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| Open AccessDeletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice
Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.
- Takayoshi Sasako
- , Toshihiro Umehara
- & Kohjiro Ueki
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Article
| Open AccessLipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion
During hypoglycemia, glucagon secretion is part of the mechanism needed to restore normal blood glucose levels. Here, Strembitska et al. report that sensing of hypoglycemia by AgRP neurons requires Agpat5, an enzyme which prevents fatty acids from entering the mitochondria for ATP production, ensuring correct neuronal activation and glucagon secretion.
- Anastasiya Strembitska
- , Gwenaël Labouèbe
- & Bernard Thorens
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| Open AccessMicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans.
- Mary P. LaPierre
- , Katherine Lawler
- & Markus Stoffel
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| Open AccessMYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open AccessInterferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Murine models of obesity suggest that decreases in the adipose tissue regulatory T cell compartment may contribute to insulin resistance, but how this corresponds in the human clinical context is less well understood. Here the authors propose a role for interferon gamma in shrinking the adipose tissue regulatory T cell compartment seen in human obesity and assess the alterations seen during induction of dietary changes.
- David Bradley
- , Alan J. Smith
- & Willa A. Hsueh
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Article
| Open AccessDiabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder
Patients with diabetes have an increased susceptibility to infections. Here the authors show that high glucose impairs innate immunity through reduced levels of the antimicrobial peptide psoriasin and impaired epithelial barrier function, resulting in an increased risk of urinary tract infection.
- Soumitra Mohanty
- , Witchuda Kamolvit
- & Annelie Brauner
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open AccessNo evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial
Exercise modulates brown adipose tissue (BAT) metabolism in murine models. Here the authors report that there is no evidence that 24 weeks of supervised exercise training modulates BAT volume or function in young sedentary adults in the ACTIBATE randomized controlled trial.
- Borja Martinez-Tellez
- , Guillermo Sanchez-Delgado
- & Jonatan R. Ruiz
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Article
| Open AccessAdipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2.
- Tianshi Feng
- , Xuemei Zhao
- & Xiaoyan Hui
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Article
| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessSpermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression
Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.
- Jin Zhou
- , Jeremy Pang
- & Paul Michael Yen
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Article
| Open AccessAdipocytes control food intake and weight regain via Vacuolar-type H+ ATPase
Energy metabolism is dysregulated in obesity, and some if these changes persist after weight loss and may contribute to weight regain. Here the authors report that a vacuolar-type H+ ATPase, ATP6v0a1, is induced in adipocytes during obesity and persists after weight loss, and regulates food intake and weight gain in C. elegans and mice.
- Rizaldy C. Zapata
- , Maria Carretero
- & Olivia Osborn
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| Open AccessA Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes
Children with type 1 diabetes (T1D) are at risk for reduced cognitive ability and atypical brain development. This study shows that brain and cognitive measures can be improved in adolescents with T1D using a semi-automated insulin delivery system.
- Allan L. Reiss
- , Booil Jo
- & Juan Marrero
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Article
| Open AccessA TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
BDNS and TrkB are involved in bone fracture healing by inhibiting AEP. Here the authors show that a TrkB agonist prodrug can inhibit AEP and promote bone formation in osteoporotic mice.
- Jing Xiong
- , Jianming Liao
- & Keqiang Ye
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Article
| Open AccessA new gene set identifies senescent cells and predicts senescence-associated pathways across tissues
Identification of senescent cells in vivo remains a challenging task. Here the authors present and validate a senescence gene set called SenMayo enriched in human and murine aged tissues.
- Dominik Saul
- , Robyn Laura Kosinsky
- & Sundeep Khosla
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Article
| Open AccessExploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment
Weight regain after weight loss is a challenge in obesity treatment and may involve altered eating and sedentary behaviour after weight loss. Here the authors report an exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment.
