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| Open AccessTrimethylamine N-oxide impairs β-cell function and glucose tolerance
β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients.
- Lijuan Kong
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessHeterozygous missense variant in GLI2 impairs human endocrine pancreas development
Mutations in the Hedgehog signaling have not been previously associated to diabetes. Here, authors identify a missense variant of GLI2 in a family with early-onset diabetes and report an essential role of this gene during human iPSC-based pancreatic differentiation.
- Laura M. Mueller
- , Abigail Isaacson
- & Francesca M. Spagnoli
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| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessPalmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability. Here, the authors show that elevated palmitic acid levels are linked to increased atherosclerotic plaque vulnerability.
- Xiqiang Wang
- , Ling Zhu
- & Zhongwei Liu
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| Open AccessRelaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status
Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice.
- Aidan Anderson
- , Nada Alfahad
- & Jose R. Hombrebueno
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| Open AccessProgrammed microalgae-gel promotes chronic wound healing in diabetes
The treatment of infected diabetic wounds faces obstacles of bacterial infection, hypoxia, hyperexpression of reactive oxygen species, and inflammation. Here, the authors address these issues by developing a programmed treatment strategy that utilizes live Haematococcus to promote healing of diabetic wounds in a comprehensive manner.
- Yong Kang
- , Lingling Xu
- & Xiaoyuan Ji
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Article
| Open AccessSox9 regulates alternative splicing and pancreatic beta cell function
Sox9 is a well-known transcriptional regulator of embryonic pancreas and endocrine cell development. Here, the authors show that loss of Sox9 in mature beta cells disrupts alternative splicing patterns and impairs insulin secretion, with significant implications for cellular function.
- Sapna Puri
- , Hasna Maachi
- & Matthias Hebrok
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Article
| 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 AccessAutonomous artificial intelligence increases screening and follow-up for diabetic retinopathy in youth: the ACCESS randomized control trial
Diabetic retinopathy is a complication of diabetes that can be prevented through screening, yet adherence is low. Here, the authors show that autonomous AI increases diabetic eye exam completion in a diverse cohort of youth with diabetes.
- Risa M. Wolf
- , Roomasa Channa
- & Michael D. Abramoff
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| Open AccessA role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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Article
| Open AccessSphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.
- Nadine Thomas
- , Nathalie H. Schröder
- & Bodo Levkau
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Article
| Open AccessGenes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
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| Open AccessThe NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to β-cell maintenance and function.
- Weidong Zhang
- , Ayako Miura
- & Masamitsu Nakazato
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| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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| Open AccessParabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a
Here, the authors show that the gut commensal Parabacteroides distasonis alleviates insulin resistance via nicotinic acid-intestinal GPR109a axis activation, a process promoted by Dendrobium officinale polysaccharide.
- Yonggan Sun
- , Qixing Nie
- & Shaoping Nie
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Article
| Open AccessA standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. Here, the authors show the implementation of such a metric using type 1 diabetes trial data, reassess and compare results from these trials, and extend its use to define response to therapy.
- Alyssa Ylescupidez
- , Henry T. Bahnson
- & Carla J. Greenbaum
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Article
| Open AccessHealthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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| Open AccessMetabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus
The retina’s role in type 2 diabetes is not well understood. Here, the authors show that retinal pigment epithelium thickness, with its metabolic fingerprints, might offer improved predictability and clinical utility beyond traditional indicators.
- Shaopeng Yang
- , Zhuoting Zhu
- & Wei Wang
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Article
| Open AccessA human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models
β-cell dysfunction in type 2 diabetes is associated with pathological aggregates of IAPP that accumulate in pancreatic islets. Here, the authors describe a novel antibody cloned from healthy elderly donors that selectively targets IAPP oligomers and protects from IAPP toxicity.
- Fabian Wirth
- , Fabrice D. Heitz
- & Jan Grimm
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| Open AccessPAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
A coding variant of the PAX4 transcription factor (p.Arg192His) is uniquely associated with Type 2 Diabetes in East Asian populations. Here, the authors show that two different coding gene variants of PAX4, p.Arg192His and the newly identified p.Tyr186X, can influence pancreatic beta cell development, identity, and function.
- Hwee Hui Lau
- , Nicole A. J. Krentz
- & Adrian Kee Keong Teo
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| Open AccessMyo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic islet β cells. Here the author show, by comparing the diabetes-sensitive NOD mouse strain with its congenic, diabetes-resistant ALR strain, and by genomic analyses of T1D patients and control, that mutations in the Myo9b gene may alter dendritic cells to contribute to autoimmune diabetes onset.
- Jing Zhang
- , Yuan Zou
- & Cong-Yi Wang
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Article
| Open AccessGlycerol contributes to tuberculosis susceptibility in male mice with type 2 diabetes
Patients with diabetes mellitus have an increased risk of developing tuberculosis. Here the authors show that increased blood levels of glycerol in mice with type 2 diabetes contributes to their susceptibility to infection, as glycerol is one of the main carbon sources for the bacteria.
