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Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages
G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.
- Jing Yan
- , Yuemei Zhang
- & Cheng Hu
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Causal deep learning reveals the comparative effectiveness of antihyperglycemic treatments in poorly controlled diabetes
Current treatment guidelines for Type-2 diabetes endorse a massive number of potential anti-hyper-glycemic treatment options in various permutations and combinations. Here, the authors present a causal deep learning approach for more personalized recommendations of treatment selection.
- Chinmay Belthangady
- , Stefanos Giampanis
- & Beau Norgeot
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Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes
Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression.
- Paul M. H. Tran
- , Fran Dong
- & Sharad Purohit
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Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration
How bone-related sexually dimorphic traits are regulated hasn’t been examined at the stem cell level. Here the authors show that skeletal stem cells (SSC), in female but not male mice, are directly controlled by estrogen signaling, which could be augmented to improve fracture repair.
- Tom W. Andrew
- , Lauren S. Koepke
- & Charles K. F. Chan
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Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
- Ying Yan
- , Zhoumin Niu
- & Hao Ying
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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes
Here, by performing multi-omics microbiome analyses in a cohort of children with new-onset T1D, the authors characterize altered microbial functional and metabolic traits involved in T1D, which they validate in animal experiments, together providing potential avenues for microbiome-based interventions.
- Xiaoxiao Yuan
- , Ruirui Wang
- & Feihong Luo
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Wnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function
Diabetes is characterized by loss or dysfunction of pancreatic β-cells. Here the authors show that the signalling protein WNT4 is heterogeneously activated by β-cells during their postnatal maturation with WNT4 positive cells being more mature, and that inactivating WNT4 in β-cells after maturation impairs beta-cell function.
- Keiichi Katsumoto
- , Siham Yennek
- & Anne Grapin-Botton
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The metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial
Combining a GLP-1 receptor agonist, to increase endogenous beta cell function, with exogenous insulin is a possible therapeutic option for the treatment of type 2 diabetes. Here, the authors show adding exenatide to basal insulin in early type 2 diabetes does not further enhance underlying pancreatic beta-cell function or the capacity to achieve diabetes remission, but may yield on-treatment glycemic benefits.
- Ravi Retnakaran
- , Chang Ye
- & Bernard Zinman
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Article
| Open Access
Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling
The insulin signalling cascade can be inhibited by phosphatases, including Ser/Thr protein phosphatase 2A (PP2A). Here the authors show that Alpha4, a regulator of the PP2A catalytic subunit, modulates insulin receptor tyrosine phosphorylation via the YBX-1/PTP1B pathway and is involved in maintenance of adipose tissue homeostasis and systemic metabolism.
- Masaji Sakaguchi
- , Shota Okagawa
- & Eiichi Araki
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A predictive computational platform for optimizing the design of bioartificial pancreas devices
Transplanting encapsulated insulin-producing cells may achieve a functional cure for type 1 diabetes, but efficacy is constrained by mass transfer limits. Here, the authors report a dynamic computational platform to investigate the therapeutic potency of such programmable bioartificial pancreas devices.
- Alexander U. Ernst
- , Long-Hai Wang
- & Minglin Ma
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Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
Retinal pigment epithelium (RPE) plays an important role in diabetic retinopathy (DR) progression. Here, the authors show AKT1 and AKT2 are reciprocally regulated in the RPE of DR donor tissue and diabetic mice, reducing Akt2 in RPE causing a compensatory increase in Akt1 and attenuating DR.
- Haitao Liu
- , Nadezda A. Stepicheva
- & Debasish Sinha
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Deletion 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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Lipid 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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MYPT1-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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Interferon 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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Liver 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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No 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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Adipocyte-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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Identification 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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Adipocytes 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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A 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 Access
A 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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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
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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Prohormone 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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EGFR-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 Access
Dicer 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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Blocking 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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| Open Access
Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis
How pancreatic islets of Langerhans are built during development is incompletely understood. Here the authors find that Synaptotagmin-13 mediates remodeling of cell-matrix adhesion to regulate endocrine cell egression and islet morphogenesis.
- Mostafa Bakhti
- , Aimée Bastidas-Ponce
- & Heiko Lickert
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Deficiency 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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A 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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ZnT8 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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Somatic 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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Adipocyte 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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| Open Access
Inherited 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 Access
Regulation 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 Access
Deep 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 Access
A 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 Access
Adipocyte-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 Access
Triiodothyronine (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 Access
Multiomics 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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Article
| Open Access
Serotonin limits generation of chromaffin cells during adrenal organ development
Adrenal glands are major organs regulating stress response., Melnikova et al., show that local release of serotonin limits adrenalin-producing cell number during rodent development, a mechanism which has implications for neuroblastoma development and stress-related maternal effects transmitted to progeny.
- Polina Kameneva
- , Victoria I. Melnikova
- & Igor Adameyko
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Comment
| Open Access
Metabolic 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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| Open Access
DNA 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 Access
Mitofusin 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 Access
A 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 Access
Glycaemic 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 Access
Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling
In vitro differentiation of pancreatic beta cells offers a potential therapeutic approach for diabetes. Here they show human pluripotent stem cell derived pancreatic progenitors differentiate into insulin-secreting cells by crosstalk of WNT5A and BMP signaling.
- Jolanta Chmielowiec
- , Wojciech J. Szlachcic
- & Malgorzata Borowiak
Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice