In this interview from Preventing Overdiagnosis 2017 (preventingoverdiagnosis.net) Stacy Carter, associate professor at Sydney Health Ethics - and the author of a recently written BMJ essay the ethical aspects of overdiagnosis, joins us to talk about how the cultural context of medicine seeps into our decision making processes and affects how...

This week we’re at the over diagnosis conference in Quebec Canada, Preventing overdiangosis is a forum to discuss the harms associated with using uncertain methods to look for disease in apparently healthy people - and is part of the BMJ’s too much medicine campaign. One of the ways in which the public’s attitudes and wishes around health is...

If you're a patient in the UK, increasingly, your first interaction with the healthcare system won't be the traditional face to fact chat with your doctor - instead you'll have a telephone consultation. The prevalence of these telephone consultations is increasing, and being promoted by CCGs and private companies who administer them - usually as...

Assessing young people with possible eating disorders can be complex for a variety of reasons. Building a therapeutic relationship with a young person with a possible eating disorder and their family is key to enabling a thorough assessment and ongoing management, but it introduces difficult issues regarding confidentiality and risk. In this...

Manflu, the phenomenon that men experience the symptoms of viral illness more than woman, is usually used with derision - but a new review, published in the Christmas edition, is asking - is there a plausible biological basis for this sex difference? Kyle Sue is a clinical assistant professor in family medicine at Memorial University of...

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,...

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...

Dyspareunia is a common but poorly understood problem affecting around 7.5% of sexually active women. It is an important and neglected area of female health, associated with substantial morbidity and distress. Women may be seen by several clinicians before a diagnosis is reached, There are also specialist psychosexual clinics, where men and women...

This week saw the latest Preventing Overdiagnosis conference - this time in Copenhagen. The conference is a is a forum where researchers and practitioners can present examples of overdiagnosis - and we heard about the various ways which disease definitions are being subtly widened, and diagnostic thresholds lowered. In this podcast we talk to...

The concept of overdiagnosis is pretty hard to get - especially if you’ve been educated in a paradigm where medicine has the answers, and it’s only every a positive intervention in someone’s life - the journey to understanding the flip side - that sometimes medicine can harm often takes what Stacey Carter director of Research for Social Change at...

We want clinical trials to be thorough - but Vinay Prasad, assistant professor of medicine at Oregon Health Science University, argues that the problem of overdiagnosis may be as prevalent, in the way we measure disease in our research, as our practice. In this podcast he joins us to discuss the problem, and why he thinks what qualifies as...

Machines that can learn and correct themselves already perform better than doctors at some tasks, but not all medicine is task based - but will AI doctors ever be able to have a therapeutic relationship with their patients? In this debate, Jörg Goldhahn, deputy head of the Institute for Translational Medicine at ETH Zurich thinks that the...

You’ll have read in a clinical trial “Most patients had an acceptable adverse-event profile.” Or that a drug “has a manageable and mostly reversible safety profile.” And that “the tolerability was good overall.” In this podcast, Bishal Gyawali (@oncology_bg) joins us to describe what events those terms were actually describing in cancer drug...

We have had two articles published recently on bmj.com, looking at drug prevention of HIV; PeP - Post-exposure Prophylaxis and PreP - Pre-exposure Prophylaxis, neither prevent the virus from entering the body, but they do prevent the infection from taking hold. There are lots of questions that doctors have about these - what are the risk...

Patients who experience chronic rhinosinusitis may way for a considerable period of time before presenting, because they believe the condition to be trivial. In this podcast, Alam Hannan, ENT Consultant at the Royal Throat Nose and Ear Hospital in London, explains why that belief is not founded, and describes which treatments can be effective at...

In every generation there are a few that know the secret; the counterintuitive effects of loop diuretics. In this podcast Steven Anisman, cardiologist at the Dartmouth Hitchcock Department of Cardiovascular Medicine, joins us to explain about the threshold effects of these drugs, and why that might change the way in which you think about...

