As journal editors, we’re aware of the fact that we have a role to play in scientific discourse - that’s why The BMJ has been so keen to talk about the way in which scientific knowledge is constructed, through our Evidence Manifesto. We also know that money has influence in the scientific literature - which is why we have a zero tolerance policy...

Acute respiratory distress syndrome was first described in 1967 and has become a defining condition in critical care. Around 40% of patients with ARDS will die, and survivors experience long term sequelae. No drug treatments exist for ARDS, however good supportive management reduces harm and improves outcome. In this podcast, John Laffey,...

Our latest debate asks, should doctors recommend acupuncture for pain? Asbjørn Hróbjartsson from the Center for Evidence-based Medicine at University of Southern Denmark argues no - evidence show's it's no worse than placebo. Mike Cummings, medical director of the British Medical Acupuncture Society argues yes - that there is evidence of efficacy,...

Doctors and the farming industry are often blamed for overuse of antibiotics that spurs the growing problem of antimicrobial resistance - but the professions are using different methods to combat resistance and reduce overuse. In this roundtable, we bring medics and vets together to discuss the problem - where antibiotic resistance arises, how...

More than ½ of patients leave hospital with changes to four or more of their long-term medications - but how appropriate are those changes? New research published on bmj.com looks at antihypertensive medication prescription changes to try and model that - and found that more than half of intensifications occurred in patients with previously well...

A new collection of articles published by The BMJ includes twelve country case studies, each an evaluation of multisectoral collaboration in action at scale on women’s, children’s, and adolescent’s health. Collectively these twelve studies inform an overarching synthesis and accompanying commentaries, drawing together lessons learned in...

The Royal College of Physicians will survey all its members in February on this most controversial question. It says that it will move from opposition to neutrality on assisted dying unless 60% vote otherwise. The BMJ explores several conflicting views. From Canada, palliative care doctor Sandy Buchman explains why he sees medical aid in dying...

Helen Macdonald and Carl Heneghan are back again talking about what's happened in the world of evidence this month. They start by talking about shoulders - what does the evidence say about treating subacromial pain, and why the potential for a subgroup effect shouldn't change our views about stop surgery (for now, more research needed). (16.00)...

Here's a taster for our new student podcast - Sharp Scratch. We're talking about the hidden curriculum, things you need to know to function as a doctor, but are rarely formally taught. This is a taster - if you enjoy, subscribe! https://podcasts.apple.com/gb/podcast/student-bmj-podcast/id331561304 Sharp Scratch episode 1: Surviving the night...

Starting in the middle of April, the group “Extinction Rebellion” have organised a series of non-violent direct action protests. Most notably bringing central London to a standstill - but these events are now continuing around the country. Predictably, they have received a lot of criticism - they have also received a lot of support - amongst...

As Syria enters its ninth year of conflict, doctors are struggling to provide health care to a badly damaged country. While dealing with medicine shortages, mass casualties and everything that comes with working in a warzone, healthcare facilities and their staff are also facing an unprecedented number of targeted and often repeated attacks....

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...

The NHS Practitioner Health Programme - once only for doctors in London, now it’s being rolled out across the NHS to provide the largest, publicly funded, comprehensive physician health service, in the world. However, while helping the individual is essential, systemic change needs to be made to support doctors in our healthcare system. Clare...

The UK general election is happening this week, and you’ve probably made your mind up which MP you’re voting for already - and maybe the NHS has influenced that decision. This year has seen an increase in the number of doctors running for parliament, and in this podcast we find out what motivates doctors to step away from clinical practice, and...

If you’re lucky enough to not be back at work, you might be feeling like you need to quickly refresh your medical knowledge - and this podcast the BMJ’s education editors take you on a whistlestop tour through the BMJ’s education articles of 2019. Tom Nolan (GP in London) is joined by Navjoyt Ladher (GP in London), Anita Jain (GP in India) and...

There comes a tipping point in all campaigns when the evidence is overwhelming and the only way to proceed is with action. According to David Williams, it’s time to tackle the disproportionate effects of race on patients in the UK. David Williams, from Harvard University, developed the Everyday Discrimination Scale that, in 1997, launched a new...

As we cover the covid-19 outbreak, we want to hear some of the stories from the frontline - And who better to heart of what this pandemic is doing to the profession in the UK, than some of the people who write regularly for The BMJ? In this first one, we wanted to look specifically at acute care - those at the sharp end of the response, so we're...

As the pandemic plays out - the way in which doctors in the UK practice is changing, hospitals are reconfigured to increase critical care capacity, GPs are working from home and doing their day to day work remotely. Some of the changes have come at the detriment of staff and patient wellbeing but covid-19 has also helped cut through some of the...

How can we help frontline clinicians? Sometimes medics may feel uneasy or even guilty and that they could be doing more. That was what a junior doctor in Abergavenny in Wales felt and she did something about it. In this podcast, we speak to Josie Cheetham about how she started her initiative to provide support boxes in hospitals for her...

