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| Open AccessA TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice
Tolerance is required to prevent rejection of intrahepatic islet allografts as a potential treatment for type 1 diabetes. Here the authors show that IL-22 produced by NK1.1+cells in the liver of streptozotocin T1D model mice can drive tolerance to allografted islets.
- Deepak Tripathi
- , Sambasivan Venkatasubramanian
- & Ramakrishna Vankayalapati
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| Open AccessIncreased DNA methylation variability in type 1 diabetes across three immune effector cell types
The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.
- Dirk S. Paul
- , Andrew E. Teschendorff
- & R. David Leslie
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| Open AccessWnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
- Fumiaki Ando
- , Eisei Sohara
- & Shinichi Uchida
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| Open AccessHyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells
Diabetes is characterized by prolonged hyperglycaemia and tissue damage in pancreatic islets. Here, Brereton et al. show that chronic high glucose levels lead to glycogen accumulation in β-cells, associated with reduced autophagy, impaired metabolism, insulin granule depletion and apoptosis.
- Melissa F. Brereton
- , Maria Rohm
- & Frances M. Ashcroft
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| Open AccessMacrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice
Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.
- Gustavo Monnerat
- , Micaela L. Alarcón
- & Emiliano Medei
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| Open AccessInhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
Glycine sensing in the dorsal vagal complex (DVC) regulates hepatic glucose production in rodents. Here the authors show that pharmacological and molecular inhibition of glycine reuptake in the DVC potentiates NMDA receptors, and improves metabolic homeostasis in animal models of obesity and diabetes.
- Jessica T. Y. Yue
- , Mona A. Abraham
- & Tony K. T. Lam
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| Open AccessThe GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch
GCN5 inhibits hepatic gluconeogenesis through acetylation of PGC-1α. Here the authors show that GCN5 also activates hepatic gluconeogenesis by acetylating histone H3K9, and that the affinity of GCN5 for its different substrates is regulated via phosphorylation at S275 by PKA in a CITED2-dependent manner.
- Mashito Sakai
- , Tomoko Tujimura-Hayakawa
- & Michihiro Matsumoto
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| Open AccessGlucose-regulated and drug-perturbed phosphoproteome reveals molecular mechanisms controlling insulin secretion
Dysfunction in insulin secretion is a main driver of type 2 diabetes development. Here the authors monitor phosphoproteome modulation in cells stimulated with glucose and treated with drugs affecting glucose-mediated insulin secretion to reveal phosphorylation sites implicated in insulin secretion control and gene expression regulation.
- Francesca Sacco
- , Sean J. Humphrey
- & Matthias Mann
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| Open AccessHyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
Patients with diabetes often have delayed wound healing, associated with excessive inflammation. Here the authors report that REG3A inhibits TLR3-driven inflammation in skin wounds, and show that REG3A is reduced in models of diabetes, which exacerbates inflammation in diabetic wounds.
- Yelin Wu
- , Yanchun Quan
- & Yuping Lai
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| Open AccessControl of diabetic hyperglycaemia and insulin resistance through TSC22D4
TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.
- Bilgen Ekim Üstünel
- , Kilian Friedrich
- & Stephan Herzig
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| Open AccessInsulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing
The TOR and insulin/IGF signalling (IIS) network are central responses to wound healing. Here the authors develop a technique of live imaging of laser-induced epidermal wounds to flies and show that TOR and IIS are independently required for wound healing, which may have implications for diabetic wound healing and its treatment.
- Parisa Kakanj
- , Bernard Moussian
- & Maria Leptin
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| Open AccessLoss of immune tolerance to IL-2 in type 1 diabetes
Type 1 diabetes is driven by T-cell autoimmunity to pancreatic islet cells. Here the authors show that autoreactive anti-IL-2 T and B cells are present in type 1 diabetes patients, and that anti-IL-2 antibodies precede diabetes onset in mice, suggesting their potential as a diagnostic marker.
