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| Open AccessLoss of bone morphogenetic protein-binding endothelial regulator causes insulin resistance
Type 2 diabetes is associated with chronic inflammation and is characterized by insulin resistance. Here, the authors identify a crucial role for endothelial BMPER function in glucose homeostasis, and BMPER overexpression was shown to alleviate insulin resistance and hyperglycemia in diabetic mice.
- Hua Mao
- , Luge Li
- & Xinchun Pi
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Article
| Open AccessMetabolic responses to mild cold acclimation in type 2 diabetes patients
Cold acclimation has been shown to have beneficial metabolic effects, including improved insulin sensitivity in patients with type 2 diabetes. Here the authors show that a mild cold acclimation regiment during which overt shivering was prevented did not result in improved insulin sensitivity in a small group of patients with type 2 diabetes.
- Carlijn M. E. Remie
- , Michiel P. B. Moonen
- & Patrick Schrauwen
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Article
| Open AccessLysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism
Dietary changes can impact the microbial constitution of the gastrointestinal tract and modulate the local immune response. Here, the authors show supplementation using lysates of Methylococcus capsulatus Bath result in changes to the microbiota, modulate Treg populations and metabolic read outs in a dietary control murine model.
- Benjamin A. H. Jensen
- , Jacob B. Holm
- & Tor E. Lea
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Review Article
| Open AccessThe metabolic impact of small intestinal nutrient sensing
The gastrointestinal tract participates in maintaining metabolic homeostasis in part through nutrient-sensing and subsequent gut-brain signalling. Here the authors review the role of small intestinal nutrient-sensing in regulation of energy intake and systemic glucose metabolism, and link high-fat diet, obesity and diabetes with perturbations in these pathways.
- Frank A. Duca
- , T. M. Zaved Waise
- & Tony K. T. Lam
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Article
| Open AccessPDX1LOW MAFALOW β-cells contribute to islet function and insulin release
Beta cell subpopulations with low expression in PDX1, MAFA, and insulin might contribute to islet function and insulin release. Here the authors show that altering the proportion of PDX1LOW MAFALOW to PDX1HIGH MAFAHIGH cells impairs islet function.
- Daniela Nasteska
- , Nicholas H. F. Fine
- & David J. Hodson
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Article
| Open AccessAn autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer
Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in hIAPP+ mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.
- Jinyoung Kim
- , Kihyoun Park
- & Myung-Shik Lee
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Article
| Open AccessSex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
- Vasiliki Lagou
- , Reedik Mägi
- & Inga Prokopenko
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Article
| Open AccessTranskingdom interactions between Lactobacilli and hepatic mitochondria attenuate western diet-induced diabetes
Western diet is one of the major causes underlying diabetes, and the microbes residing in the gut playing a critical role in mediating the effects of diet. Here the authors utilize network analysis to discover two species of Lactobacilli decreased by western diet, which improve glucose metabolism and restore of hepatic mitochondria in mice.
- Richard R. Rodrigues
- , Manoj Gurung
- & Natalia Shulzhenko
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Article
| Open AccessWisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells
The proliferation of pancreatic beta cells decreases with age, partly due to systemic changes. Here the authors identify Wisp1 as a circulating factor enriched in young serum that induces adult beta cell proliferation, supporting the idea that young blood factors may be useful to expand beta cell mass.
- Rebeca Fernandez-Ruiz
- , Ainhoa García-Alamán
- & Rosa Gasa
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Article
| Open AccessMyeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation
Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.
- David R. Sweet
- , Neelakantan T. Vasudevan
- & Mukesh K. Jain
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Article
| Open AccessMetformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits
Metformin is an anti-diabetic drug that has shown promise to reduce M. tuberculosis susceptibility. Here the authors show that this effect is a result of metformin-mediated activation of anti-mycobacterial memory-like antigen-inexperienced CD8+CXCR3+ T cells, an effect that also boosts response to BCG vaccination.
- Julia Böhme
- , Nuria Martinez
- & Amit Singhal
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Article
| Open AccessAberrant methylation underlies insulin gene expression in human insulinoma
Insulinomas are rare, benign beta cell tumours which overproduce insulin and have been associated to epigenetic alterations. Here the authors characterise insulinoma methylomes, finding changes in promoter methylation and chromatin structure proposed to drive the pathological expression of insulin.
