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| Open AccessDiabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Article
| Open AccessGut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here, the authors show in a mice model that insulin action in the gut may play a protective role in the development of NASH and HCC in diabetes.
- Kotaro Soeda
- , Takayoshi Sasako
- & Kohjiro Ueki
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| Open AccessPhosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance
The failure of metabolic tissues to respond to insulin is an early marker of type 2 diabetes. Here, the authors show, using global phosphoproteomics, that insulin resistance is caused by a marked rewiring of both canonical and non-canonical insulin signalling, and includes dysregulated GSK3 activity.
- Daniel J. Fazakerley
- , Julian van Gerwen
- & Sean J. Humphrey
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Article
| Open AccessCircular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity
Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here, the authors show that circGlis3 levels are affected by QKI and FUS expression, and that increasing circGlis3 lengthens β-cell compensation via enhancing insulin secretion and reducing apoptosis.
- Yue Liu
- , Yue Yang
- & Liang Jin
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Article
| Open AccessUnique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.
- Hirofumi Nagao
- , Ashok Kumar Jayavelu
- & C. Ronald Kahn
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Article
| Open AccessThe dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.
- Alessandra Dall’Agnese
- , Jesse M. Platt
- & Richard A. Young
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Article
| Open AccessFunctional selectivity of insulin receptor revealed by aptamer-trapped receptor structures
DNA aptamers can activate insulin receptor as selective agonists or positive allosteric modulators. Here, authors determine structures of the insulin receptor bound to aptamers and provide a basis for the selective activation or allosteric regulation of insulin receptor.
- Junhong Kim
- , Na-Oh Yunn
- & Yunje Cho
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Article
| Open AccessIntestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost
The role of lifespan-regulating protein expression in specific tissues in C. elegans is murky. Here, the authors provide clarity by inducible degradation of longevity-related proteins, demonstrating that intestinal DAF-2 is a major determinant of lifespan in the worm.
- Yan-Ping Zhang
- , Wen-Hong Zhang
- & Meng-Qiu Dong
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Article
| Open AccessStructure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism
The metalloproteinase PAPP-A promotes insulin-like growth factor (IGF) signaling by cleavage of inhibitory IGF binding proteins. Here, the authors report the 3D structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2.
- Sara Dam Kobberø
- , Michael Gajhede
- & Claus Oxvig
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Article
| Open AccessPhenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ
Whether amino acids act on cellular insulin signaling remains unclear. Here, the authors find that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake and positively correlated with T2D onset.
- Qian Zhou
- , Wan-Wan Sun
- & Shi-Min Zhao
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Article
| Open AccessTRIM24 is an insulin-responsive regulator of P-bodies
Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.
- Wen Wei
- , Qiaoli Chen
- & Shuai Chen
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Article
| Open AccessRegulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor
Insulin sensitivity declines with age via unclear mechanisms. Here, the authors show that the activity of membrane type 1 matrix metalloproteinase (MT1-MMP) is increased with ageing, leading to cleavage of the insulin receptor, and show that metabolic effects can be rescued by MT1-MMP inhibition in mice.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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| Open AccessBrain adiponectin signaling controls peripheral insulin response in Drosophila
Circulating adiponectin controls sensitivity to insulin in tissues. Here, Arquier et al. show that adiponectin receptor activity in neurons of the Drosophila brain controls insulin response in peripheral tissues via juvenile hormone signaling.
- Nathalie Arquier
- , Marianne Bjordal
- & Pierre Léopold
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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 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 AccessNeuronal fragile X mental retardation protein activates glial insulin receptor mediated PDF-Tri neuron developmental clearance
Glia are involved in remodelling of neural circuits during development. Here, the authors show that FMRP is required within neurons to activate glial insulin receptor to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.
- Dominic J. Vita
- , Cole J. Meier
- & Kendal Broadie
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Article
| Open AccessVav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis
Skeletal muscle plays a key role in regulating systemic glucose and metabolic homeostasis. Here, the authors show that the catalytic activity of Vav2, an activator of Rho GTPases, modulates those processes by favoring the responsiveness of this tissue to insulin and related factors.
- Sonia Rodríguez-Fdez
- , L. Francisco Lorenzo-Martín
- & Xosé R. Bustelo
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Article
| Open AccessA PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
Molecular mechanisms linking myocardial insulin resistance to diabetic cardiomyopathy are incompletely understood. Here the authors show that myocardial insulin resistance impairs a PKB-SPEG-SERCA2a signaling axis, which contributes to the development of diabetic cardiomyopathy.
