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Erratum. Liraglutide and Exercise Synergistically Attenuate Vascular Inflammation and Enhance Metabolic Insulin Action in Early Diet-Induced Obesity. Diabetes 2023;72:918–931 Diabetes (IF 7.7) Pub Date : 2024-04-23 Jia Liu, Kevin W. Aylor, Zhenqi Liu
In the article cited above, Fig. 7G mistakenly featured the same images as Fig. 7E due to an error during manuscript preparation. The corresponding graphs and associated data interpretation were not affected, and the conclusions remain unchanged. The correct image for Fig. 7G appears below. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db22-0745) has
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The Expanding Problem of Regional Adiposity: Revisiting a 1985 Diabetes Classic by Ohlson et al. Diabetes (IF 7.7) Pub Date : 2024-04-19 Olga T. Gupta, Rana K. Gupta
Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link
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Glucose Regulation of β-Cell KATP Channels: Is a New Model Needed? Diabetes (IF 7.7) Pub Date : 2024-04-19 Guy A. Rutter, Ian R. Sweet
The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins
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Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model! Diabetes (IF 7.7) Pub Date : 2024-04-19 Matthew J. Merrins, Richard G. Kibbey
An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)–driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess
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Engineering a Pathway to Glucose-Responsive Therapeutics Diabetes (IF 7.7) Pub Date : 2024-04-12 Matthew J. Webber
In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes® Program. Pathway took a multifaceted approach to provide key funding to diabetes researchers in advancing a broad spectrum of research programs centered on all aspects of understanding, managing, and treating diabetes. Herein the personal perspective of a
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Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise Diabetes (IF 7.7) Pub Date : 2024-04-12 Christian S. Carl, Marie M. Jensen, Kim A. Sjøberg, Dumitru Constantin-Teodosiu, Ian R. Hill, Rasmus Kjøbsted, Paul L. Greenhaff, Jørgen F.P. Wojtaszewski, Erik A. Richter, Andreas M. Fritzen, Bente Kiens
Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake
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The Early Pathogenesis of Diabetic Retinopathy and Its Attenuation by Sodium-Glucose Transporter 2 Inhibitors Diabetes (IF 7.7) Pub Date : 2024-04-12 Mayumi Yamato, Nao Kato, Ken-ichi Yamada, Toyoshi Inoguchi
The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we investigated the early pathogenic alterations in DR using streptozotocin-induced diabetic mice and the protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness
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Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance Diabetes (IF 7.7) Pub Date : 2024-04-12 Christian Springer, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K. Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M. Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt
The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function
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Engineering a Pathway to Glucose-Responsive Therapeutics Diabetes (IF 7.7) Pub Date : 2024-04-11 Matthew J. Webber
In 2014, the American Diabetes Association instituted a novel funding paradigm to support diabetes research through its Pathway to Stop Diabetes® Program. Pathway took a multifaceted approach to provide key funding to diabetes researchers in advancing a broad spectrum of research programs centered on all aspects of understanding, managing, and treating diabetes. Herein the personal perspective of a
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Genetic subtypes of prediabetes, healthy lifestyle, and risk of type 2 diabetes Diabetes (IF 7.7) Pub Date : 2024-04-11 Yang Li, Guo-Chong Chen, Jee-Young Moon, Rhonda Arthur, Daniela Sotres-Alvarez, Martha L. Daviglus, Amber Pirzada, Josiemer Mattei, Krista M. Perreira, Jerome I. Rotter, Kent D. Taylor, Yii-Der Ida Chen, Sylvia Wassertheil-Smoller, Tao Wang, Thomas E. Rohan, Joel D. Kaufman, Robert Kaplan, Qibin Qi
Prediabetes is a heterogenous metabolic state with various risk for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic whites without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing
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Efficient vascular and neural engraftment of stem cell-derived islets Diabetes (IF 7.7) Pub Date : 2024-04-11 Julia Thorngren, Anja Brboric, Svitlana Vasylovska, Daisy Hjelmqvist, Gunilla T Westermark, Jonna Saarimäki-Vire, Jouni Kvist, Diego Balboa, Timo Otonkoski, Per-Ola Carlsson, Joey Lau
Pluripotent stem cell-derived islets (SC-islets) now emerge as a new source for beta-cell replacement therapy. While the function of human islet transplants is hampered by excessive cell death post-transplantation, contributing factors include inflammatory reactions, insufficient revascularization and islet amyloid formation, there is a gap in knowledge on the engraftment process of the SC-islets.