- Esra Karakose
- , Huan Wang
- & Luca Lambertini
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Article
| Open AccessGut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study)
The gut microbiome affects systemic metabolism and is a therapeutic target for type 2 diabetes. Here the authors demonstrate in a randomized controlled trial that effects of berberine, a plant alkaloid known to lower blood glucose, may be explained by the inhibition of Ruminococcus bromii mediated biotransformation of the bile acid deoxycholic acid.
- Yifei Zhang
- , Yanyun Gu
- & Weiqing Wang
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Article
| Open AccessGenetic variant effects on gene expression in human pancreatic islets and their implications for T2D
Mechanistic inference following GWAS is hampered by the lack of tissue-specific transcriptomic resources. Here the authors combine genetic variants predisposing to type 2 diabetes with human pancreatic islet RNA-seq data. They identify 7741 islet expression quantitative trait loci (eQTLs), providing a resource for functional interpretation of association signals mapping to non-coding sequence.
- Ana Viñuela
- , Arushi Varshney
- & Mark I. McCarthy
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Article
| Open AccessRepurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development
Inflammasome activation may contribute to type 2 diabetes, but whether targeting inflammasome is beneficial is unclear. Here the authors show that repurposing nucleoside reverse transcriptase inhibitors for inhibiting inflammasome activation is associated with reduced diabetes development in people and improves insulin sensitivity in experimental settings.
- Jayakrishna Ambati
- , Joseph Magagnoli
- & Bradley D. Gelfand
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Article
| Open AccessDR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus
Group 2 innate lymphoid cells (ILC2s) are immune cells present in adipose tissue that contribute to metabolic homeostasis. Here the authors show that Death Receptor 3 (DR3) engagement on ILC2s ameliorates glucose tolerance, protects against insulin-resistance onset and reverses established insulin-resistance.
- Pedram Shafiei-Jahani
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessTranscriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission
In rodent models of type 2 diabetes, sustained remission of hyperglycemia can be induced by FGF1 action in the mediobasal hypothalamus. Here, the authors show that FGF1-injection is followed by marked changes in glial cell populations and that the sustained glycemic response is dependent on intact melanocortin signaling.
- Marie A. Bentsen
- , Dylan M. Rausch
- & Tune H. Pers
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Article
| Open AccessTargeting QKI-7 in vivo restores endothelial cell function in diabetes
Vascular endothelial cell (EC) dysfunction contributes to the occurrence of diabetic complications. Here the authors report that in diabetic conditions, upregulation of the RNA binding protein QKI-7 in ECs due to the imbalance of RNA splicing factors CUG-BP and hnRNPM contributes to EC dysfunction, and that in vivo QKI-7 silencing improves blood flow recovery in diabetic mice with limb ischemia.
- Chunbo Yang
- , Magdalini Eleftheriadou
- & Andriana Margariti
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Article
| Open AccessMucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity
Inflammation, immune cells and the host microbiota are intimately linked in the pathophysiology of obesity and diabetes. Here the authors show mucosal-associated invariant T cells fuel inflammation in the tissues and serve a function in promoting metabolic breakdown, polarising macrophage populations and inducing dysbiosis of the intestinal microbiota.
- Amine Toubal
- , Badr Kiaf
- & Agnès Lehuen
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Article
| Open AccessAn integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells
The cytokine IFNα is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells. Here, the authors provide a global multiomics view of IFNα-induced changes in human beta cells at the level of chromatin, mRNA and protein expression.
- Maikel L. Colli
- , Mireia Ramos-Rodríguez
- & Décio L. Eizirik
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Article
| Open AccessRaptor determines β-cell identity and plasticity independent of hyperglycemia in mice
During the progression of type 2 diabetes, insulin-producing β-cells can lose their identity and become reprogrammed into other cell types. Here the authors show that murine diabetic β-cells require the protein Raptor for maintaining β-cell health and preventing them from turning into α-cells, independent of Raptor’s involvement in regulating blood sugar levels.
- Qinglei Yin
- , Qicheng Ni
- & Guang Ning
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Article
| Open AccessMD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways.