- Chao Quan
- , Qian Du
- & Shuai Chen
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Article
| Open AccessNovel metabolic role for BDNF in pancreatic β-cell insulin secretion
Glucose metabolism is regulated by hypothalamic brain functions and factors produced by peripheral tissues. Here, the authors show that the regulator of food intake Brain-derived neurotrophic factor is also produced and secreted by muscle and stimulates pancreas insulin release.
- Gianluca Fulgenzi
- , Zhenyi Hong
- & Lino Tessarollo
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| Open AccessIGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche
The signals regulating the establishment and maintenance of the pluripotent epiblast in human embryos are unclear. Here, the authors use a bioinformatics approach to identify the role of IGF1 in human embryo development, and from this, propose a culture medium with IGF1 together with Activin to sustain hESCs in the absence of FGF.
- Sissy E. Wamaitha
- , Katarzyna J. Grybel
- & Kathy K. Niakan
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Article
| Open AccessGlobal redox proteome and phosphoproteome analysis reveals redox switch in Akt
Crosstalk between protein oxidation and other post-translational modifications remains unexplored. Here, the authors map the phosphoproteome, cysteine redox proteome and total proteome of adipocytes under acute oxidative stress and reveal crosstalk between cysteine oxidation and phosphorylation-based signalling.
- Zhiduan Su
- , James G. Burchfield
- & David E. James
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Article
| Open AccessHomozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes
Both insulin and IGF-1 signaling have been implicated in arterial intimal hyperplasia. Here the authors dissect the relative contributions of insulin and IGF-1 receptors, showing that homodimers of insulin receptors, but not IGF-1 receptor, induce proliferation of vascular smooth muscle cells.
- Qian Li
- , Jialin Fu
- & George L. King
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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 AccessSMPDL3b modulates insulin receptor signaling in diabetic kidney disease
Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.
- A. Mitrofanova
- , S. K. Mallela
- & A. Fornoni
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Article
| Open AccessFoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism
Insulin signaling represses Forkhead transcription factor FoxO activity, which contributes to organismal metabolism. Here, the authors use proteomics to identify positively regulated insulin signaling targets FoxK1/K2 and demonstrate their role in lipid metabolism and mitochondrial regulation.
- Masaji Sakaguchi
- , Weikang Cai
- & C. Ronald Kahn
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Article
| Open AccessMitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling
The mechanisms promoting insulin resistance at the receptor level are poorly understood. Here, Choi et al. show that mitotic proteins and the SHP2-MAPK pathway regulate receptor endocytosis and insulin signaling feedback, identifying a potential role for SHP2 inhibitors to treat diabetes.
- Eunhee Choi
- , Sotaro Kikuchi
- & Hongtao Yu
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Article
| Open AccessTAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression
Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
- Jun-Ha Hwang
- , A Rum Kim
- & Jeong-Ho Hong
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Article
| Open AccessInsulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.
- Elisa Vergari
- , Jakob G. Knudsen
- & Patrik Rorsman
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Article
| Open AccessNeurohormonal signaling via a sulfotransferase antagonizes insulin-like signaling to regulate a Caenorhabditis elegans stress response
Reduced insulin-like signaling is required for C. elegans response to many environmental stressors, but how distinct outcomes are achieved is unknown. The authors show that the cytosolic sulfotransferase SSU-1 controls neurohormonal signaling via NHR-1 to specify the animals’ osmotic stress response.
- Nicholas O. Burton
- , Vivek K. Dwivedi
- & H. Robert Horvitz
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Article
| Open AccessThe signalling conformation of the insulin receptor ectodomain
The insulin receptor plays a key role in many physiological processes, yet how insulin effects receptor signaling at the structural level remains incomplete. Here the authors present a high-resolution cryo-EM structure of a high-affinity form of the insulin-bound insulin receptor ectodomain that sheds light on the mechanism of signal transduction.
- Felix Weis
- , John G. Menting
- & Michael C. Lawrence
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Article
| Open AccessStructures of insect Imp-L2 suggest an alternative strategy for regulating the bioavailability of insulin-like hormones
Insulin-like polypeptide binding proteins (IBPs) from insects can bind diverse insulin-like proteins (ILPs) including human insulin and IGFs. Here, the authors present structures of a Drosophila IBP in its free and ILP-bound forms, providing insights into the regulation of ILP bioavailability by insect IBPs.
- Nikolaj Kulahin Roed
- , Cristina M. Viola
- & Andrzej M. Brzozowski
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Article
| Open AccessInsulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis
Insulin promotes lipogenesis but, on the other hand, insulin resistance is associated with increased lipogenesis in the liver. Here the authors show that Snail1 is upregulated by insulin and inhibits lipogenesis by repressing Fasn expression but insulin-mediated Snail1 upregulation is impaired during obesity and insulin resistance.