- Louis Pérol
- , John M. Lindner
- & Eliane Piaggio
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| Open AccessDifferential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.
- Naoto Kubota
- , Tetsuya Kubota
- & Takashi Kadowaki
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| Open AccessAldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice
Diabetes is associated with the de-differentiation of β-cells into a more progenitor-like cell type. Here, the authors identify Aldh3 as a marker of de-differentiating β-cell in animal models of diabetes, and show Aldh3+cells have impaired insulin secretion and mitochondrial dysfunction.
- Ja Young Kim-Muller
- , Jason Fan
- & Domenico Accili
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| Open AccessHuman islets contain four distinct subtypes of β cells
Dysfunction or loss of insulin-secreting β cells in the pancreas is a hallmark of diabetes. Here, Dorrell et al.identify four subpopulations of β cells in humans, which differ in gene expression and insulin secretion kinetics, and the abundance of which is altered in patients with type 2 diabetes.
- Craig Dorrell
- , Jonathan Schug
- & Markus Grompe
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| Open AccessThe genetic regulatory signature of type 2 diabetes in human skeletal muscle
More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al. report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.
- Laura J. Scott
- , Michael R. Erdos
- & Stephen C. J. Parker
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| Open AccessThe MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells
Mice lacking the tumour suppressor p53 are partially protected from developing diabetes. Here the authors show that p53 is upregulated in the pancreas of diabetic mice where it impairs β cell function by repressing expression of mitochondrial pyruvate carboxylase, thereby inhibiting insulin secretion.
- Xiaomu Li
- , Kenneth K. Y. Cheng
- & Aimin Xu
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| Open AccessBlood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes
Aging is associated with impaired pancreatic islet function, increased risk of type 2 diabetes, and changes in DNA methylation. Here the authors find blood-based biomarkers that reflect age-associated DNA methylation changes in human pancreatic islets associated with insulin secretion and diabetes.
- Karl Bacos
- , Linn Gillberg
- & Charlotte Ling
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| Open AccessGenome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes
Here, Imamuraet al. conduct meta-analysis of genome-wide association studies to identify novel susceptibility loci for type 2 diabetes (T2D) in the Japanese population. By doing so, this study shows that both ethnicity-specific and ethnically-shared genetic loci can contribute to T2D risk.
- Minako Imamura
- , Atsushi Takahashi
- & Takashi Kadowaki
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| Open AccessHuman pancreatic beta-like cells converted from fibroblasts
Insulin-producing pancreatic beta cells, generatedin vitro, could lead to new anti-diabetic therapies. Here, Zhu et al. convert human fibroblasts into endodermal progenitors that differentiate in vitrointo glucose-responsive beta-like cells that, following transplantation in mice, protect from diabetes.
- Saiyong Zhu
- , Holger A. Russ
- & Sheng Ding
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| Open AccessAutocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects
GLP-1 is a gut hormone with glucose-lowering activity. Here the authors report the peptide, P5, a variant of the GLP-1 receptor agonist exendin-4, with 'biased' signalling activity, and show that P5 improves glucose homeostasis in diabetic mice by increasing adipose tissue hyperplasia.
- Hongkai Zhang
- , Emmanuel Sturchler
- & Richard A. Lerner
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| Open AccessSENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
Pro-inflammatory NF-κB signalling is regulated by protein sumoylation. Here the authors show that lack of the desumoylating protease SENP1 in fat tissue induces NF-κB activity and inflammation in peri-pancreatic adipocytes, leading to symptoms of type 1 diabetes in mice.
- Lan Shao
- , Huanjiao Jenny Zhou
- & Wang Min
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| Open AccessInhibition of DYRK1A and GSK3B induces human β-cell proliferation
All forms of diabetes eventually lead to a reduction in insulin-secreting pancreatic β-cells. Here, the authors report aminopyrazine derivatives, which induce proliferation of rodent as well as human β-cells and improve glucose metabolism in a mouse model of type 1 diabetes.
