2.46 million people in England have osteoarthritis of the hip, and many of those go on to eventually have a hip replacement - which is now widely considered one of the most commonly performed and successful operations in the world. Jessamy Bagenal, clinical fellow with The BMJ, talks to Nick Nicholas, an obstetrician who has had OA and one of...

2.46 million people in England have osteoarthritis of the hip, and many of those go on to eventually have a hip replacement - which is now widely considered one of the most commonly performed and successful operations in the world. Jessamy Bagenal, clinical fellow with The BMJ, talks to Nick Aresti, a specialist registrar in trauma and...

Pharma companies say that money spent on promotion is essential to educate doctors about the best drugs - but when a medical student asked Joseph Ross, associate professor of medicine and public health at Yale, if those companies are promoting the right drugs for that message to be true, the answer wasn't available. Ross and Tyler Greenaway, his...

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...

Sue Farrington is chair of the Patient Information Forum, a member organisation which promotes best practice in anyone who produces information for patients. In this podcast, she discusses what makes good patient information, why doctors should be pleased when patients arrive at an appointment with a long list of questions, and why patients are...

Diabetes is synonymous with sugar, but diabetes insipidus, "water diabetes", can't be forgotten. Between 2009 and 2016, 4 people died in hospital in England, when lifesaving treatment for the condition was not given. In this podcast, we hear some practical tips for non-specialists to aid diagnosis, and how patients should be managed during...

At EBM live recently, we ran a workshop with researchers, patients and clinicians to talk about patient rights in research - should patients be setting the full research agenda? Should they be full participants and authors? Helen Macdonald, BMJ’s UK research editor and co-host of our talk evidence podcast sat down to Paul Wicks, researcher and...

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...

This edition of talk evidence was recorded before the big increase in covid-19 infections in the UK, and then delayed by some self isolation. We'll be back with more evidence on the pandemic very soon. As always Duncan Jarvies is joined by Helen Macdonald (resting GP and editor at The BMJ) and Carl Heneghan (active GP, director of Oxford...

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

Masayuki Saito
Jul 1, 2009; 58:1526-1531
Metabolism

Marc Prentki
Mar 1, 1996; 45:273-283
Original Article

Charles M. Alexander
May 1, 2003; 52:1210-1214
Complications

D Dabelea
Dec 1, 2000; 49:2208-2211
Articles

Roger H Unger
Aug 1, 1995; 44:863-870
Perspectives in Diabetes

Samar I. Itani
Jul 1, 2002; 51:2005-2011
Rapid Publications

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

Norikazu Maeda
Sep 1, 2001; 50:2094-2099
Pathophysiology

Steven E Kahn
Nov 1, 1993; 42:1663-1672
Original Article

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

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ~1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine.

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children’s plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and -aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

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.

Tears flowed yesterday down the face of Donaree Anderson, cousin of 15-year-old Nyron Taylor, one of two children shot dead in west Kingston hours apart on Wednesday. Eight-year-old Toya Brown was the other child killed just days into the month...

It was not the landing the Jamaicans who arrived at Kingston’s Norman Manley International Airport on Wednesday evening would want again. The 43 Jamaican ship workers of the Marella Discovery 2 were among the 115 people aboard the TUI charter flight that touched down amid the Kingston breeze and evening sunset.

PORT OF SPAIN, Trinidad, CMC – Prime Minister Dr Keith Rowley Saturday dismissed as a “dishonest last gasp and gamble of a dangerously delusional woman” a statement by Opposition Leader Kamla Persad Bissessar calling for him...

Led by vice president of home clubhouse operations Rick Stowe, who began working for the club in 1981 and became head of the clubhouse in 1997, the Reds have a well-oiled machine with regard to packing up and moving out.

Beat reporter Mark Sheldon answers questions about David Bell's managing style, free agents and who will play center field.

The COVID-19 pandemic around the world has taken the world by storm, touching the lives of every human being on Earth. The global nature of the crisis has united us as human beings and tragedy and deaths in any country by COVID-19 worry us all....

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.

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.

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.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or "vasocrine," signaling. However, direct experimental evidence supporting a role of local PVAT in regulating IMVR and insulin sensitivity in vivo is lacking. Here, we studied muscles with and without PVAT in mice using combined contrast-enhanced ultrasonography and intravital microscopy to measure IMVR and gracilis artery diameter at baseline and during the hyperinsulinemic-euglycemic clamp. We show, using microsurgical removal of PVAT from the muscle microcirculation, that local PVAT depots regulate insulin-stimulated muscle perfusion and glucose uptake in vivo. We discovered direct microvascular connections between PVAT and the distal muscle microcirculation, or adipomuscular arterioles, the removal of which abolished IMVR. Local removal of intramuscular PVAT altered protein clusters in the connected muscle, including upregulation of a cluster featuring Hsp90ab1 and Hsp70 and downregulation of a cluster of mitochondrial protein components of complexes III, IV, and V. These data highlight the importance of PVAT in vascular and metabolic physiology and are likely relevant for obesity and 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.