- Simon Birk Kjær Jensen
- , Charlotte Janus
- & Signe Sørensen Torekov
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Article
| Open AccessProhormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing
Defective insulin secretion is observed early in the development of diabetes. Here the authors report that β cell-specific deficiency of the insulin prohormone convertase 1/3 (PC1/3) leads not only to hyperglycemia, but also to hyperphagic obesity in mice.
- Daniel T. Meier
- , Leila Rachid
- & Marc Y. Donath
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Article
| Open AccessEGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance
In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.
- Shirong Cao
- , Yu Pan
- & Ming-Zhi Zhang
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Article
| Open AccessDicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Kiss1 neurons are essential for puberty and fertility. Here, the authors show that canonical microRNA biosynthesis in Kiss1 neurons plays an essential role in the control of puberty and fertility, especially in females, likely via repression of repressors on the Kiss1 gene.
- Juan Roa
- , Miguel Ruiz-Cruz
- & Manuel Tena-Sempere
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| Open AccessBlocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
- Andre Lima Queiroz
- , Ezequiel Dantas
- & Marcus D. Goncalves
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Article
| Open AccessAdaptation to chronic ER stress enforces pancreatic β-cell plasticity
Pancreatic β-cells are naturally prone to ER stress due to their role in insulin production and secretion. Here, the authors show that chronic ER stress adaptive exhaustion results in an irreversible loss of β-cell function leading to T1D pathogenesis
- Chien-Wen Chen
- , Bo-Jhih Guan
- & Maria Hatzoglou
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Article
| Open AccessDeficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)
Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH
- Xinzhi Li
- , Kaixin Ding
- & Zheng Chen
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Article
| Open AccessMaladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure
ChREBP is a glucose-responsive transcription factor, which regulates glucose-mediated proliferation and cell death in pancreatic β-cells. Here the authors show that the acute feed forward induction of ChREBPβ is required for adaptive β-cell expansion, that chronic overexpression of ChREBPβ is toxic to β-cells, and offer mitigation strategies
- Liora S. Katz
- , Gabriel Brill
- & Donald K. Scott
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Article
| Open AccessRare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity
Abdominal fat has been shown to increase cardiometabolic disease risk. In this study, the authors report that loss-of-function variants in the gene INHBE associate with lower BMI-adjusted waist-to-hip ratio, a surrogate measure of abdominal fat.
- Aimee M. Deaton
- , Aditi Dubey
- & Paul Nioi
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Article
| Open AccessA critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells
Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.
- Yingying Ye
- , Mohammad Barghouth
- & Erik Renström
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Article
| Open AccessZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes
Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.
- Qing Ma
- , Yini Xiao
- & Weida Li
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Article
| Open AccessSomatic cell fate maintenance in mouse fetal testes via autocrine/paracrine action of AMH and activin B
Fate determination and maintenance of foetal testes in most animals occurs cell autonomously. Here the authors show in mouse XY embryos that Sertoli cell derived AMH and activin B together maintain Sertoli cell identity, and lack of both AMH and activin B leads to transdifferentiation into female granulosa cells.
- Karina F. Rodriguez
- , Paula R. Brown
- & Humphrey Hung-Chang Yao
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| Open AccessAdipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism
Dysregulation of plasmalogen metabolism in adipose tissue is associated with metabolic diseases. Here the authors characterize the role of adipocyte TMEM86A as a lysoplasmalogenase and show its deletion is protective against high fat diet induced metabolic disease, an effect that can be recapitulated by plasmenyl lysophosphatidylethanolamine 18:0 supplementation.
- Yoon Keun Cho
- , Young Cheol Yoon
- & Yun-Hee Lee
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Article
| Open AccessInherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots
The inherited basis of body fat distribution is not fully understood. Here, the authors use genetic data and MRI-derived measures of local adiposity to highlight fat depot-specific genetic architecture with implications for cardiometabolic health.