- Weijun Shen
- , Brandon Taylor
- & Bryan Laffitte
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| Open AccessCatalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice
Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.
- Rebecca Deprez-Poulain
- , Nathalie Hennuyer
- & Benoit Deprez
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| Open AccessTRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations
High insulin/IGF is a biologic link between diabetes and cancer. Here, the authors show a tumour promoting mechanism for stress protein TRB3 which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion.
- Fang Hua
- , Ke Li
- & Zhuo-Wei Hu
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| Open Accessp75NTR-dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia
Vascular function and repair is impaired in patients with diabetes. Here, Caporali et al.report that activation of the neurotrophin receptor in vascular endothelial cells induces the antiangiogenic miR-503, which impairs the function of neighbouring pericytes upon microparticle-mediated transfer.
- Andrea Caporali
- , Marco Meloni
- & Costanza Emanueli
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Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
Bile acids exert metabolic effects by modulating FXR receptor activity. Here, Trabelsi et al.show that FXR negatively regulates production of the incretin GLP-1 in enteroendocrine L-cells by reducing glycolysis and that inhibition of FXR improves glucose metabolism by increasing GLP-1 in obese mice.
- Mohamed-Sami Trabelsi
- , Mehdi Daoudi
- & Sophie Lestavel
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| Open AccessPI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling
The kinase PI3K is crucial for insulin signalling in the liver but the roles of individual PI3K isoforms are largely unclear. Using mice that lack class II PI3K isoform γ (PI3K-C2γ), the authors here show that PI3K-C2γ selectively activates endosomal Akt2 by regulating the localized production of PIP2.
- Laura Braccini
- , Elisa Ciraolo
- & Emilio Hirsch
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| Open AccessA Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease
In order to effectively design interventions, it is useful to understand the complex interplay between multiple syndromes. Here, Ahmad et al. use genome-wide association study data and Mendelian randomisation to examine the influence of Type 2 diabetes and fasting glucose levels on coronary heart disease.
- Omar S. Ahmad
- , John A. Morris
- & J. Brent Richards
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| Open AccessDrosophila glucome screening identifies Ck1alpha as a regulator of mammalian glucose metabolism
Diabetes is associated with aberrations in glucose metabolism. Here the authors perform a genomic screen in fruit flies to identify new regulators of fly glucose metabolism, and show that mice lacking the murine homologue of one of their hits, the protein kinase CK1alpha, in the adipose lineage develop diabetes.
- Rupali Ugrankar
- , Eric Berglund
- & Jonathan M. Graff
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Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Insulin and the transcription factor FoxO1 are key regulators of hepatic glucose metabolism. Here, Titchenell et al. provide evidence for the existence of an insulin-dependent extrahepatic pathway that is fully capable of regulating hepatic glucose production in the absence of hepatic FoxO1.
- Paul M. Titchenell
- , Qingwei Chu
- & Morris J. Birnbaum
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| Open AccessFGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis
Fibroblast growth factor (FGF) family proteins have anti-diabetic effects, but how they work is currently unclear. Here the authors show that injections of FGF1 or FGF19 into the brain of diabetic rats alter glucose and lipid homeostasis by suppressing activity of the hypothalamic-pituitary-adrenal signalling axis.
- Rachel J. Perry
- , Sangwon Lee
- & Gerald I. Shulman
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| Open AccessFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.
- Ji Miao
- , Alisha V. Ling
- & Sudha B. Biddinger
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| Open AccessReduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2requirement for antiviral response in insulin-producing cells.
- Kenichi Izumi
- , Keiichiro Mine
- & Seiho Nagafuchi
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The insulin and IGF1 receptor kinase domains are functional dimers in the activated state
In contrast to most receptor tyrosine kinases, the insulin and insulin-like growth factor-1 receptors are preformed, disulfide-linked dimers. Here the authors show that, after the two kinase domains of IR and IGF1R undergo autophosphorylation, they form a specific dimer to phosphorylate downstream substrates.
