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| Open AccessRNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells
Development of probes specific for human β-cells could aid in delivery of therapeutics and monitoring β-cells mass during diabetes progression or islet transplantation. Here the authors identify two RNA aptamers specific for β-cells that allow efficient transfection of human islets and β-cell quantification of human islet grafts in immunodeficient mice.
- Dimitri Van Simaeys
- , Adriana De La Fuente
- & Paolo Serafini
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Article
| Open AccessAdipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice
Obesity impairs regulation of adipocyte lipolysis, which contributes towards development of insulin resistance. Here the authors report that adipocyte Gq signaling functions as a regulator of lipolysis and systemic glucose and lipid homeostasis in mice, suggesting that agents able to stimulate this pathway may prove useful as antidiabetic drugs.
- Takefumi Kimura
- , Sai P. Pydi
- & Jürgen Wess
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| Open AccessTargeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors
BRAF-V600E mutation is common in patients with papillary thyroid carcinoma (PTC) and has been associated with an aggressive phenotype. Here the authors show that the mutation supports cancer progression by reactivating the developmental factor TBX3 and promoting the recruitment of myeloid derived suppressive cells.
- Peitao Zhang
- , Haixia Guan
- & Li Zhao
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Article
| Open AccessAdrenal tropism of SARS-CoV-2 and adrenal findings in a post-mortem case series of patients with severe fatal COVID-19
Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19.
- Tanja Paul
- , Stephan Ledderose
- & Martina Rudelius
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Article
| Open AccessProgression of type 1 diabetes from latency to symptomatic disease is predicted by distinct autoimmune trajectories
Presence of islet autoantibodies precedes the onset of type 1 diabetes but it does not predict whether and how fast symptomatic disease appears. Here authors present a model to predict and visualize progression to diabetes by using a large longitudinal data set on autoantibodies and clinical parameters as input.
- Bum Chul Kwon
- , Vibha Anand
- & Brigitte I. Frohnert
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Article
| Open AccessAged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.
- Zhen-Xing Wang
- , Zhong-Wei Luo
- & Hui Xie
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Article
| Open AccessDeep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis.
- Magdalene K. Montgomery
- , Jacqueline Bayliss
- & Matthew J. Watt
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Article
| Open AccessIntestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis
Mammalian 5′-AMP-activated protein kinase (AMPK) is a nutrient sensor and a therapeutic target for Type 2 Diabetes. Here the authors report that intestinal AMPK modulates brown adipose tissue thermogenesis through anti-microbial peptide controlled gut microbiota and may partially underlie the anti-diabetic effects of metformin.
- Eryun Zhang
- , Lihua Jin
- & Wendong Huang
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Article
| Open AccessExploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes
Oral verapamil lowers inflammatory markers and daily insulin needs in subjects with type 1 diabetes and helps preserve pancreatic beta cell function for at least two years. In this context, serum chromogranin A provides a promising therapy marker.
- Guanlan Xu
- , Tiffany D. Grimes
- & Anath Shalev
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Article
| Open AccessMethionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis
High methionine and S-adenosylmethionine serum levels are related with obesity. Here the authors show that knockdown of methionine adenosyltransferase by using antisense oligonucleotides provides beneficial effects in obesity and comorbidities.
- Diego Sáenz de Urturi
- , Xabier Buqué
- & Patricia Aspichueta
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Article
| Open AccessSIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase
NAD + metabolism is potential target to treat metabolic disorders, in part due to the effects of the NAD + dependent enzyme Sirt1. Here the authors report that hepatic nicotinamide phosphoribosyltransferase, a rate-limiting step in the NAD + salvage pathway, regulates dark-cycle thermogenesis in a Sirt1-dependent but light-cycle thermogenesis and glucose homeostasis in a Sirt1-independent manner.
- Cassandra B. Higgins
- , Allyson L. Mayer
- & Brian J. DeBosch
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Article
| Open AccessRandomized controlled trial for time-restricted eating in healthy volunteers without obesity
Time-restricted eating, both early (eTRF) and mid-day (mTRF), have been shown to have metabolic benefits. Here the authors report a randomized controlled trial to compare the effects of eTRF and mTRF in healthy volunteers without obesity, and find that eTRF is more effective in improving the primary outcome insulin sensitivity.