Cannabinoid hyperemesis syndrome is a relatively newly recognised condition - but, according to one study, can account for up to 6% of patients presenting to emergency departments. The causal mechanism is as yet unclear - but currently the only known way to prevent the syndrome is for the patient to stop their cannabis use. Yaniv Chocron, chief...

Burnout is a problem in healthcare - it’s a problem for individuals, those who experience it and decide to leave a career they formerly loved, but it’s also a problem for our healthcare system. Burnout is associated with an increase in medical errors, and poor quality of care. Fundamentally it’s a patient safety issue. But, unlike other patient...

We heard a few podcasts ago about burnout - what it is, and why it should be thought of as a systems issue. Now a project in the Netherlands is trying to investigate who it is that is particularly at risk of burnout, and hopes to test whether individually tailored coaching and counselling can help those who are experiencing the symptoms change the...

Reverse innovation may sound like some attempt to return to the dark ages - but it has a specific meaning, especially when it comes to med-tech. It’s about where we look for innovation - and overturning our preconceived ideas of where new ideas come from. Mark Skopec, and Matthew Harris - both from Imperial College London are two of the authors...

In October 2019, Mary Dixon-Woods, director of the THIS Institute, dedicated to healthcare improvement. In that she explained how she believed healthcare improvement could be improved. The essay took the position that "Quality Improvement" isn't necessarily the best way to improve healthcare, and that more rigour needs to be brought to the field....

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...

Around the world, as the covid pandemic plays out, and some countries are starting to ease their restrictions, this narrative of the economy and public health being opposing weights on a set of scales keeps returning - they need to be balanced. But before this, a healthy population is very much seen as being supportive of the economy. So is a...

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...

Joseph G. Yu
Oct 1, 2002; 51:2968-2974
Obesity Studies

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

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

R A DeFronzo
Dec 1, 1981; 30:1000-1007
Original Contribution

Giulio Marchesini
Aug 1, 2001; 50:1844-1850
Pathophysiology

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

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

The Diabetes Control and Complications Trial Research Group
Aug 1, 1995; 44:968-983
Original Article

National Diabetes Data Group
Dec 1, 1979; 28:1039-1057
Articles

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (P_interaction = 3.7 x 10^–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Western Bureau: Some displaced Iberostar employees in Rose Hall, St James, are angry with their employer, charging that they have been unable to benefit from the Government’s COVID-19 relief programme because of the hotel’s failure to pay over...

Edmond Campbell/Senior Parliamentary Reporter Conceding that healthcare workers in the public sector are burnt out as they combat COVID-19, Health and Wellness Minister Dr Christopher Tufton says the Government is taking steps to boost its...

Days after The Gleaner reported a clarion call from Port Maria Mayor Richard Creary for the quarantine of St Mary communities owing to growing concerns about the spread of COVID-19 in the parish, the Government responded with the lockdown of three...

BRIDGETOWN, Barbados, CMC – A few weeks before the official start of the 2020 Atlantic Hurricane Season, forecasters at the US-based Colorado State University are warning that the six-month period will be more active than normal. The CSU...

As of May 6, officials in Nevis are reporting that there are no active cases of the deadly COVID-19 virus on the island. This was confirmed Tuesday by Premier Mark Brantley, Minister responsible for Health, in the Nevis Island Administration....

Reds Spring Training in Goodyear, Ariz., will feature a new manager in David Bell, a new coaching staff and several new players. Here is what you need to know about 2019 camp.

Upon the passing of his physical on Tuesday, the Reds signed infielder/outfielder Derek Dietrich to a Minor League contract with an invitation to big league camp for Spring Training.

THE EDITOR, Madam: How many more will have to suffer? How many more will have to die to end the discrimination often meted out to persons suspected of or confirmed with COVID-19? The novel coronavirus is highly contagious, seems so mysterious, and...

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.

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.