- Yan Liu
- , Lin Jiang
- & Liangyou Rui
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Article
| Open AccessThe beta secretase BACE1 regulates the expression of insulin receptor in the liver
A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.
- Paul J. Meakin
- , Anna Mezzapesa
- & Franck Peiretti
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| Open AccessSWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia
Insulin secretion by β-cells is stimulated by glucose and is dependent on the induction of β-cell membrane depolarization, mainly driven by the closure of KATP channels, which in turn promotes voltage-gated Ca2+ channel opening. Here Kang et al. show that the volume-regulated anion channel, SWELL1, is involved in glucose-stimulated calcium increase and insulin secretion.
- Chen Kang
- , Litao Xie
- & Rajan Sah
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Article
| Open AccessEGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration
In response to gut epithelial damage,Drosophilastem cells proliferate to produce large polyploid enterocytes (EC), which comprise the bulk of the epithelium. Here, the authors show that stress-dependent EGFR/MAP kinase signalling drives both endoreplication and cell growth in newborn ECs.
- Jinyi Xiang
- , Jennifer Bandura
- & Bruce A. Edgar
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Article
| Open AccessDomain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.
- Weikang Cai
- , Masaji Sakaguchi
- & C. Ronald Kahn
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Article
| 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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Article
| 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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Article
| Open AccessMARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels
Insulin receptor levels at the cell surface are reduced in insulin resistance, for reasons that are not fully understood. Here, the authors identify the E3 ubiquitin ligase MARCH1 as a direct regulator of basal insulin receptor surface levels and, therefore, insulin signalling.
- Arvindhan Nagarajan
- , Max C. Petersen
- & Narendra Wajapeyee
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Article
| Open AccessInsulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock
The effect of the liver clock is modified by food entrainment via Bmal1/Clock core machinery. Here the authors show that insulin promotes postprandial Akt-dependent phosphorylation of Bmal1, resulting in association with 14-3-3 and Bmal1 shuttling out of the nucleus, thereby disrupting Bmal1 transcriptional effects on the clock.
- Fabin Dang
- , Xiujie Sun
- & Yi Liu
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Article
| 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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Article
| 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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Article
| Open AccessDiapause is associated with a change in the polarity of secretion of insulin-like peptides
Insulin-like peptides INS-7 and INS-35 suppress larval diapause in Caenorhabditis elegans via unknown mechanism. Here, Matsunaga et al.show that the secretory polarity of both peptides changes in diapause, when these peptides are secreted into the intestinal lumen instead of the body cavity like in other larval stages.
- Yohei Matsunaga
- , Yoko Honda
- & Tsuyoshi Kawano
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Article
| Open AccessInsulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward
Insulin signals satiety after a meal; however, the rising incidence of obesity and chronic insulin elevation suggests that insulin may also signal reward. Here, Stouffer et al. show that insulin amplifies dopamine release in rodent striatum depending on diet, and that striatal insulin can influence food choice.
- Melissa A. Stouffer
- , Catherine A. Woods
- & Margaret E. Rice
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Article
| Open AccessClass III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling
PI3K is activated as a result of insulin receptor (IR) signalling. Here the authors show that activation of specific class III PI3Ks in response to insulin promotes IR endocytosis and lysosomal degradation, providing negative feedback on IR signalling by reducing the time IR is activated.
- Ivan Nemazanyy
- , Guillaume Montagnac
- & Ganna Panasyuk
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Article
| Open AccesseIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription
Insulin enhances mRNA translation via the translation initiation factor eIF6. Here, Brina et al. show that insulin-mediated activation of eIF6 is associated with the selective translation of genes involved in glycolysis and lipid synthesis with characteristic G/C-rich and uORF sequences in their mRNA.
- Daniela Brina
- , Annarita Miluzio
- & Stefano Biffo
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Article
| Open AccessSelective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements
Insulin resistance in adipose tissue is a hallmark of obesity. Here, the authors generate inducible adipocyte-specific PTEN knockout mice to demonstrate that enhanced insulin sensitivity in adipose tissue is directly linked to improved systemic metabolic homeostasis, despite an increase in fat mass.
- Thomas S. Morley
- , Jonathan Y. Xia
- & Philipp E. Scherer
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Article
| Open AccessGenome-wide microRNA screening reveals that the evolutionary conserved miR-9a regulates body growth by targeting sNPFR1/NPYR
Insulin signaling governs many physiological processes but the molecular and neural mechanisms of its regulation are largely unknown. Here the authors describe a novel molecular pathway controlling sNPF regulation of insulin signalling in the fruit fly, which is mediated by the evolutionary conserved miR-9a.
- Yoon Seok Suh
- , Shreelatha Bhat
- & Kweon Yu
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Article
| 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