As the pandemic plays out - hospitals are reconfigured to increase critical care capacity, outpatient clinics become virtual, and elective procedures delayed. How are these affecting care for those who are in hospital but don't have covid-19? In this podcast, Matt Morgan,honorary senior research fellow at Cardiff University, consultant in...

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give you...

Dilys J. Freeman
May 1, 2002; 51:1596-1600
Complications

Shane Rea
Nov 1, 1997; 46:1667-1677
Perspectives in Diabetes

Cindy J.M. Loomans
Jan 1, 2004; 53:195-199
Complications

Christophe Bonny
Jan 1, 2001; 50:77-82
Islet Studies

Joachim Spranger
Mar 1, 2003; 52:812-817
Pathophysiology

Gökhan S Hotamisligil
Nov 1, 1994; 43:1271-1278
Perspectives in Diabetes

Andreas Festa
Apr 1, 2002; 51:1131-1137
Complications

BM Spiegelman
Apr 1, 1998; 47:507-514
Articles

No sooner than the Government’s announced its intention to restart the economy, private sector groups are advocating for longer working hours to fast-track recovery during the COVID-19 pandemic. In a collaborative move, the Jamaica Manufacturers...

New Reds outfielder Yasiel Puig has been in camp for about a week, often hitting on his own on the backfields. With the first full-squad workout taking place on Monday, Puig was able to warm up, throw and hit with his teammates.

THE EDITOR, Madam: In times of great challenge and hardship we must continue, as a people, to uphold the values and attitudes that make us truly Jamaican. It is a time for true patriotism and for us to reach down and pull up those among us with...

THE EDITOR, Madam: I am an educator at the secondary level. I teach at a school that is located in the western part of Jamaica. I am writing this letter with a high level of distress. The Ministry of Education is asking for too much at this point...

The Editor, Madam: Today, as we celebrate Teachers’ Day, I pause in reflection, looking back at some of the educators who have deeply impacted me. Let me start with the principal of my primary school. She was a God-fearing woman, but I suppose,...

Parish Histories of Jamaica Project, a publication by the JN Foundation in collaboration with the Department of History and Archaeology at The University of the West Indies, Mona, was launched recently. Jenny Jemmott of Department of History and...

Redlining a Holocaust is a rigorously researched oeuvre that establishes Dòwòti Désir as one of the most important figures in contemporary African thought. Redlining is an imaginative and monumental undertaking, a literary, visual, and oratorical...

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the K_ATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia.

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)–producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.

Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins2^+/–) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor l-N^G-nitro-l-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes.

Invitation Only Research Event

Event participants

Paula Hodges QC, Partner; Head, Global Arbitration Practice, Herbert Smith Freehills
Stéphane Brabant, Partner; Chairman, Africa Practice Group, Herbert Smith Freehills

Research Event

Event participants

Charles Wanguhu, Coordinator, Kenya CSO Platform on Oil and Gas
Ndanga Kamau, Oil and Gas Policy Adviser, Oxfam Kenya
John Ochola, Chairman, Kenya CSO Platform on Oil and Gas / EcoNews Africa
Simon Thompson, Chairman, Tullow Oil
Chair: Alex Vines, Research Director, Area Studies and International Law; Head, Africa Programme, Chatham House 

25 November 2014

This paper accompanies a series of assessments on China, France, Japan, the Netherlands, the UK, the US and Vietnam, providing details on how the estimates of the level of illegality of imports of wood-based products into those countries were derived.

Invitation Only Research Event

Research Event

Event participants

HE Dr Kayode Fayemi, Minister of Solid Minerals Development, Nigeria
HE Aminu Bello Masari, Governor of Katsina State, Nigeria
Chair: Chi Onwurah MP, Vice Chair, All Party Parliamentary Group on Nigeria

There will be a lot of attention paid to D-backs infielder Jake Lamb when Spring Training gets underway. Lamb, of course, is coming off a season that was almost entirely lost to a left shoulder injury. His healthy return would play a big part in helping the D-backs' offense overcome the departures of Paul Goldschmidt and A.J. Pollock during the offseason.

Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D₂ and D₃ receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (¹¹C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14–30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20–30 min; spleen as reference region) demonstrated a statistically significant reduction (–36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20–30 min) (R² = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20–30 min) (R² = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20–30 min) (R² = 0.57, P = 0.05), nor did mean baseline proinsulin (R² = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D₃ receptor and dopamine D₂ receptor in HCs. No colocalization of the dopamine D₃ receptor or dopamine D₂ receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D₃ receptor, dopamine D₂ receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D₃ receptor and dopamine D₂ receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for ¹¹C-(+)-PHNO, a dopamine D₃ receptor–preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.