- Yi Wang
- , Wu Luo
- & Guang Liang
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Article
| Open AccessSGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease
SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.
- So Ra Kim
- , Sang-Guk Lee
- & Yong-ho Lee
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Article
| Open AccessHepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance
Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.
- Kay H. M. Roumans
- , Lucas Lindeboom
- & Vera B. Schrauwen-Hinderling
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Article
| Open AccessParacrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of α-cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.
- Muhmmad Omar-Hmeadi
- , Per-Eric Lund
- & Sebastian Barg
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Article
| Open AccessBrain insulin sensitivity is linked to adiposity and body fat distribution
Brain insulin action regulates eating behavior and whole-body energy fluxes, however the impact of brain insulin resistance on long-term weight and body fat composition is unknown. Here, the authors show that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution.
- Stephanie Kullmann
- , Vera Valenta
- & Martin Heni
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Article
| Open AccessObesity-induced overexpression of miR-802 impairs insulin transcription and secretion
Obesity predisposes to type 2 diabetes, but the mechanisms of obesity-associated β cell dysfunction are incompletely understood. Here the authors report that obesity increases the levels of miR-802, which impairs insulin transcription and secretion by targeting NeuroD1 and Fzd5.
- Fangfang Zhang
- , Dongshen Ma
- & Liang Jin
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Article
| Open AccessVascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina
hPSCs in culture acquire a more naïve pluripotent state upon tankyrase inhibition. Here, the authors show that tankyrase inhibitor-regulated naïve hiPSCs from diabetic donors generate more vascular progenitors and more efficient engraftment into mouse retina than conventional PSCs.
- Tea Soon Park
- , Ludovic Zimmerlin
- & Elias T. Zambidis
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Article
| Open AccessGenetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance
Serotonin inhibits adipose tissue thermogenesis. Here the authors show that obese mice housed in thermoneutrality have increased mast cell serotonin synthesis, and that inhibiting this pathway through deletion of mast cell Tph1 increases white adipose tissue browning and protects against diet-induced obesity, insulin resistance and liver steatosis.
- Julian M. Yabut
- , Eric M. Desjardins
- & Gregory R. Steinberg
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Article
| Open AccessPredicting optical coherence tomography-derived diabetic macular edema grades from fundus photographs using deep learning
Diabetic eye disease is a cause of preventable blindness and accurate and timely referral of patients with diabetic macular edema is important to start treatment. Here the authors present a deep learning model that can predict the presence of diabetic macular edema from color fundus photographs with superior specificity and positive predictive value compared to retinal specialists.
- Avinash V. Varadarajan
- , Pinal Bavishi
- & Dale R. Webster
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Article
| Open AccessNAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD+ depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.
- Evandro F. Fang
- , Yujun Hou
- & Vilhelm A. Bohr
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Article
| Open AccessZwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation
Cellular overgrowth and fibrosis in the foreign body response can compromise the function of transplanted cells. Here, the authors report on the zwitterionically modified alginates for the encapsulation of cells to reduce cellular overgrowth and demonstrate application in mice, dogs and pigs.
- Qingsheng Liu
- , Alan Chiu
- & Minglin Ma
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Article
| Open AccessNeratinib protects pancreatic beta cells in diabetes
Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.
- Amin Ardestani
- , Sijia Li
- & Kathrin Maedler
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Article
| Open AccessEngineering transferrable microvascular meshes for subcutaneous islet transplantation
The success of engineered tissue depends on the integration of a dense vascular network to supply nutrients and remove waste products. Here the authors design high density microvascular meshes made through an anchored self-assembly mechanism, and use these meshes to support subcutaneous pancreatic islet survival in a mouse diabetes model.
- Wei Song
- , Alan Chiu
- & Minglin Ma
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Article
| Open AccessGut-associated IgA+ immune cells regulate obesity-related insulin resistance
The effect of diet-induced obesity on intestinal B cell populations is not well understood despite emerging evidence of a critical role for the intestinal immune system in contributing to insulin resistance. Here, the authors show important functions of IgA in regulating metabolic disease and for intestinal immunity in modulating systemic glucose metabolism.