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Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults with Diabetes Diabetes (IF 7.7) Pub Date : 2024-03-29 Sofhia V. Ramos, Giovanna Distefano, Li-Yung Lui, Peggy M. Cawthon, Philip Kramer, Ian J. Sipula, Fiona M. Bello, Theresa Mau, Michael J. Jurczak, Anthony J. Molina, Erin E. Kershaw, David J. Marcinek, Eric Shankland, Frederico G.S. Toledo, Anne B. Newman, Russell T. Hepple, Stephen B. Kritchevsky, Bret H. Goodpaster, Steven R. Cummings, Paul M. Coen
Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial oxidative capacity on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults
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Genetic evidence for distinct biological mechanisms that link adiposity to type 2 diabetes: towards precision medicine Diabetes (IF 7.7) Pub Date : 2024-03-26 Angela Abraham, Madeleine Cule, Marjola Thanaj, Nicolas Basty, M. Amin Hashemloo, Elena P. Sorokin, Brandon Whitcher, Stephen Burgess, Jimmy D. Bell, Naveed Sattar, E. Louise Thomas, Hanieh Yaghootkar
We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We employed MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated
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Adiponectin Reduces Glomerular Endothelial Glycocalyx Disruption and Restores Glomerular Barrier Function in a Mouse Model of Type 2 Diabetes Diabetes (IF 7.7) Pub Date : 2024-03-26 Sarah Fawaz, Aldara Martin Alonso, Yan Qiu, Raina Ramnath, Holly Stowell-Connolly, Monica Gamez, Carl May, Colin Down, Richard J. Coward, Matthew J. Butler, Gavin I. Welsh, Simon C. Satchell, Rebecca R. Foster
Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes
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Epistasis Between HLA-DRB1*16:02:01 and SLC16A11 T-C-G-T-T Reduces Odds for Type 2 Diabetes in Southwest American Indians Diabetes (IF 7.7) Pub Date : 2024-03-26 Robert C. Williams, Robert L. Hanson, Bjoern Peters, Kendall Kearns, William C. Knowler, Clifton Bogardus, Leslie J. Baier
We sought to identify genetic/immunologic contributors of type 2 diabetes in an indigenous American community by genotyping all study participants for both high resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals
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Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2DM and NGT Subjects Diabetes (IF 7.7) Pub Date : 2024-03-21 Xi Chen, Devjit Tripathy, Robert Chilton, Andrea Hansis-Diarte, Marzieh Salehi, Carolina Solis-Herrera, Eugenio Cersosimo, Ralph A DeFronzo
Acute and chronic SGLT-2 inhibition increase endogenous glucose production (EGP). However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. 20 T2DM and 12 NGT subjects received [3-3H]-glucose infusion (to measure total EGP) in combination with arterial and renal vein catheterization and PAH infusion for determination of renal blood flow. Total EGP, net
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The Ailing β-Cell in Diabetes: Insights From a Trip to the ER: The 2023 Outstanding Scientific Achievement Award Lecture Diabetes (IF 7.7) Pub Date : 2024-03-20 Carmella Evans-Molina
The synthesis, processing, and secretion of insulin by the pancreatic β-cell is key for the maintenance of systemic metabolic homeostasis, and loss or dysfunction of β-cells underlies the development of both type 1 diabetes (T1D) and type 2 diabetes (T2D). Work in the Evans-Molina laboratory over the past 15 years has pioneered the idea that regulation of calcium dynamics is critical to β-cell biology
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Response to Comment Letter: Muscle Metabolomics and Exercise Effects on Cardiometabolic Risk Diabetes (IF 7.7) Pub Date : 2024-03-20 Mark W. Pataky, K. Sreekumaran Nair
We appreciate Dr. Astrada’s interest in our recent article (1). Although he raised concern around using BMI as a screening parameter for our study, BMI was not the only “defining parameter” screening criteria in our study. Fasting glucose > 110mg/dL was also a critical exclusion criterion for the study which limits variation in metabolic characteristics in our study cohort. These and other criteria
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CPT1A Protects Podocytes from Lipotoxicity and Apoptosis In Vitro and Alleviates Diabetic Nephropathy In Vivo Diabetes (IF 7.7) Pub Date : 2024-03-20 Yajuan Xie, Qian Yuan, Ben Tang, Yaru Xie, Yiling Cao, Yang Qiu, Jieyu Zeng, Zhiwen Wang, Hua Su, Chun Zhang
Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from diabetic patients
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Comparison of beta-cell function and insulin sensitivity between normal-weight and obese Chinese with young-onset type 2 diabetes Diabetes (IF 7.7) Pub Date : 2024-03-20 Yingnan Fan, Elaine Chow, Cadmon K.P. Lim, Yong Hou, Sandra T.F. Tsoi, Baoqi Fan, Eric S.H. Lau, Alice P.S. Kong, Ronald C.W. Ma, Hongjiang Wu, Juliana C.N. Chan, Andrea O.Y. Luk
Normal-weight individuals with usual-onset type 2 diabetes had reduced beta-cell function and greater insulin sensitivity compared to their obese counterparts. The relative contribution of beta-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 normal-weight and 20 obese) and 24 healthy
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Metabolic Fluxes in the Renal Cortex are Dysregulated In Vivo in Response to High-Fat Diet Diabetes (IF 7.7) Pub Date : 2024-03-19 Clinton M. Hasenour, Deveena R. Banerjee, Jamey D. Young
Diabetes and obesity are risk factors for kidney disease. While renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here we examined how diet-induced insulin resistance disrupts mitochondrial metabolic
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Intermittent fasting improves glucose homeostasis not entirely dependent on caloric restriction in db/db male mice Diabetes (IF 7.7) Pub Date : 2024-03-19 Dinghao Zheng, Xiaosi Hong, Xiaodan He, Jianghong Lin, Shujin Fan, Jinli Wu, Zhuoxian Liang, Sifan Chen, Li Yan, Meng Ren, Wei Wang
Intermittent fasting (IF), which involves prolonged fasting intervals accompanied by caloric restriction, is an effective dietary treatment for obesity and diabetes. Although IF offers many benefits, it is difficult to determine whether these benefits are the consequences of caloric restriction. Every-other-day feeding (EODF) is a commonly used IF research model. This study was designed to identify
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Genetic evidence of causal relation between intestinal glucose absorption and early postprandial glucose response: a Mendelian randomization study Diabetes (IF 7.7) Pub Date : 2024-03-18 Simon Peschard, Violeta Raverdy, Pierre Bauvin, Rebecca Goutchtat, Veronique Touche, Bruno Derudas, Celine Gheeraert, Julie Dubois-Chevalier, Robert Caiazzo, Gregory Baud, Camille Marciniak, Helene Verkindt, Naima Oukhouya Daoud, Carel W Le Roux, Philippe Lefebvre, Bart Staels, Sophie Lestavel, François Pattou
The post-prandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose-co-transporter-1 (SGLT1). This study utilizes Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on
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Risk of diabetic retinopathy according to subtype of type 2 diabetes Diabetes (IF 7.7) Pub Date : 2024-03-18 Frederik N. Pedersen, Lonny Stokholm, Nis Andersen, Jens Andresen, Toke Bek, Javad Hajari, Steffen Heegaard, Kurt Højlund, Ryo Kawasaki, Caroline S. Laugesen, Sören Möller, Katja Schielke, Jens Steen Nielsen, Jacob V. Stidsen, Reimar W. Thomsen, Benjamin Thinggaard, Jakob Grauslund
Type 2 diabetes is a heterogeneous disease that can be subdivided based on beta-cell function and insulin sensitivity. We aimed to investigate the presence, incidence and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes which included classical, hyperinsulinemic and insulinopenic type 2 diabetes
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Gut microbiota–tryptophan metabolism–GLP-1 axis participates in β-cell regeneration induced by dapagliflozin Diabetes (IF 7.7) Pub Date : 2024-03-12 Yafei Jiang, Jin Yang, Li Xia, Tianjiao Wei, Xiaona Cui, Dandan Wang, Zirun Jin, Xiafang Lin, Fei Li, Kun Yang, Shan Lang, Ye Liu, Jing Hang, Zhe Zhang, Tianpei Hong, Rui Wei
Sodium-glucose co-transporter 2 (SGLT2) inhibitor, an efficacious anti-diabetic agent, which has cardiovascular and renal benefits, can promote pancreatic β-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multi-omics to identify the mediators involved in β-cell regeneration induced by dapagliflozin. We showed that dapagliflozin
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Polygenic Risk for Type 2 Diabetes in African Americans Diabetes (IF 7.7) Pub Date : 2024-03-12 Marguerite R. Irvin, Tian Ge, Amit Patki, Vinodh Srinivasasainagendra, Nicole D. Armstrong, Brittney Davis, Alana C Jones, Emma Perez, Lauren Stalbow, Matthew Lebo, Eimear Kenny, Ruth J.F. Loos, Maggie C. Y. Ng, Jordan W. Smoller, James B. Meigs, Leslie A. Lange, Elizabeth W. Karlson, Nita A. Limdi, Hemant K. Tiwari