- Zhibo Xie
- , Yuning Sun
- & Yilei Mao
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Article
| Open AccessFunctionally selective signaling and broad metabolic benefits by novel insulin receptor partial agonists
Insulin therapies for patients with diabetes have challenges, including diminished hepatic preference of insulin action compared with endogenous insulin. Here the authors characterize insulin dimers that function as insulin receptor partial agonists, and exhibit hepatic and adipose tissue preference of insulin action and metabolic benefits in preclinical models.
- Margaret Wu
- , Ester Carballo-Jane
- & James Mu
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Article
| Open AccessSmall molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.
- Susheel K. Gunasekar
- , Litao Xie
- & Rajan Sah
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Article
| Open AccessAn optogenetic approach for regulating human parathyroid hormone secretion
Parathyroid hormone (PTH) plays a role in maintaining calcium and phosphorus homeostasis, and in secondary hyperparathyroidism excess PTH secretion contributes to bone loss. Here the authors report an optogenetic approach to inhibit PTH secretion in human hyperplastic parathyroid cells, and prevented hyperplastic parathyroid tissue-induced bone loss in mice.
- Yunhui Liu
- , Lu Zhang
- & Fan Yang
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Article
| Open AccessLymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis
Hashimoto’s Thyroiditis is an autoimmune disease with a complex pathomechanism. Authors here show by single cell RNA sequencing that the thyroidal microenvironment in the disease is characterised by three stromal cell subtypes that are potentially responsible for the recruitment of infiltrating inflammatory immune cells, such as macrophages and dendritic cells.
- Qian-Yue Zhang
- , Xiao-Ping Ye
- & Huai-Dong Song
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Article
| Open AccessCaffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.
- Paul F. Lebeau
- , Jae Hyun Byun
- & Richard C. Austin
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Article
| Open AccessBeta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance
Insulin receptor protein is present in pancreatic β-cells, but the consequences of β-cell insulin resistance are incompletely understood. Here the authors use a combination of mouse studies and mathematical modelling to show that loss of beta-cell insulin receptor affects male and female mice differently and can contribute to hyperinsulinemia in the context of glucose stimulation.
- Søs Skovsø
- , Evgeniy Panzhinskiy
- & James D. Johnson
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Article
| Open AccessThe gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress
Intestinal nutrient-sensing is important in metabolic control. Here the authors show that the gut-derived hormone Allatostatin C, a somatostatin homolog in fruit flies, links enteric nutrient sensing to behavioral and metabolic adaptations that maintain energetic homeostasis in Drosophila melanogaster.
- Olga Kubrak
- , Takashi Koyama
- & Kim Rewitz
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| Open AccessThe IGFBP3/TMEM219 pathway regulates beta cell homeostasis
In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
- Francesca D’Addio
- , Anna Maestroni
- & Paolo Fiorina
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| Open AccessPharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity
Signalling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects in obesity. Here the authors report that a selective pharmacologic activator of IRE1/XBP1s signalling stimulates an adaptive remodelling of liver and pancreas in diet-induced obese mice and mitigates obesity-linked systemic metabolic dysfunction.
- Aparajita Madhavan
- , Bernard P. Kok
- & R. Luke Wiseman
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Article
| Open AccessAccumulation of microbial DNAs promotes to islet inflammation and β cell abnormalities in obesity in mice
Obesity is associated with increased gut permeability, and microbial products that are leaked from the gut may contribute towards obesity-associated inflammation. Here the authors show that the leakage of gut extracellular vesicles containing microbial DNA leads to bacterial DNA accumulation in pancreatic β-cells, promoting obesity-associated islet inflammation.
- Hong Gao
- , Zhenlong Luo
- & Wei Ying
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Article
| Open AccessEnrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1
STX4 is a regulator of the glucose transporter GLUT4 vesicle fusion at the plasma membrane in skeletal muscle. Here, the authors show that skeletal muscle-specific STX4 enrichment reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress.
- Karla E. Merz
- , Jinhee Hwang
- & Debbie C. Thurmond
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Article
| Open AccessThe mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production
Disordered hepatic glucagon response contributes to hyperglycemia in diabetes via gluconeogenesis. Here the authors report that the mitochondrial β-oxidation enzyme HADHA promotes β-hydroxybutyrate production, which negatively regulates hepatic gluconeogenesis during glucagon challenge by targeting HDAC7 in mice.
- An Pan
- , Xiao-Meng Sun
- & Lian-Wen Qi
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Article
| Open AccessSingle cell transcriptomic landscape of diabetic foot ulcers
Diabetic foot ulcers (DFUs) remain a complication of diabetes that are difficult to heal and lead to disability. Here the authors use single-cell RNA-sequencing and spatial transcriptomics to characterize the DFU cellular landscape and identify a population of fibroblasts that is associated with successful wound closure.
