up in 1944. In the aftermath of the second world war, the institution was there to give loans to countries rebuilding after the conflict. Their first loan went to France - but with stipulations about repayment that set a tone for future funds. A new series, authored by Devi Sridhar, and her team from the University of...

A new Rapid Recommendation from The BMJ suggests that for pregnant women, they may wish to avoid certain antiviral treatments for HIV. This recommendation differs from the WHO's, and to discuss why that is, and what makes that difference important, we're joined by Reed Siemieniuk, a physician and methodologist from McMaster University, and Alice...

Neoadjuvant chemotherapy for breast cancer is a new strategy that was introduced towards the end of the 20th century with the aim of reducing tumour size - rendering an otherwise inoperable tumour operable, allowing more conservative surgery, and hopefully improving overall survival. Although data indicate that the first rationale remains valid,...

A study published by The BMJ today reports a possible association between intake of highly processed (“ultra-processed”) food in the diet and cancer. Ultra-processed foods include packaged baked goods and snacks, fizzy drinks, sugary cereals, ready meals and reconstituted meat products - often containing high levels of sugar, fat, and salt, but...

We talk about financial conflicts of interest a lot atThe BMJ - and have take taken the decision that our educational content should be without them. We also talk a lot about non-financial conflicts of interest, but the choppy waters of those are much more difficult to navigate. In this podcast, we discuss whether we should, or if we could even...

Brits have a reputation as Europe’s boozers - and for good reason, with alcohol consumption higher than much of the rest of the continent. That reputation is extended to our young people too - but is it still deserved? Joanna Inchley, senior research fellow at the University of St Andrews, explains new research on decreasing drinking -...

Helen Macdonald and Carl Heneghan are back again talking about what's happened in the world of evidence this month. (1.05) Carl rants about bacon causing cancer (7.10) Helen talks about prostate cancer, and we hear from the author of the research paper which won Research Paper Of The Year at the BMJ awards. We also cover disease definition and...

Fertility awareness based methods of contraception are increasingly being used for pregnancy prevention. In the US, the proportion of contraceptive users who choose such methods has grown from 1% in 2008 to approximately 3% in 2014.  Relative to other methods of pregnancy prevention, however, substantial misinformation exists around fertility...

Around half of trials that supported new cancer drug approvals in Europe between 2014 and 2016 were judged to be at high risk of bias, in a new study. Huseyin Naci,assistant professor of health policy a the London School of Economics joins us to talk about why potential bias may mean potential exaggeration of treatment effects, and could be...

Direct-to-consumer genetic tests are sold online and in shops as a way to “find out what your DNA says". They insights into ancestry or disease risks; others claim to provide information on personality, athletic ability, and child talent. However, interpretation of genetic data is complex and context dependent, and DTC genetic tests may produce...

If you read the Christmas BMJ in the last few weeks, you might have noticed a lot around art and health - the way in which engagement in arts can help in prevention and treatment, but can also affect those more nebulous things which really matter to patients - loneliness, self expression, being connected to the wider community. That obviously...

In a British cohort, 30% of patients who had survived childhood cancer had died within 45 years of diagnosis; only 6% were expected to have died. 51% had developed a new primary cancer, but a 26% died of cardiovascular disease - thought to be caused by their treatment. Consequently, efforts to reduce long term mortality have focused on reducing...

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