African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Herein, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method (PRS-CS). We further tested the score in three independent studies with a total
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Inhibition of HSP20 ameliorates steatotic liver disease by stimulating ERK2-dependent autophagy Diabetes (IF 7.7) Pub Date : 2024-03-11 Yanli Miao, Yi Zhong, Yutian Li, Haojie Qin, Ling Yang, Guojun Cao, Yong Tang, Ting Yu, Di Fan, Yang Lu1, Jiangtong Peng, Kai Huang
Heat shock protein 20 (HSP20) emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in liver and its effect on autophagy remain unknown. Here, we observed that HSP20 expression is increased in liver tissues from mice and patients with metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD)
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GRP78 contributes to the beneficial effects of SGLT2 inhibitor on proximal tubular cells in DKD Diabetes (IF 7.7) Pub Date : 2024-02-23 Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Wada
Beneficial effects of SGLT2 inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78 kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and Integrin ß1 beyond the chaperone property of GRP78. In STZinduced diabetic mouse kidneys, GRP78, SGLT2, and Integrin ß1 increased in the plasma membrane fraction, while they were
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TRIB2-mediated modulation of AMPK promotes hepatic insulin resistance Diabetes (IF 7.7) Pub Date : 2024-02-23 Dan Wang, Xiaonan Kang, Lu Zhang, Yaoyao Guo, Ziyin Zhang, Huihui Ren, Gang Yuan
Insulin resistance and its linked health complications are increasing in prevalence. Recent work has caused the role of Tribbles2 (TRIB2) in metabolism and cellular signaling to be increasingly appreciated, but its role in the progression of insulin resistance has not been elucidated. Here, we explore the functions of TRIB2 in modulating insulin resistance and the mechanism involved in insulin resistance
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Macrophage SHP2 Deficiency Alleviates Diabetic Nephropathy via Suppression of MAPK/NF-ĸB-Dependent Inflammation Diabetes (IF 7.7) Pub Date : 2024-02-23 Xue Han, Jiajia Wei, Ruyi Zheng, Yu Tu, Mengyang Wang, Lingfeng Chen, Zheng Xu, Lei Zheng, Chao Zheng, Qiaojuan Shi, Huazhong Ying, Guang Liang
Increasing evidence implicates chronic inflammation as the main pathological cause of diabetic nephropathy (DN). Exploration of key targets in the inflammatory pathway may provide new treatment options for DN. Here, we aim to investigate the role of Src Homology 2 Containing Protein Tyrosine Phosphatase 2 (SHP2) in macrophages and its association with DN. The upregulated phosphorylation of SHP2 was
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Coagulation factor FVII fine-tunes hepatic steatosis by blocking AKT-CD36-mediated fatty acid uptake Diabetes (IF 7.7) Pub Date : 2024-02-23 Yao Zhang, Quanxin Jiang, Xingxing Liang, Qiqi Qian, Jie Xiong, Chuchu Liu, Junting Xu, Ning Wang, Ying Xu, Peihui Zhou, Sijia Lu, Qian Zhou, Yanmei Yuan, Xuemei Fan, Junli Liu, Suzhen Chen
NAFLD is considered as a risk factor for cardiovascular and cerebrovascular disease owing to its close association with coagulant disturbances. However, the precise biological functions and mechanisms that connect coagulation factors to NAFLD pathology remain inadequately understood. Herein, with unbiased bioinformatic analyses followed by functional test, we demonstrate that hepatic expression of
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Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease Diabetes (IF 7.7) Pub Date : 2024-02-23 DengFeng Li, Fang-Chi Hsu, Nicholette D. Palmer, Liang Liu, Young A Choi, Mariana Murea, John S. Parks, Donald W. Bowden, Barry I. Freedman, Lijun Ma
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. As many genes associate with DKD, multi-omics approaches were employed to narrow the list of functional genes, gene products and related pathways providing insights into the pathophysiological mechanisms of DKD. The Kidney Precision Medicine Project human kidney single-cell RNA-sequencing (scRNAseq) dataset and Mendeley