- Saaket Agrawal
- , Minxian Wang
- & Amit V. Khera
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Article
| Open AccessRegulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor
Insulin sensitivity declines with age via unclear mechanisms. Here, the authors show that the activity of membrane type 1 matrix metalloproteinase (MT1-MMP) is increased with ageing, leading to cleavage of the insulin receptor, and show that metabolic effects can be rescued by MT1-MMP inhibition in mice.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessDeep learning to diagnose Hashimoto’s thyroiditis from sonographic images
Hashimoto’s thyroiditis (HT) is the main cause of hypothyroidism. Here the authors develop a deep learning model for diagnosis of HT on a large multi-site dataset including image and video data.
- Qiang Zhang
- , Sheng Zhang
- & Xiangchun Li
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Article
| Open AccessA phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes
Glucagon-like peptide-1 receptor (GLP1R) agonists are used to treat type 2 diabetes (T2D), and polyagonists targeting multiple hormone receptors are investigated as potential therapeutics for T2D. Here the authors report that IBI362 (LY3305677), a balanced once-weekly GLP-1 and glucagon receptor dual agonist, showed favourable safety and tolerability in Chinese patients with type 2 diabetes in a randomized controlled phase 1b clinical trial.
- Hongwei Jiang
- , Shuguang Pang
- & Wenying Yang
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Article
| Open AccessIslet autoantibody seroconversion in type-1 diabetes is associated with metagenome-assembled genomes in infant gut microbiomes
Here, by characterizing gut metagenomes of at-risk children in the TEDDY project, the authors associate onset of autoimmunity leading to Type-1 diabetes with certain sets of microorganisms in the gut microbiota, and identify metabolic capabilities encoded in the genomes of these microorganisms that provide functional insights to the association.
- Li Zhang
- , Karen R. Jonscher
- & Chongle Pan
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Article
| Open AccessMicroRNA-21 promotes pancreatic β cell function through modulating glucose uptake
The microRNA miR-21 is induced in the islets of patients with glucose intolerance and diabetic mice. Here the authors report that deletion of miR-21 in pancreatic β-cells impairs glucose-stimulated insulin secretion via reduced glucose uptake, while a miR-21 agomir reduces blood glucose leves in diabetic male mice.
- Ruiling Liu
- , Cuilian Liu
- & Qingguo Ruan
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Article
| Open AccessAdipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling
Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.
- Teng Huang
- , Jia Song
- & Cong-Yi Wang
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Article
| Open AccessTriiodothyronine (T3) promotes brown fat hyperplasia via thyroid hormone receptor α mediated adipocyte progenitor cell proliferation
Thyroid hormone (TH) action regulates brown adipose tissue thermogenic capacity through incompletely understood mechanisms. Here the authors report that T3, the active form of TH, increases thermogenic capacity via thyroid hormone receptor α-mediated hyperplasia of brown adipose tissue adipocyte progenitor cells.
- Shengnan Liu
- , Siyi Shen
- & Hao Ying
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Article
| Open AccessThe gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases
Chronic insomnia is associated with cardiometabolic diseases. Here, in two clinical cohorts (n = 7,931), authors show that gut microbiota-bile acid axis may be an intervention target to attenuate the impact of chronic insomnia on cardiometabolic health.
- Zengliang Jiang
- , Lai-bao Zhuo
- & Ju-Sheng Zheng
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Article
| Open AccessMultiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice
Adipose immune cells contribute to obesity-related disease, but less is known about weight cycling. Here, authors show that weight loss reduces diabetes risk, but inflammatory adipose immune cell populations persist and may contribute to worsened diabetes risk upon weight regain.
- Matthew A. Cottam
- , Heather L. Caslin
- & Alyssa H. Hasty
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| Open AccessMetabolic regulation by the intestinal metformin-AMPK axis
AMP-activated protein kinase (AMPK) mediates the glucose-lowering effect of the antidiabetic agent metformin, but the sites of action remain unclear. In the March issue of Nature Communications, Zhang and colleagues reported that intestinal epithelium-specific AMPKα1 knockout mice fail to respond to metformin and exhibit disruption in metabolic homeostasis secondary to changes in the gut microbiome. This highlights a therapeutic potential of targeting intestinal AMPK for diabetes.