- Georgios Theocharidis
- , Beena E. Thomas
- & Manoj Bhasin
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| Open AccessMechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts.
- Ziang Xie
- , Lei Hou
- & Shunwu Fan
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Article
| Open AccessParacrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects
Fibroblast growth factors are involved in systemic glucose homeostasis and of interest for developing therapies for type 2 diabetes and associated metabolic diseases. Here the authors identify paracrine FGF4 as an anti-hyperglycemic FGF, which targets skeletal muscle to upregulate the glucose transporter GLUT4 cell surface abundance.
- Lei Ying
- , Luyao Wang
- & Zhifeng Huang
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Article
| Open AccessEpigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.
- Adrienne Tin
- , Pascal Schlosser
- & Anna Köttgen
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Article
| Open AccessGPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1
Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism.
- Lucia Balazova
- , Miroslav Balaz
- & Christian Wolfrum
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Article
| Open AccessSexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome
Male sex is a risk factor for impaired glucose metabolism and type 2 diabetes. Here the authors identify that androgen modulates the gut microbiome, which drives insulin resistance and contributes to sexual dimorphism in glucose metabolism in mice.
- Aibo Gao
- , Junlei Su
- & Weiqing Wang
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Article
| Open AccessThe multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes
The p53 tumor suppressor is also a regulator of metabolism, but the mechanisms controlling p53-associated metabolic activities remain poorly understood. Here the authors report that the deletion of the multifunctional protein E4F1 is protective against diet-induced obesity in mice, and E4F1 regulates adipocyte lipid metabolism through p53.
- Matthieu Lacroix
- , Laetitia K. Linares
- & Laurent Le Cam
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| Open AccessSpatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis
How enhancers transition from a hypoacetylated primed state to a hyperacetylated-active state in response to differentiation stimuli is incompletely understood. Here the authors show that SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of master adipogenic gene enhancers, while SETD5 degradation triggers enhancer hyperacetylation and transition to active state.
- Yoshihiro Matsumura
- , Ryo Ito
- & Juro Sakai
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Article
| Open AccessDietary excess regulates absorption and surface of gut epithelium through intestinal PPARα
Intestinal surface changes in size and function, but what propels these alterations is unknown. Here, the authors show that food excess increases the gut absorptive capacity, and that in presence of dietary lipids, intestinal PPARα is indispensable for the adaptive increase in villi length and function.
- Ozren Stojanović
- , Jordi Altirriba
- & Mirko Trajkovski
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Article
| Open AccessWFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells
The role of cargo receptors in proinsulin export from the ER is unclear. Here, the authors identify the WFS1 protein, which is mutated in Wolfram syndrome and associated with diabetes, as an ER to Golgi cargo receptor required for normal insulin processing and secretion.
- Linlin Wang
- , Hongyang Liu
- & Zonghong Li
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Article
| Open AccessHigh-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control
Factors underlying the effects of gastric bypass surgery on glucose homeostasis are incompletely understood. Here the authors developed and applied high-throughput mediation analysis to identify proteome/metabolome mediators of improved glucose homeostasis after to gastric bypass surgery, and report that improved glycemia was mediated by the growth hormone receptor.
- Jonathan M. Dreyfuss
- , Yixing Yuchi
- & Mary Elizabeth Patti
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Article
| Open AccessAGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway
AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the synthesis of all glycerolipids. Here, the authors show that AGPAT2 and CDP-DAG synthases (CDS1 and CDS2) form functional complexes that promote further conversion of PA along the CDP-DAG pathway of phospholipid synthesis.
- Hoi Yin Mak
- , Qian Ouyang
- & Hongyuan Yang
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Article
| Open AccessImprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance
Maternal obesity predisposes offspring to obesity and metabolic disorders through incompletely understood mechanisms. Here the authors report that Dio3os is an imprinted long-coding RNA that modulates brown adipose tissue development and obesity resistance in the offspring.
- Yan-Ting Chen
- , Qi-Yuan Yang
- & Min Du
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Article
| Open AccessBST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities
Nicotinamide riboside (NR) is a NAD + precursor exhibiting beneficial effects against aging. Here the authors demonstrate that orally administered NR increases NAD + levels in a diphasic manner and that bone marrow stromal cell antigen 1 plays a crucial role for NAD + synthesis from NR.