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Brief Review and Perspective: Antioxidants for early treatment of Type 2 Diabetes in Rodents and Humans: Lost in Translation? Diabetes (IF 7.7) Pub Date : 2024-02-22 R. Paul Robertson
Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/ Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus where it upregulates antioxidant gene
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Cell-surface ZnT8 antibody prevents and reverses autoimmune diabetes in mice Diabetes (IF 7.7) Pub Date : 2024-02-22 Devi Kasinathan, Zheng Guo, Dylan C. Sarver, G. William Wong, Shumei Yun, Aaron W. Michels, Liping Yu, Chandan Sona, Matthew N. Poy, Maria L. Golson, Dax Fu
Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work
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CD4+ T cells from individuals with type 1 diabetes respond to a novel class of deamidated peptides formed in pancreatic islets Diabetes (IF 7.7) Pub Date : 2024-02-22 Aïsha Callebaut, Perrin Guyer, Rita Derua, Mijke Buitinga, Anthony Manganaro, Xiaoyan Yi, Fernanda Marques Câmara Sodré, Saurabh Vig, Mara Suleiman, Piero Marchetti, Decio L. Eizirik, Sally C. Kent, Chantal Mathieu, Eddie A. James, Lut Overbergh
The β-cell plays a crucial role in the pathogenesis of type 1 diabetes, in part through the posttranslational modification of self-proteins by biochemical processes such as deamidation. These neoantigens are potential triggers for breaking immune tolerance. We report the detection by LC-MS/MS of 16 novel Gln and 27 novel Asn deamidations in 14 disease-related proteins within inflammatory cytokine-stressed
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Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of its Pathology Diabetes (IF 7.7) Pub Date : 2024-02-22 Lisa C. Heather, Keshav Gopal, Nikola Srnic, John R. Ussher
Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension
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The Afferent Function of Adipose Innervation Diabetes (IF 7.7) Pub Date : 2024-02-20 Yu Wang, Li Ye
Adipose tissue innervation is critical for regulating metabolic and energy homeostasis. While the sympathetic efferent innervation of fat is well characterized, the role of sensory or afferent innervation remains less explored. This article reviews previous work on adipose innervation and recent advances in the study of sensory innervation of adipose tissues. We discuss key open questions, including
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Wiring the Brain for Wellness: Sensory Integration in Feeding and Thermogenesis: A Report on Research Supported by Pathway to Stop Diabetes Diabetes (IF 7.7) Pub Date : 2024-02-20 Céline E. Riera
The recognition of sensory signals from within the body (interoceptive) and from the external environment (exteroceptive), along with the integration of these cues by the central nervous system, plays a crucial role in maintaining metabolic balance. This orchestration is vital for regulating processes related to both food intake and energy expenditure. Animal model studies indicate that manipulating
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Evidence for C-peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes Diabetes (IF 7.7) Pub Date : 2024-02-13 Esther Latres, Carla J Greenbaum, Maria L Oyaski, Colin M Dayan, Helen M Colhoun, John M Lachin, Jay S Skyler, Michael R Rickels, Simi T Ahmed, Sanjoy Dutta, Kevan C Herold, Marjana Marinac
Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic beta cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of beta cell
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Relationship of fat mass ratio – a biomarker for lipodystrophy – with cardiometabolic traits Diabetes (IF 7.7) Pub Date : 2024-02-12 Saaket Agrawal, Jian’an Luan, Beryl B. Cummings, Ethan Weiss, Nick J. Wareham, Amit V. Khera
Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR) – defined as trunk fat percentage (trunk fat %) divided by leg fat percentage (leg fat %) – as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out
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Acetyllevocarnitine hydrochloride for the treatment of diabetic peripheral neuropathy: A phase 3, randomized clinical trial in China Diabetes (IF 7.7) Pub Date : 2024-02-06 Lixin Guo, Qi Pan, Zhifeng Cheng, Zhiyong Li, Hongwei Jiang, Fang Zhang, Yufeng Li, Wei Qiu, Song Lu, Junhang Tian, Yanqin Fu, Fangqiong Li, Danqing Li
Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type-2 diabetes mellitus (T2DM), for which no effective treatment is available. In this multi-center, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, T2DM patients with DPN received acetyllevocarnitine hydrochloride (ALC, 1,500 mg/day, n = 231) or placebo (n = 227) for 24 weeks, during which
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Adipocyte-specific Hnrnpa1 knockout aggravates obesity-induced metabolic dysfunction via upregulating of CCL2 Diabetes (IF 7.7) Pub Date : 2024-02-06 Xiaoya Li, Yingying Su, Yiting Xu, Tingting Hu, Xuhong Lu, Jingjing Sun, Wenfei Li, Jian Zhou, Xiaojing Ma, Ying Yang, Yuqian Bao
Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is involved in lipid and glucose metabolism via mRNA processing. However, whether and how HNRNPA1 alters adipocyte function in obesity remain obscure. Here, we found that obese state downregulated HNRNPA1 expression in white adipose tissue (WAT). The depletion of adipocyte HNRNPA1 promoted markedly increased macrophage infiltration, proinflammatory
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The hepatokine orosomucoid 2 mediates beneficial metabolic effects of bile acids Diabetes (IF 7.7) Pub Date : 2024-02-06 Sung Ho Lee, Ji Ho Suh, Mi Jeong Heo, Jong Min Choi, Yang Yang, Hyun-Jung Jung, Zhanguo Gao, Yu Yongmei, Sung Yun Jung, Mikhail G. Kolonin, Aaron R. Cox, Sean M. Hartig, Holger K. Eltzschig, Cynthia Ju, David D. Moore, Kang Ho Kim
Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the present study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role
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In vivo inhibition of dipeptidyl peptidase 4 allows measurement of GLP-1 secretion in mice Diabetes (IF 7.7) Pub Date : 2024-01-31 Mark M. Smits, Katrine D. Galsgaard, Sara Lind Jepsen, Nicolai Wewer Albrechtsen, Bolette Hartmann, Jens J. Holst
Dipeptidyl peptidase (DPP)-4 and neprilysin (NEP) rapidly degrade glucagon-like peptide 1 (GLP-1) in mice. Commercially available sandwich ELISA kits may not accurately detect the degradation products, leading to potentially misleading results. We aimed to stabilize GLP-1 in mice allowing reliable measurement with sensitive commercially available ELISA kits. Non-anesthetized male C57Bl/6JRj mice were
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An Insulin-Chromogranin A Hybrid Peptide activates DR11 restricted T cells in human type 1 diabetes Diabetes (IF 7.7) Pub Date : 2024-01-31 Aïsha Callebaut, Perrin Guyer, Rocky L. Baker, Joylynn B. Gallegos, Anita C. Hohenstein, Peter A. Gottlieb, Chantal Mathieu, Lut Overbergh, Kathryn Haskins, Eddie A. James
Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule peptides are detectable within murine and human islets. The 2.5HIP (C-peptide-Chromogranin A (CgA) HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in the NOD mouse. However, the relevance of this epitope in human disease is currently unclear. A recent study probed
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DNA methylation-based assessment of cell composition in human pancreas and islets Diabetes (IF 7.7) Pub Date : 2024-01-24 Zeina Drawshy, Daniel Neiman, Ori Fridlich, Ayelet Peretz, Judith Magenheim, Andrea V Rozo, Nicolai M Doliba, Doris A Stoffers, Klaus H Kaestner, Desmond A Schatz, Clive Wasserfall, Martha Campbell-Thompson, James Shapiro, Tommy Kaplan, Ruth Shemer, Benjamin Glaser, Agnes Klochendler, Yuval Dor
Assessment of pancreas cell type composition is crucial to the understanding of the genesis of diabetes. Current approaches use immunodetection of protein markers, for example insulin as a marker of beta-cells. A major limitation of these methods is that protein content varies in physiological and pathological conditions, complicating the extrapolation to actual cell number. Here we demonstrate the
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Adipose Signals Regulating Distal Organ Health and Disease Diabetes (IF 7.7) Pub Date : 2024-01-19 Ankit Gilani, Lisa Stoll, Edwin A. Homan, James C. Lo
Excessive adiposity in obesity is a significant risk factor for development of type 2 diabetes (T2D), nonalcoholic fatty liver disease, and other cardiometabolic diseases. An unhealthy expansion of adipose tissue (AT) results in reduced adipogenesis, increased adipocyte hypertrophy, adipocyte hypoxia, chronic low-grade inflammation, increased macrophage infiltration, and insulin resistance. This ultimately
