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.

Jackie Applebee is a GP in Tower Hamlets in London, and is concerned that the way the GP funding formula is working doesn't take account of the earlier health needs of people in deprived areas. For more about the Tower Hamlets Save Our Surgery campaign, visit their facebook page https://www.facebook.com/SaveOurGPsurgeries BMJ Voices is a...

We’re taught that patients' ideas, concerns, and expectations are central to a successful consultation, but has ICEing gone too far? A “What your patient is thinking” article published this week talks about the pressure that asking questions in the wrong way can put on a patient. Sophie Cook, education editor for The BMJ, is joined by the author...

Ravi Gupta, is a resident in internal medicine at Johns Hopkins in Baltimore - and as he said has seen the influence of sudden price hikes on his patients - between 2010 and 2015 more than 300 drugs in the U.S. have seen sudden increases of over %100. Ravi and his co-authors have suggested, and tested the feasibility of, a possible answer to...

The first digital banking in the UK was launched in 1983, Skype turns 15 this year, but 2017 finally saw panic over the impact that online consultations may have on general practices. In this podcast Martin Marshall, professor of healthcare improvement at University College London joins us to discuss whether video conference actually is a...

Until recently, The BMJ had a campaign of patient partnership - now we have a patient and public partnership campaign. The reason for that change is that medicine has an effect beyond the individual being treated - and this podcast interview is a very good example of that. Anya De Iong, patient editor for The BMJ, talks to Christine Morgan -...

In the second of our EBM round-ups, Carl Heneghan, Helen Macdonald and Duncan Jarvies are joined by Deborah Cohen, investigative journalist and scourge of device manufacturers. We're giving our verdict on the sensitivity and specificity of ketone testing for hyperemesis, and the advice to drinking more water to prevent recurrent UTIs in...

The problem we had publishing our feed has been fixed, and normal service has resumed. Thank you for subscribing to the podcast, if you have thoughts you'd like to express, we'd love to hear them. https://www.bmj.com/podcasts

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...

Wellbeing might not seem the obvious place to talk about PPE - but lack of appropriate PPE is causing healthcare staff a great deal of stress now. Mary Brindle is a pediatric surgeon and the director of The EQuIS (Efficiency Quality Innovation and Safety) Research platform at Alberta Children’s hospital. In this podcast she reflects on the use...

We’ve published info on Telehealth in primary care - and have been overwhelmed by the response from GPs who are finding it useful. But it’s not only primary care that is dramatically shifting to remote care - routine hospital care is moving online too, so we’ve asked Rowena McCash - GP and out of hours triage trainer joins us to give some tips...

There is no doubt that anxiety levels that clinicians are feeling during this pandemic are high. One military medic believes the current situation is comparable to his experience when posted during British campaigns in Afghanistan and Iraq. Cormac Doyle offers advice on how to deal with high-stress conditions, both in a work and at home, as...

Richard S Surwit
Sep 1, 1988; 37:1163-1167
Original Article

Patrice D. Cani
Jun 1, 2008; 57:1470-1481
Metabolism

One of the best catchers in baseball was available all winter in J.T. Realmuto, and the Reds were very much one of the teams in hot pursuit in trade talks with the Marlins. But on Thursday, it was the Phillies who acquired Realmuto from Miami.

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using ²H₂O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of ¹³C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

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.

2 July 2014 , Volume 90, Number 4

1 December 2014

15 November 2016

A rise in mortality is a price worth paying to restart the US economy, President Trump has said, as many states flout advice from scientists and reopen beaches, cinemas, or hair salons while new...

Members Event

Event participants

Katrín Jakobsdóttir, Prime Minister, Iceland
Chair: Professor Tim Benton, Director, Energy Environment and Resources Department, Chatham House
 

Marking the release of an MPI report, this webinar examines what the growing intersection between U.S. immigration and child welfare systems means for protection agencies. Speakers also discuss promising child welfare policies and agency approaches to address the needs of children of immigrants and their families amid demographic change and rising immigration enforcement.

As federal and state governments ramp up efforts to implement the Workforce Innovation and Opportunity Act, these fact sheets compare key characteristics of the foreign born and the U.S. born that are relevant to understanding needs for adult education and workforce training services. The fact sheets cover the United States, the 20 states and 25 counties with the largest immigrant populations, and New York City.

As policymakers look for ways to address the drivers of illegal immigration, many have called for migration aims to be incorporated into development work and development tools into migration partnerships. This policy brief analyzes the benefits and risks of heightened cooperation between actors in these fields, and identifies areas where joint initiatives may prove fruitful.

While it has been years since the Association of Southeast Asian Nations signed accords to facilitate the movement of professionals in seven occupations, implementation of these Mutual Recognition Arrangements remains "painfully slow and uneven across countries." This final report in an MPI-Asian Development Bank series explores MRA implementation by sector, and offers recommendations to help achieve the goal of greater skill mobility in Southeast Asia.

A webinar releasing a report examining deportations to Central America and reception and reintegration services in El Salvador, Guatemala, and Honduras.

For a growing population of migrants deported from Mexico and the United States to Central America, the conditions upon return typically are worse than when they left, setting up a revolving-door cycle of migration, deportation, and remigration. This report provides a detailed profile of reception and reintegration services offered in El Salvador, Guatemala, and Honduras to deported migrants, examining their challenges and opportunities for improvement. 

A webinar releasing a report examining deportations to Central America and reception and reintegration services in El Salvador, Guatemala, and Honduras.

Police and firefighters in Michigan came to the rescue of a family of baby geese that wandered out onto a busy highway and fell into a storm sewer.

Police in the Netherlands said officers responding to reports of a loose camel ended up capturing an emu running wild through the city of Rotterdam.

Police and public works employees in Wisconsin came to the rescue of a deer that found itself struggling to escape a soccer net.

Pratik Choudhary
Jun 1, 2015; 38:1016-1029
Type 1 Diabetes at a Crossroads

Police in India said security forces killed a top Hizbul Mujahideen commander amid a series of gunfights in the disputed Jammu and Kashmir region on Wednesday.

As the COVID-19 pandemic begins to take root in Africa, experts say that digitizing financial services could help keep the continent safe

Military Entrance Processing Stations won't process individuals who have had COVID-19 for military service, even if they've fully recovered from the virus, the Pentagon confirmed this week.

Jan 1, 2019; 42:S3-S3
Professional Practice Committee

Jan 1, 2020; 43:S3-S3
Professional Practice Committee