- Nuria Martinez
- , Lorissa J. Smulan
- & Hardy Kornfeld
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| Open AccessSingle cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A
The mechanism and disease-relevance of pancreatic b-cell heterogeneity remains elusive. Here the authors show that variable HNF1A-FXYD2 activity drives single b-cell heterogeneity at transcriptomic, epigenomic, and electro-physiological levels, which strongly mark the progression of type 2 diabetes.
- Chen Weng
- , Anniya Gu
- & Yan Li
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| Open AccessImpact of dietary interventions on pre-diabetic oral and gut microbiome, metabolites and cytokines
Here, analyzing data from a six-month clinical trial in pre-diabetes, the authors found 166 of 2,803 measured features, including oral and gut microbiome, metabolites and cytokines, significantly changed in response to dietary interventions; highlighting the microbiome’s role in cardiometabolic health and revealing potential therapeutic avenues.
- Saar Shoer
- , Smadar Shilo
- & Eran Segal
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| Open AccessEndothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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Article
| Open AccessDeterminants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes
In early type 2 diabetes, “induction” with short-term insulin therapy followed by “maintenance” with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization.
- Ravi Retnakaran
- , Jiajie Pu
- & Bernard Zinman
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| Open AccessEffect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes
A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.
- Doris R. Pierce
- , Malcolm McDonald
- & Paul R. Giacomin
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| Open AccessPrevalence of diabetic retinopathy and vision-threatening diabetic retinopathy in adults with diabetes in China
Current data on the national distribution of diabetic retinopathy (DR) is lacking. Here, the authors show the national distribution, associated multi-level factors, and visual impairment of DR and vision-threatening DR in Chinese adults with diabetes.
- Xuhong Hou
- , Limin Wang
- & Weiping Jia
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Article
| Open AccessRestoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
Type 2 diabetes (T2D) is characterized by pancreatic beta-cell failure. Here, the authors show restoration of Phosphatidylinositol transfer protein alpha (PITPNA), a mediator of PtdIns-4-phosphate synthesis in the trans-Golgi network, in human T2D islets reverses impaired insulin granule maturation, exocytosis, and ER stress.
- Yu-Te Yeh
- , Chandan Sona
- & Matthew N. Poy
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| Open AccessOpportunistic detection of type 2 diabetes using deep learning from frontal chest radiographs
Traditional type 2 diabetes (T2D) screening methods often depend on age, BMI guidelines and glucose measurements. Here, authors use a deep learning model that leverages chest radiographs and electronic health record data to screen for T2D, highlighting potential for early detection and intervention.
- Ayis Pyrros
- , Stephen M. Borstelmann
- & William Galanter
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| Open AccessModeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages
Hepatic insulin resistance is an established driver of type 2 diabetes but is difficult to model in vitro. Here researchers use co-culture of hepatocytes and macrophages derived from the same human iPSC line to show how inflammation disrupts insulin-mediated regulation of hepatic glucose metabolism and identify targets for therapy of hepatic insulin resistance.
- Marko Groeger
- , Koji Matsuo
- & Holger Willenbring
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| Open AccessCausal associations between cardiorespiratory fitness and type 2 diabetes
Being fit has been linked to a lower risk of type 2 diabetes, but it is unclear whether this relationship is causal. Using large scale studies with genetic data and measurements of cardiorespiratory fitness, the authors show evidence that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity.
- Lina Cai
- , Tomas Gonzales
- & Nicholas J. Wareham
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| Open AccessEmbryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes
Environmental conditions during pregnancy contribute to offspring metabolic disease. Here, the authors show that immune cells reprogrammed in utero by maternal vitamin D deficiency increase lifetime diabetes risk in the offspring and are sufficient to transplant diabetes.
- Jisu Oh
- , Amy E. Riek
- & Carlos Bernal-Mizrachi
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Article
| Open AccessA versatile bioelectronic interface programmed for hormone sensing
Ultrasensitive, real-time profiling of bio-analytes is a prerequisite for precision medicine. Here, the authors present a versatile bio-electronic interface (VIBE) to sense signaling cascade-guided receptor-ligand interactions and show that it can detect hormone levels in blood samples and differentiate individual metabolic conditions.
- Preetam Guha Ray
- , Debasis Maity
- & Martin Fussenegger
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| Open AccessTranscriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice
Glucocorticoids are known to induce insulin resistance via transcriptional activation of genes related to liver gluconeogenesis and insulin resistance. Here the authors report that in male mice treated with glucocorticoids, the transcriptional co-regulator EHMT2 is involved in the induction of Irs2 (a gene promoting insulin action) to restrict the extent of insulin resistance in the liver.