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Molecular Insights From Multiomics Studies of Physical Activity Diabetes (IF 7.7) Pub Date : 2024-01-19 Wei Wei, Steffen H. Raun, Jonathan Z. Long
Physical activity confers systemic health benefits and provides powerful protection against disease. There has been tremendous interest in understanding the molecular effectors of exercise that mediate these physiologic effects. The modern growth of multiomics technologies—including metabolomics, proteomics, phosphoproteomics, lipidomics, single-cell RNA sequencing, and epigenomics—has provided unparalleled
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Excess Salt Intake Activates IL-21-dominant Autoimmune Diabetogenesis via A Saltregulated Ste20-related Proline/alanine-rich Kinase in CD4 T Cells Diabetes (IF 7.7) Pub Date : 2024-01-19 Jing-Jie Ciou, Ming-Wei Chien, Chao-Yuan Hsu, Yu-Wen Liu, Jia-Ling Dong, Shin-Ying Tsai, Sung-Sen Yang, Shih-Hua Lin, B. Lin-Ju Yen, Shin-Huei Fu, Huey-Kang Sytwu
The fundamental mechanisms whereby a diet affects susceptibility to or modifies autoimmune diseases are poorly understood. Despite excess dietary salt intake acts as a risk factor for autoimmune diseases, little information exists on the impact of salt intake on type 1 diabetes. To elucidate the potential effect of high-salt intake on autoimmune diabetes, non-obese diabetic (NOD) mice were fed with
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Mitochondrial Dynamics, Diabetes, and Cardiovascular Disease Diabetes (IF 7.7) Pub Date : 2024-01-19 Luis Miguel García-Peña, E. Dale Abel, Renata O. Pereira
Mitochondria undergo repeated cycles of fusion and fission that regulate their size and shape by a process known as mitochondrial dynamics. Numerous studies have revealed the importance of this process in maintaining mitochondrial health and cellular homeostasis, particularly in highly metabolically active tissues such as skeletal muscle and the heart. Here, we review the literature on the relationship
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Distinct Amino Acid Profile Characterizes Youth with or at risk for Type 2 Diabetes Diabetes (IF 7.7) Pub Date : 2024-01-12 Fida Bacha, Heba El-Ayash, Mahmoud Mohamad, Susan Sharma, Maurice Puyau, Rupa Kanchi, Cristian Coarfa
Branched-chain amino acids (BCAA) and aromatic AAs (AAA) are associated with increased risk for type 2 diabetes in adults. Studies in youth show conflicting results. We hypothesized that an AA metabolomic signature can be defined to identify youth at risk for β-cell failure and the development of type 2 diabetes. We performed targeted AA metabolomics analysis on 127 adolescents (65 females, 15.5±1
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Local dialogues between the endocrine and exocrine cells in the pancreas Diabetes (IF 7.7) Pub Date : 2024-01-12 Marjan Slak Rupnik, Manami Hara
For many years, it has been taught in medical textbooks that the endocrine and exocrine parts of the pancreas have separate blood supplies that do not mix. Therefore, they have been studied by different scientific communities, and patients with pancreatic disorders are treated by physicians in different medical disciplines, endocrinologists and gastroenterologists, respectively. The conventional model
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KD025 is a casein kinase 2 inhibitor that protects against glucolipotoxicity in beta cells Diabetes (IF 7.7) Pub Date : 2024-01-12 Ranjan Devkota, Jonnell C. Small, Kaycee Carbone, Michael A. Glass, Amedeo Vetere, Bridget K. Wagner
Glucolipotoxicity (GLT), in which elevated levels of glucose and fatty acids have deleterious effects on β-cell biology, is thought to be one of the major contributors in progression of type 2 diabetes. In search of novel small molecules that protects β-cells against GLT, we previously discovered KD025, an inhibitor of Rho-associated coiled-coil containing kinase isoform 2 (ROCK2), as a GLT-protective
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Higher HbA1c is Associated with Greater Two-Year Progression of White Matter Hyperintensities Diabetes (IF 7.7) Pub Date : 2024-01-12 Noah Schweitzer, Sang Joon Son, Howard Aizenstein, Shaolin Yang, Bistra Iordanova, Chang Hyung Hong, Hyun Woong Rho, Yong Hyuk Cho, Bumhee Park, Na-Rae Kim, Jin Wook Choi, Jae Youn Cheong, Sang Woon Seo, Young-Sil An, So Young Moon, Seung Jin Han, Minjie Wu