- Keisuke Yaku
- , Sailesh Palikhe
- & Takashi Nakagawa
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Article
| Open AccessThe APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages
Inflammasome regulation is not fully understood. Here the authors show that the early endosomal APPL1-Rab5 axis removes damaged mitochondria and then restricts the inflammasome response in macrophages, alleviating the inflammatory diseases.
- Kelvin Ka Lok Wu
- , KeKao Long
- & Kenneth King Yip Cheng
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Article
| Open AccessElevated circulating follistatin associates with an increased risk of type 2 diabetes
Follistatin promotes in type 2 diabetes (T2D) pathogenesis in model animals and is elevated in patients with T2D. Here the authors report that plasma follistatin associates with increased risk of incident T2D in two longitudinal cohorts, and show that follistatin regulates insulin-induced suppression lipolysis in cultured human adipocytes.
- Chuanyan Wu
- , Yan Borné
- & Yang De Marinis
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Article
| Open AccessDiet composition influences the metabolic benefits of short cycles of very low caloric intake
Understanding the contribution of diet composition, calories and length of fasting in health maintenance is still challenging. Here the authors compare the effects of cycles of intermittent very low calorie intake achieved with a plant-based fasting mimicking diet or standard laboratory chow to provide insights into the role played by diet composition in mediating the metabolic benefits of short cycles of very low-calorie intake in mice.
- Alberto Diaz-Ruiz
- , Tyler Rhinesmith
- & Rafael de Cabo
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Article
| Open AccessMMAB promotes negative feedback control of cholesterol homeostasis
The mechanisms governing cholesterol homeostasis remain incompletely understood. Here, the authors develop an integrative genomic strategy to identify MMAB, and enzyme in the adenosylcobalamin pathway, as a regulator of hepatic LDLR activity and cholesterol biosynthesis.
- Leigh Goedeke
- , Alberto Canfrán-Duque
- & Carlos Fernández-Hernando
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Article
| Open AccessControl of osteocyte dendrite formation by Sp7 and its target gene osteocrin
The molecular circuitry that drives dendrite formation during osteocytogenesis remains poorly understood. Here the authors show that deletion of Sp7, a gene linked to rare and common skeletal disease, in mature osteoblasts and osteocytes causes severe defects in osteocyte dendrites.
- Jialiang S. Wang
- , Tushar Kamath
- & Marc N. Wein
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Article
| Open AccessEndurance exercise training-responsive miR-19b-3p improves skeletal muscle glucose metabolism
Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.
- Julie Massart
- , Rasmus J. O. Sjögren
- & Anna Krook
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Article
| Open AccessA bioinspired scaffold for rapid oxygenation of cell encapsulation systems
Cell encapsulation into biomaterials for transplantation is currently limited by inadequate oxygenation. Here the authors present a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels and demonstrate correction of diabetes in immunocompetent mice using rat islets for over 6 months.
- Long-Hai Wang
- , Alexander Ulrich Ernst
- & Minglin Ma
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Article
| Open AccessAnalyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach
Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen.
- Jonathan Yinhao Huang
- , Shirong Cai
- & Shiao-Yng Chan
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Article
| Open AccessBerberine is an insulin secretagogue targeting the KCNH6 potassium channel
Berberine is a compound with glucose-lowering effects in mice and humans. Here, the authors show that in mice berberine has beneficial glycemic effects by promoting insulin secretion, which requires the potassium channel KCNH6 in beta cells, and that berberine can promote insulin secretion in healthy men in a phase 1 clinical trial.
- Miao-Miao Zhao
- , Jing Lu
- & Jin-Kui Yang
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Article
| Open AccessA phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes
Berberine ursodeoxycholate has been studied for its serum lipid and lipoprotein lowering effects. Here the authors report an 18-week phase 2, randomised, double-blind, placebo-controlled clinical trial that tested the effect of berberine ursodeoxycholate in patients with fatty liver disease and diabetes, and showed that the group taking the higher dose of the drug had reduced liver fat content.
- Stephen A. Harrison
- , Nadege Gunn
- & Adrian M. Di Bisceglie
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| Open AccessA randomized controlled trial of pharmacist-led therapeutic carbohydrate and energy restriction in type 2 diabetes
Community pharmacists are accessible healthcare providers with expertise in medication management. Here the authors show that a low-carbohydrate, low-energy diet implemented by community pharmacists reduced diabetes medication use and improved glucose control in people with type 2 diabetes.
- Cody Durrer
- , Sean McKelvey
- & Jonathan P. Little