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.

¹⁶⁶Ho-microspheres have recently been approved for clinical use for hepatic radioembolization in the European Union. The aim of this study was to investigate the absorbed dose–response relationship and its association with overall survival for ¹⁶⁶Ho radioembolization in patients with liver metastases. Methods: Patients treated in the HEPAR I and II studies who underwent an ¹⁸F-FDG PET/CT scan at baseline, a posttreatment ¹⁶⁶Ho SPECT/CT scan, and another ¹⁸F-FDG PET/CT scan at the 3-mo follow-up were included for analysis. The posttreatment ¹⁶⁶Ho-microsphere activity distributions were estimated with quantitative SPECT/CT reconstructions using a quantitative Monte Carlo–based method. The response of each tumor was based on the change in total lesion glycolysis (TLG) between baseline and follow-up and was placed into 1 of 4 categories, according to the PERCIST criteria, ranging from complete response to progressive disease. Patient-level response was grouped according to the average change in TLG per patient. The absorbed dose–response relationship was assessed using a linear mixed model to account for correlation of tumors within patients. Median overall survival was compared between patients with and without a metabolic liver response, using a log-rank test. Results: Thirty-six patients with a total of 98 tumors were included. The relation between tumor-absorbed dose and both tumor-level and patient-level response was explored. At a tumor level, a significant difference in geometric mean absorbed dose was found between complete response (232 Gy; 95% confidence interval [CI], 178–303 Gy; n = 32) and stable disease (147 Gy; 95% CI, 113–191 Gy; n = 28) (P = 0.01) and between complete response and progressive disease (117 Gy; 95% CI, 87–159 Gy; n = 21) (P = 0.0008). This constitutes a robust absorbed dose–response relationship. At a patient level, a significant difference was found between patients with complete or partial response (210 Gy; 95% CI, 161–274 Gy; n = 13) and patients with progressive disease (116 Gy; 95% CI, 81–165 Gy; n = 9) (P = 0.01). Patients were subsequently grouped according to their average change in TLG. Patients with an objective response (complete or partial) exhibited a significantly higher overall survival than nonresponding patients (stable or progressive disease) (median, 19 mo vs. 7.5 mo; log-rank, P = 0.01). Conclusion: These results confirm a significant absorbed dose–response relationship in ¹⁶⁶Ho radioembolization. Treatment response is associated with a higher overall survival.

β-Cell antigen recognition by autoreactive T cells is essential in type 1 diabetes (T1D) pathogenesis. Recently, insulin hybrid peptides (HIPs) were identified as strong agonists for CD4 diabetogenic T cells. Here, using BDC2.5 transgenic and NOD mice, we investigated T-cell recognition of the HIP2.5 epitope, which is a fusion of insulin C-peptide and chromogranin A (ChgA) fragments, and compared it with the WE14 and ChgA_29–42 epitopes. We measured in situ two-dimensional affinity on individual live T cells from thymus, spleen, pancreatic lymph nodes, and islets before and after diabetes. Although preselection BDC2.5 thymocytes possess higher affinity than splenic BDC2.5 T cells for all three epitopes, peripheral splenic T cells maintained high affinity only to the HIP2.5 epitope. In polyclonal NOD mice, a high frequency (~40%) of HIP2.5-specific islet T cells were identified at both prediabetic and diabetic stages comprising two distinct high- and low-affinity populations that differed in affinity by 100-fold. This high frequency of high- and low-affinity HIP2.5 T cells in the islets potentially represents a major risk factor in diabetes pathogenesis.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

28 February 2020

Invitation Only Research Event

HE Raffaele Trombetta, Italian Ambassador to the UK, Co-Host, COP 26
Archie Young, UK Lead Climate Negotiator, Cabinet Office 
Peter Betts, Associate Fellow, Energy, Environment and Resources Department, Chatham House
Chair: Professor Tim Benton, Research Director, Energy, Environment and Resources, Chatham House  

In the run-up to COP26 in Glasgow, Chatham House is organizing monthly briefings about the UN climate negotiations and climate change more broadly. The events provide an excellent opportunity to discuss the most pressing and complex climate issues of the day with government officials, renowned experts and members of the London-based diplomatic community.

Research Event

Event participants

Research Event

Event participants

Even as the 1.8 million number swirls in the discussion of how many DREAMers would be placed on a path to citizenship, proposals debated in the Senate in February 2018 would have resulted in the legalization of smaller numbers, as this commentary explains. It offers estimates of potential beneficiaries of several Senate proposals, including one backed by the White House, and analysis of key criteria.

Approximately 11,500 unaccompanied children were apprehended at the U.S.-Mexico border in May, putting this year on track to exceed 2014's surge. As the U.S. government struggles to care for these child migrants, with public outrage mounting over reports of unsafe, filthy conditions in initial Border Patrol custody, the failure of the executive branch and Congress to plan for increased shelter and care demands are increasingly apparent, as this article explores.