White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease (CSVD). Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting
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Therapeutic targets for diabetic kidney disease: proteome-wide Mendelian randomization and colocalization analyses Diabetes (IF 7.7) Pub Date : 2024-01-12 Wei Zhang, Leilei Ma, Qianyi Zhou, Tianjiao Gu, Xiaotian Zhang, Haitao Xing
At present, safe and effective treatment drugs are urgently needed for diabetic kidney disease (DKD). Circulating protein biomarkers with causal genetic evidence represent promising drug targets, which provides an opportunity to identify new therapeutic targets. Summary data from two protein quantitative trait loci (pQTL) studies: one involving 4,907 plasma proteins data from 35,559 individuals, and
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Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function Diabetes (IF 7.7) Pub Date : 2024-01-08 Mi Huang, Rashmi B. Prasad, Daniel E. Coral, Line Hjort, Daniel T. R. Minja, Hindrik Mulder, Paul W. Franks, Sebastian Kalamajski
Human genetic variation in PPARGC1B has been associated with adiposity, but the genetic variants that affect PPARGC1B expression have not been experimentally determined. Here, guided by previous observational data, we used CRISPR/Cas9 to scarlessly edit the alleles of the candidate causal genetic variant rs10071329 in a human brown adipocyte cell line (hBAs). Switching the rs10071329 genotype from
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Discovery of a novel benzothiadiazine-based selective aldose reductase inhibitor as potential therapy for diabetic peripheral neuropathy Diabetes (IF 7.7) Pub Date : 2023-12-21 Ruyi Jin, Jin Wang, Mingyue Li, Tian Tang, Yidong Feng, Sha Zhou, Honglei Xie, Haiyu Feng, Jianshuang Guo, Ruijia Fu, Jiping Liu, Yuping Tang, Yajun Shi, Hui Guo, Yuwei Wang, Fayi Nie, Jing Li
Aldose reductase2 (ALR2), an activated enzyme in polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for diabetic complications especially in diabetic peripheral neuropathy (DPN). However, lots of ALR2 inhibitors showed serious sideeffects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of benzothiadiazine
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Bridging the Gap: Pancreas Tissue Slices From Organ and Tissue Donors for the Study of Diabetes Pathogenesis Diabetes (IF 7.7) Pub Date : 2023-12-20 Christian M. Cohrs, Chunguang Chen, Mark A. Atkinson, Denise M. Drotar, Stephan Speier
Over the last two decades, increased availability of human pancreatic tissues has allowed for major expansions in our understanding of islet biology in health and disease. Indeed, studies of fixed and frozen pancreatic tissues, as well as efforts using viable isolated islets obtained from organ donors, have provided significant insights toward our understanding of diabetes. However, the procedures
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Multi-omics analyses with stool-type stratification in patient cohorts and Blautia identification as a potential bacterial modulator in T2DM Diabetes (IF 7.7) Pub Date : 2023-12-11 Qian Guo, Zezheng Gao, Linhua Zhao, Han Wang, Zhen Luo, Doris Vandeputte, Lisha He, Mo Li, Sha Di, Yanwen Liu, Jiaheng Hou, Xiaoqing Jiang, Huaiqiu Zhu, Xiaolin Tong
Heterogeneity in host and gut microbiota hampers microbial precision intervention of type 2 diabetes mellitus (T2DM). Here, we investigate novel features for patient-stratification and bacterial modulators for intervention, using cross-sectional patient cohorts and animal experiments. We collected stool/blood/urine samples from 103 recent-onset T2DM patients and 25 healthy controls (HCs), performed
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Overexpression of UBE2E2 in mouse pancreatic β-cells leads to glucose intolerance via reduction of the β-cell mass Diabetes (IF 7.7) Pub Date : 2023-12-08 Yoshitaka Sakurai, Naoto Kubota, Iseki Takamoto, Nobuhiro Wada, Masakazu Aihara, Takanori Hayashi, Tetsuya Kubota, Yuta Hiraike, Takayoshi Sasako, Harumi Nakao, Atsu Aiba, Yoko Chikaoka, Takeshi Kawamura, Takashi Kadowaki, Toshimasa Yamauchi
Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes (E2s) involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Herein, we showed upregulated UBE2E2 expression in the islets of a mouse