- Rebecca A. Lee
- , Maggie Chang
- & Jen-Chywan Wang
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| Open AccessDNA methylation markers for kidney function and progression of diabetic kidney disease
Epigenetic markers are potential biomarkers for diabetes and related complications. Here, the authors identify CpG sites associated with kidney function and its subsequent decline using both single-site and multisite analyses, which are shown to have functional significance in the kidney.
- Kelly Yichen Li
- , Claudia Ha Ting Tam
- & Ronald C. W. Ma
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| Open AccessIntegrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
DNA methylation variation is associated with human obesity but a whether it plays a causal role in disease pathogenesis is unclear. Here, the authors perfom an integrative genomic study in human adipocytes to show that DNA methylation variations contribute to obesity and type 2 diabetes susceptibility, revealing underlying genomic and molecular mechanisms.
- Liam McAllan
- , Damir Baranasic
- & William R. Scott
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Article
| Open AccessUSP7 controls NGN3 stability and pancreatic endocrine lineage development
Tightly controlled NGN3 expression is essential for endocrine cell generation in the developing pancreas, with dysregulation leading to hyperglycemia in mice. Here they identify USP7 as a key post-translational regulator of NGN3 stability and show that this axis is required for endocrine development and beta-cell differentiation.
- Teodora Manea
- , Jessica Kristine Nelson
- & Rocio Sancho
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| Open AccessA phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity
Dorzagliatin, which acts on the glucose sensor glucokinase, is a new class of anti-diabetic medicine. Here the authors report that in a phase I open-label trial co-administration of dorzagliatin and sitagliptin (a different class of anti-diabetic medicine) does not significantly change the pharmacokinetics of either medicine in patients with type 2 diabetes and obesity.
- Li Chen
- , Jiayi Zhang
- & Gregory J. Tracey
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Article
| Open AccessTHADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass
THADA has been identified as a type 2 diabetes-associated gene whose function is not fully understood. Here the authors report that THADA deficiency protects mice from hyperglycemia and glucose intolerance by promoting insulin secretion and inhibiting β-cell apoptosis, suggesting THADA could be explored as a potential therapeutic target for diabetes.
- Yuqing Zhang
- , Shan Han
- & Han Zhao
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Article
| Open AccessDirected self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes
Cell therapy for diabetes requires the combination of bioengineering and new sources of beta cells. Here, the authors report a self-assembly platform based on neonatal pig islets, human endothelial cells and native organ extracellular matrix, which improves ex vivo islet maturation and in vivo function in a mouse model of diabetes.
- Antonio Citro
- , Alessia Neroni
- & Lorenzo Piemonti
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Article
| Open AccessCryo-EM structure supports a role of AQP7 as a junction protein
Glycerol flux across the plasma membrane is critical to metabolism and linked to disease. Here, authors present the cryo-EM structure of the glycerol channel AQP7 composed of two adhering tetramers and displaying well-defined densities in the central pore.
- Peng Huang
- , Raminta Venskutonytė
- & Karin Lindkvist-Petersson
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Article
| Open AccessGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.
- Jinsook Son
- , Wen Du
- & Domenico Accili
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Article
| Open AccessEpigenetic regulation of Neuregulin 1 promotes breast cancer progression associated to hyperglycemia
Despite hyperglycemia has been associated to breast cancer, the underlying mechanisms are not completely understood. Here, the authors show that epigenetic regulation of Nrg1 gene during hyperglycemia promotes breast cancer development.
- Changhu Lee
- , Min Kim
- & Jiyoung Park
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Article
| Open AccessLong-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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Article
| Open AccessA natural biological adhesive from snail mucus for wound repair
Natural adhesives have received a lot of attention recently. Here, the authors develop a natural biological adhesive from snail mucus that can adhere to wet tissue and be used to accelerate healing of skin wounds.
- Tuo Deng
- , Dongxiu Gao
- & Mingyi Wu
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Article
| Open AccessRevealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling
Visualizing endogenous GPCRs is challenging. Here the authors generate mice with an enzyme self-label genome-edited into the endogenous glucagon-like peptide-1 receptor locus, design fluorescent dyes for specific labelling in complex tissue, and reveal tissue-level organisation and dynamics of an endogenous class B GPCR.
- Julia Ast
- , Daniela Nasteska
- & David J. Hodson
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Article
| Open AccessBMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases
Different location of adipose tissue may have different consequences to cardiometabolic risk. Here the authors report that deep learning enabled accurate prediction of specific adipose tissue volumes, and that after adjustment for BMI, visceral adiposity was associated with increased risk of cardiometabolic disease, while gluteofemoral adiposity was associated with reduced risk.
- Saaket Agrawal
- , Marcus D. R. Klarqvist
- & Amit V. Khera
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Article
| Open AccessHyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
- Yulong Gong
- , Bingyuan Yang
- & Wenbiao Chen