- Song-Yang Zhang
- & Tony K. T. Lam
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Article
| Open AccessStructural insights into the mechanism of pancreatic KATP channel regulation by nucleotides
KATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic KATP in both the closed state and the pre-open state. These structures illuminate the mechanism of KATP channel regulation by the intracellular nucleotides.
- Mengmeng Wang
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessIL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice
TLRs/IL-1R signaling play a role in high-fat diet induced adipose tissue dysfunction and obesity-associated metabolic syndrome. Here the authors report that adipocyte-specific deficiency of IL-1 Receptor-Associated Kinase M (IRAKM) ameliorates diet induced obesity, potentially via the mitochondrial citrate carrier Slc25a1 and reduced de novo lipogenesis.
- Weiwei Liu
- , Hao Zhou
- & Xiaoxia Li
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Article
| Open AccessDNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases
Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.
- Matthias Wielscher
- , Pooja R. Mandaviya
- & Marjo-Riitta Järvelin
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Article
| Open AccessMitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis
Sidarala et al. examine the importance of the mitochondrial structural proteins, Mitofusins 1 and 2 (Mfn1/2), in diabetes. They find that Mfn1/2 control blood glucose by preserving mitochondrial DNA content, rather than mitochondrial structure.
- Vaibhav Sidarala
- , Jie Zhu
- & Scott A. Soleimanpour
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Article
| Open AccessA parallel randomised controlled trial of the Hypoglycaemia Awareness Restoration Programme for adults with type 1 diabetes and problematic hypoglycaemia despite optimised self-care (HARPdoc)
Impaired awareness of hypoglycaemia (IAH) is a risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). Here the authors report that a group programme focussing on changing cognitive barriers to avoiding hypoglycaemia (HARPdoc) does not reduce severe hypoglycaemia more than a programme focussing on behaviours (BGAT) in a randomized control trial in adults with T1D and treatment-resistant IAH and severe hypoglycaemia.
- Stephanie A. Amiel
- , Laura Potts
- & Nicole de Zoysa
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Article
| Open AccessGlycaemic control is associated with SARS-CoV-2 breakthrough infections in vaccinated patients with type 2 diabetes
In this study, Marfella et al. show that patients with diabetes and poor glycaemic control have a blunted response to COVID-19 vaccine and are more prone to develop breakthrough infections, with further analysis suggesting smoking and male sex as potential risk factors to get COVID-19 despite vaccination.
- Raffaele Marfella
- , Celestino Sardu
- & Giuseppe Paolisso
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Article
| Open AccessGeneration of human islet cell type-specific identity genesets
Cell therapy to replace β-cells is a potential therapeutic avenue to treat diabetes, but the production of insulin-secreting replacement cells requires reliable tools to assess islet cellular identity. Here the authors use single-cell transcriptomics meta-analysis to construct gene sets that describe the identity of human α-, β-, γ- and δ-cells.
- Léon van Gurp
- , Leon Fodoulian
- & Pedro L. Herrera
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Article
| Open AccessInsulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis
The downstream mechanisms involved in insulin signaling and resistance remain incompletely understood. Here the authors report that insulin-dependent dephosphorylation stabilizes ERRα via the GSK3β/FBXW7 axis, and disruption of this post-translational mechanism results in insulin resistance in mice.
- Hui Xia
- , Charlotte Scholtes
- & Vincent Giguère
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Article
| Open AccessGut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice
Caloric restriction is a common approach to weight reduction, however, weight regain is common. Here the authors report that caloric restriction reduces the abundance of Parabacteroides distasonis in the gut and alters serum bile acid (BA) profile, which contribute to weight regain in mice.
- Mengci Li
- , Shouli Wang
- & Wei Jia
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Article
| Open AccessMitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice
Senescent cells play a role in pathogenesis of diabetes, and senolytic agents can improve obesity- and diabetes-related pathologies. Here the authors report that mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, alleviates symptoms of obesity and prediabetes in mice, potentially via reduction of food intake and elimination of senescent cells.
- Eliska Vacurova
- , Jaroslava Trnovska
- & Jiri Neuzil