- Helen Luck
- , Saad Khan
- & Daniel A. Winer
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Article
| Open AccessS100A9 extends lifespan in insulin deficiency
Insulin replacement is a valuable therapy for insulin deficiency, however, other therapies are being investigated to restore metabolic homeostasis. Here, the authors identify S100A9 as a leptin induced circulating cue that improves glucose and lipid homeostasis and extends survival in insulin deficient mice.
- Giorgio Ramadori
- , Sanda Ljubicic
- & Roberto Coppari
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Article
| Open AccessRole of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism
Diabetes is associated with decreased PI3K activation in skeletal muscle. Here, the authors show that p110a is the predominant PI3K subunit in muscle, and show that its ablation in muscle, but not ablation of p110beta, leads to insulin resistance, increased proteosomal and autophagic activity, and altered mitochondria homeostasis in mice.
- Mengyao Ella Li
- , Hans P. M. M. Lauritzen
- & C. Ronald Kahn
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Article
| Open AccessLysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes
Impaired beta-cell insulin secretion is a key pathological feature of type 2 diabetes. Here, the authors describe metabolic stress induced lysosomal degradation of newly formed insulin granules, independent of macroautophagy, as a potential mechanism for beta-cell dysfunction.
- Adrien Pasquier
- , Kevin Vivot
- & Romeo Ricci
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Article
| Open AccessAdipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity
Whether adipose ILC1s regulate adipose tissue fibrogenesis is unknown. Here, the authors report a direct role of adipose ILC1s in adipose tissue fibrogenesis and provide insights into the mechanisms of local immune dysfunction in obesity-associated metabolic disorders.
- Hongdong Wang
- , Lei Shen
- & Yan Bi
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Article
| Open AccessZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response
Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.
- Adebowale A. Adeyemo
- , Norann A. Zaghloul
- & Charles N. Rotimi
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Article
| Open AccessIAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function
Type 2 diabetes is associated with islet amyloid deposits derived from islet amyloid polypeptide (IAPP) expressed by β-cells. Here the authors show that IAPP misfolded protein stress induces the hypoxia inducible factor 1 alpha injury repair pathway and activates survival metabolic changes mediated by PFKFB3.
- Chiara Montemurro
- , Hiroshi Nomoto
- & Slavica Tudzarova
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Article
| Open AccessAn integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.
- Jun Liu
- , Elena Carnero-Montoro
- & Cornelia M. van Duijn
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Article
| Open AccessDiabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells
Pancreatic beta-cell glucose metabolism is coupled to insulin secretion. Here the authors set out to characterize changes in beta-cell metabolism in hyperglycemia which may contribute to insufficient insulin secretion in type 2 diabetes and, using a multi-omics approach, find that mitochondrial metabolism is perturbed.
- Elizabeth Haythorne
- , Maria Rohm
- & Frances M. Ashcroft
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Article
| Open AccessAntidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Mitochondrial uncoupling is a treatment strategy for metabolic diseases that reduces the efficiency of mitochondrial oxidative phosphorylation and ATP generation. Here the authors characterize the pharmacokinetic and therapeutic properties of the liver-localized mitochondrial uncoupler OPC-163493, which leads to amelioration of diabetes and hypertension in several rodent disease models.
- Naohide Kanemoto
- , Takashi Okamoto
- & Seiji Sato
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Article
| Open AccessPancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.
- William W. Greenwald
- , Joshua Chiou
- & Kyle J. Gaulton
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Article
| Open AccessA fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion
The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.
- Michael J. Texada
- , Anne F. Jørgensen
- & Kim F. Rewitz
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Article
| Open AccessAdenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons
Glucagon-like peptide 1 (GLP-1) is released from intestinal L-cells following nutrient uptake and enhances insulin release as well as promotes satiety. Here, the authors demonstrate that GLP-1 secreting cells release ATP and that this stimulates nodose neurons and enterocytes in a paracrine manner in vitro.
- Van B. Lu
- , Juraj Rievaj
- & Frank Reimann
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Article
| Open AccessIntradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.
- Li-Ming Gan
- , Maria Lagerström-Fermér
- & Regina Fritsche-Danielson
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Article
| Open AccessInhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production
The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
- T. M. Zaved Waise
- , Mozhgan Rasti
- & Tony K. T. Lam