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| 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 AccessCitrullination of glucokinase is linked to autoimmune diabetes
Post translational modifications are involved in the regulation of a number of proteins and can be themselves modified by the cellular environment. Here the authors implicate citrullination of glucokinase in autoimmune diabetes
- Mei-Ling Yang
- , Sheryl Horstman
- & Mark J. Mamula
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Article
| 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 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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| 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 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 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 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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Article
| 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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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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Article
| Open AccessClenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells
In this study, the authors demonstrated that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling may prove beneficial as novel antidiabetic drugs.
- Jaroslawna Meister
- , Derek B. J. Bone
- & Jürgen Wess
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Article
| Open AccessGrainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan
Life- and healthspan of organisms can be modulated by dietary, genetic, or pharmacological interventions, which often affect metabolic pathways. Here the authors report that Grainyhead 1 is an evolutionarily conserved, drug-inducible transcription factor that promotes longevity in C. elegans, and thus a potential target for the development of geroprotective drugs.
- Giovanna Grigolon
- , Elisa Araldi
- & Fabian Fischer
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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 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 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 AccessPGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones
Degradation of misfolded proteins from the endoplasmic reticulum (ER) is important for maintaining proper cellular protein homeostasis. Here, the authors discovered that the ER membrane protein PGRMC1 binds to misfolded prohormones for recruitment into the ER-phagy degradative pathway.
- Yu-Jie Chen
- , Jeffrey Knupp
- & Billy Tsai
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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 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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Article
| Open AccessAdipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue
Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.
- Xin Cui
- , Jia Jing
- & Hang Shi
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Article
| 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
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Article
| Open AccessEndothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin
The vascular endothelium contributes to metabolic regulation, however, the underlying mechanisms are not fully understood. Here the authors show that endothelial low-density lipoprotein receptor-related protein 1 regulates glucose homeostasis via osteocalcin expression.
- Hua Mao
- , Luge Li
- & Xinchun Pi
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Article
| Open AccessOrexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity
The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here the authors report that inactivation of the orexin receptor type 1 or 2 in serotonergic neurons differentially regulate systemic glucose homeostasis in the context of diet induced obesity.
- Xing Xiao
- , Gagik Yeghiazaryan
- & A. Christine Hausen
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Article
| Open AccessIntravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice
Bariatric surgery procedures reduce weight and improve metabolic diseases. Here the authors investigate the effects of Vertical Sleeve Gastrectomy (VSG) on beta-cell function in mice using in vivo Ca2 + imaging and show that VSG increases beta-cell function and intra-islet connectivity.
- Elina Akalestou
- , Kinga Suba
- & Guy A. Rutter
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Article
| Open AccessTet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.
- Jinxiu Rui
- , Songyan Deng
- & Kevan C. Herold
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Article
| Open AccessAdipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis
Hyaluronan is a naturally occurring linear polysaccharide that together with collagens, enzymes, and glycoproteins forms the extracellular matrix. Here the authors show that adipose tissue overproduction of Hyaluronan reduces fat accumulation in mice fed high-fat diet and improves systemic glucose homeostasis.
- Yi Zhu
- , Na Li
- & Philipp E. Scherer
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Article
| Open AccessBrown adipose tissue is the key depot for glucose clearance in microbiota depleted mice
Gut microbiota deficient mice demonstrate enhanced glucose clearance, but which tissues are responsible for this improvement are still unclear. Here the authors report that brown adipose tissue contributes to the enhanced glucose clearance in gut microbiota depleted mice and that this response is dissociated from adaptive thermogenesis.
- Min Li
- , Li Li
- & John R. Speakman
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Article
| Open AccessPancreatic Ppy-expressing γ-cells display mixed phenotypic traits and the adaptive plasticity to engage insulin production
The cellular identity and function of the pancreatic polypeptide (Ppy)-producing γ-cells are incompletely understood. Here the authors show that these cells are heterogeneous and display adaptive plasticity to engage in insulin production following β-cell injury, but loss of the Ppy gene or γ-cells in mice does not affect weight or glycemia under basal conditions.
- Marta Perez-Frances
- , Léon van Gurp
- & Pedro L. Herrera
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Article
| Open AccessLarge parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects
A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.
- Xing Jian
- & Gary Felsenfeld
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Article
| Open AccessGIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health
Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.
- Yajie Zhao
- , Stasa Stankovic
- & John R. B. Perry
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Article
| Open AccessThe long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice
Beta-cell function is often impaired in obesity through incompletely understood mechanisms. Here the authors show that the long noncoding RNA βFaar is reduced by diet-induced obesity in mice, which leads to impaired beta-cell function via miR-138-5p and survival via TRAF3 Interacting Protein 2.
- Fangfang Zhang
- , Yue Yang
- & Liang Jin
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Article
| Open AccessViral infiltration of pancreatic islets in patients with COVID-19
New-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients, however, the underlying mechanisms are not fully understood. Here, the authors show that SARS-CoV-2 is detectable in both endocrine and exocrine cells of the pancreata of patients with COVID-19.
- Charlotte Steenblock
- , Stefanie Richter
- & Stefan R. Bornstein
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Article
| Open AccessCellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue
During the expansion of adipose tissue adipocyte progenitor cells proliferate and undergo adipogenesis. Here, the authors show that adipocyte progenitor cell proliferation in visceral adipose tissue has a diurnal pattern, which is dependent on both energy intake and the circadian clock.
- Aleix Ribas-Latre
- , Rafael Bravo Santos
- & Kristin L. Eckel-Mahan
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Article
| Open Accessβ-Arrestin-1 is required for adaptive β-cell mass expansion during obesity
During insulin-resistance, the compensatory expansion of beta-cell mass is able to delay or the onset of overt type 2 diabetes. Here, the authors report that beta-arrestin-1, an intracellular protein known to regulate signalling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice.
- Luiz F. Barella
- , Mario Rossi
- & Jürgen Wess
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Article
| Open AccessSmart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes
Wearable smart devices often have green light diodes to monitor health. Here the authors use this to control a light-activated genetic switch for GLP1 production in diabetic mice.
- Maysam Mansouri
- , Marie-Didiée Hussherr
- & Martin Fussenegger
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Article
| Open AccessChemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells
Human pluripotent stem cell (hPSC) derived pancreatic beta cells are a promising and potentially limitless source for cell replacement therapy. Here the authors perform stage-wise chemical screening to develop an improved protocol for hPSC differentiation to functional pancreatic beta cells at high efficiency.
- Haisong Liu
- , Ronghui Li
- & Juan Carlos Izpisua Belmonte
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Article
| Open AccessSam68 promotes hepatic gluconeogenesis via CRTC2
Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.
- Aijun Qiao
- , Junlan Zhou
- & Gangjian Qin
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Article
| Open AccessA small molecule HIF-1α stabilizer that accelerates diabetic wound healing
Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.
- Guodong Li
- , Chung-Nga Ko
- & Chung-Hang Leung
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Article
| Open AccessReinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.
- Christos Karampelias
- , Habib Rezanejad
- & Olov Andersson
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Article
| Open AccessA deep learning system for detecting diabetic retinopathy across the disease spectrum
As the leading cause of vision loss in working-age adults, diabetic retinopathy requires routinely retinal screening. Here the authors develop a deep learning system that can facilitate the screening by providing real-time image quality assessment, lesions detection, and grades across the disease spectrum.
- Ling Dai
- , Liang Wu
- & Weiping Jia
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Article
| Open AccessDecreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells
Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.
- Blaise Su Jun Low
- , Chang Siang Lim
- & Adrian Kee Keong Teo