- M. Zulema Cabail
- , Shiqing Li
- & W. Todd Miller
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| Open AccessLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.
- Jennifer Wessel
- , Audrey Y Chu
- & Mark O Goodarzi
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| Open AccessAn integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.
- Wei Yuan
- , Yudong Xia
- & Tim D. Spector
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Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents
Cilia are hair-like protuberances on the cellular surface that have been implicated in sensing and signal transduction. Here Gerdes et al. show cilia are involved in insulin signalling and secretion in pancreatic β-cells of rodents, and suggest that ciliary dysfunction could contribute to type 2 diabetes.
- Jantje M. Gerdes
- , Sonia Christou-Savina
- & Per-Olof Berggren
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| Open AccessOptical control of insulin release using a photoswitchable sulfonylurea
Sulfonylureas are widely used anti-diabetic drugs, which promote insulin release by blocking a pancreatic ion channel. Here the authors create a photoswitchable sulfonylurea derivative and use it to control insulin release from cultured cells and isolated pancreatic islets by illumination with blue light.
- Johannes Broichhagen
- , Matthias Schönberger
- & Dirk Trauner
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Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
The transcription factors FoxoO1 and Srebp-1 control hepatic glucose and lipid production, respectively. Here, Haeusler et al.propose a model that integrates glucose and lipid regulation in the normal and diabetic liver under the unifying control of FoxO transcription factors.
- Rebecca A. Haeusler
- , Kirsten Hartil
- & Domenico Accili
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Article |
Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes
The mechanisms underlying the relationship between autophagy and metabolism remain unclear. Here, the authors demonstrate that mice with a systemic reduction in the autophagy pathway have an impaired response to metabolic stress, developing insulin resistance and an increase in intracellular lipid content.
- Yu-Mi Lim
- , Hyejin Lim
- & Myung-Shik Lee
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| Open AccessReversible changes in pancreatic islet structure and function produced by elevated blood glucose
In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al. show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.
- Melissa F. Brereton
- , Michaela Iberl
- & Frances M. Ashcroft
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| Open AccessHGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance
HGK kinase is involved in signalling in many cell types but its function in T cells remains unclear. Here, using T-cell-specific HGK knockout mice, the authors show that HGK prevents the development of systemic inflammation and insulin resistance by inhibiting production of the proinflammatory cytokines IL-6 and IL-17.
- Huai-Chia Chuang
- , Wayne H. -H. Sheu
- & Tse-Hua Tan
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| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures
The transcription factor FOXO1 has been shown to control the differentiation of enteroendocrine cells in mice. Here the authors extend these findings to humans by showing that FOXO1-expressing cells also exist in the human gut, and that inhibition of FOXO1 generates insulin-secreting cells in human gut organoid cultures.
- Ryotaro Bouchi
- , Kylie S. Foo
- & Domenico Accili
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| Open AccessThe serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Hepatic insulin resistance is a hallmark of diabetes, but its aetiology is incompletely understood. Here, Uchimura and colleagues show that the serine protease prostasin cleaves Toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity by modulating TLR4-mediated signalling.
- Kohei Uchimura
- , Manabu Hayata
- & Kenichiro Kitamura
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| Open AccessDisruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity
Thioredoxin binding protein-2 (TBP-2) mutant mice have abnormal insulin sensitivity and secretion. In this study, TBP-2-null obese mice are shown to have improved insulin sensitivity and glucose intolerance, suggesting a potential role for TBP-2 inhibition in diabetes treatment.
- Eiji Yoshihara
- , Shimpei Fujimoto
- & Hiroshi Masutani
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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes
Pseudogenes are prevalent in the human genome; however, their biological function is relatively unknown. In this study, the high mobility group A1 (HMGA1) pseudogene is shown to destabilizeHMGA1 mRNA. These findings have implications for diabetes, as two patients are reported to express high levels of the HMGA1pseudogene.
- Eusebio Chiefari
- , Stefania Iiritano
- & Antonio Brunetti