-
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
-
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
-
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)
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
Acute activation of GFRAL in the area postrema contributes to glucose regulation independent of weight. Diabetes (IF 7.7) Pub Date : 2023-12-08 Song-Yang Zhang, Zahra Danaei, Kyla Bruce, Jennifer F.M. Chiu, Tony K.T. Lam
GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct acute GDF15 infusion
-
RFX6 maintains gene expression and function of adult human islet α cells Diabetes (IF 7.7) Pub Date : 2023-12-08 Vy M. N. Coykendall, Mollie F. Qian, Krissie Tellez, Austin Bautista, Romina J. Bevacqua, Xueying Gu, Yan Hang, Martin Neukam, Weichen Zhao, Charles Chang, Patrick E. MacDonald, Seung K. Kim
Mutations in the gene encoding the transcription factor RFX6 are associated with human diabetes mellitus. Within pancreatic islets, RFX6 expression is most abundant in islet α cells, and α cell RFX6 expression is altered in diabetes. However, the roles of RFX6 in regulating gene expression, glucagon output and other crucial human adult α cell functions are not yet understood. We developed a method
-
A translational regulatory mechanism mediated by hypusinated eukaryotic initiation factor 5A facilitates beta cell identity and function Diabetes (IF 7.7) Pub Date : 2023-12-06 Craig T. Connors, Catharina B.P. Villaca, Emily K. Anderson-Baucum, Spencer R. Rosario, Caleb D. Rutan, Paul J. Childress, Leah R. Padgett, Morgan A. Robertson, Teresa L. Mastracci
As professional secretory cells, beta cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic beta cell, the majority of factors identified to promote growth and development function
-
Critical assessment of indices used to assess beta-cell function Diabetes (IF 7.7) Pub Date : 2023-11-28 Chao Cao, Han-Chow E. Koh, Dominic N. Reeds, Bruce W. Patterson, Samuel Klein, Bettina Mittendorfer
The assessment of beta-cell function—defined as insulin secretion rate (ISR) in relationship to plasma glucose—is not standardized and often involves any of a number of beta-cell function indices. We compared beta-cell function by using popular indices obtained during basal conditions and after glucose ingestion, including the HOMA-B index, the basal ISR (or plasma insulin)-to-plasma glucose concentration
-
High doses of exogenous glucagon stimulate insulin secretion and reduce insulin clearance in healthy humans Diabetes (IF 7.7) Pub Date : 2023-11-28 Sarah M. Gray, Elisha Goonatilleke, Michelle A. Emrick, Jessica O. Becker, Andrew N. Hoofnagle, Darko Stefanovski, Wentao He, Guofang Zhang, Jenny Tong, Jonathan Campbell, David A. D’Alessio
Glucagon is generally defined as a counter-regulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP) in response to hypoglycemia. However, glucagon has long been known to stimulate insulin release, and recent preclinical findings support a paracrine action of glucagon directly on islet β-cells that augments secretion. In mice, the
-
Interactive effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals with Type 1 Diabetes Diabetes (IF 7.7) Pub Date : 2023-11-28 Luxcia Kugathasan, Vikas S. Sridhar, Leif Erik Lovblom, Shane Matta, Afaf Saliba, Subrata Debnath, Fadhl M. AlAkwaa, Viji Nair, Petter Bjornstad, Matthias Kretzler, Bruce A. Perkins, Kumar Sharma, David Z.I. Cherney
Optimizing energy utilization in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter-2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of oral empagliflozin 25 mg/day in 40 normotensive, normoalbuminuric young adults
-
PTPN2 regulates metabolic flux to affect beta cell susceptibility to inflammatory stress Diabetes (IF 7.7) Pub Date : 2023-11-28 Yong Kyung Kim, Youngjung Rachel Kim, Kristen L Wells, Dylan Sarbaugh, Michelle Guney, Chia-Feng Tsai, Tiffany Zee, Gerard Karsenty, Ernesto S. Nakayasu, Lori Sussel
Protein tyrosine phosphatase N2 (Ptpn2) is a type 1 diabetes (T1D) candidate gene identified from human genome-wide association studies. PTPN2 is highly expressed in human and murine islets and becomes elevated upon inflammation and models of T1D, suggesting that PTPN2 may be important for beta cell survival in the context of T1D. To test whether PTPN2 contributed to beta cell dysfunction in an inflammatory
-
Increased plasma branched short-chain fatty acids and improved glucose homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES) Diabetes (IF 7.7) Pub Date : 2023-11-22 Arianne Aslamy, Alexis C. Wood, Elizabeth T. Jensen, Alain G. Bertoni, Patricia A. Sheridan, Kari E. Wong, Gautam Ramesh, Jerome I. Rotter, Yii-Der I. Chen, Mark O. Goodarzi
Short chain fatty acids (SCFA) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched short chain fatty acids (BSCFA), isobutyrate, isovalerate, and methylbutyrate, is largely unknown. In a cohort of 219 non-Hispanic Whites and 126
-
Increased sub-clinical coronary artery pathology in type 2 diabetes with albuminuria Diabetes (IF 7.7) Pub Date : 2023-11-22 Ida Kirstine Bull Rasmussen, Anne-Cathrine Skriver-Moeller, Rasmus Sejersten Ripa, Philip Hasbak, Victor Soendergaard Wasehuus, Katra Hadji-Turdeghal, Emilie Hein Zobel, Martin Lyngby Lassen, Lene Holmvang, Piotr Slomka, Peter Rossing, Andreas Kjaer, Tine Willum Hansen
Diabetes affects the kidneys, and presence of albuminuria reflects widespread vascular damage and is a risk factor for cardiovascular disease (CVD). Still, the pathophysiological association between albuminuria and CVD remains incompletely understood. Recent advantages in non-invasive imaging enable functional assessment of coronary artery pathology and present an opportunity to explore the association
-
Mechanical regulation of retinal vascular inflammation and degeneration in diabetes Diabetes (IF 7.7) Pub Date : 2023-11-21 Sathishkumar Chandrakumar, Irene Santiago Tierno, Mahesh Agarwal, Emma M. Lessieur, Yunpeng Du, Jie Tang, Jianying Kiser, Xiao Yang, Anthony Rodriguez, Timothy S. Kern, Kaustabh Ghosh
Vascular inflammation is known to cause degeneration of retinal capillaries in early diabetic retinopathy (DR), a major microvascular complication of diabetes. Past studies investigating these diabetes-induced retinal vascular abnormalities have focused primarily on the role of molecular or biochemical cues. Here we show that retinal vascular inflammation and degeneration in diabetes are also mechanically
-
Conflicting Views About Interactions Between Pancreatic α-Cells and β-Cells Diabetes (IF 7.7) Pub Date : 2023-11-20 Gordon C. Weir, Susan Bonner-Weir
In type 1 diabetes, the reduced glucagon response to insulin-induced hypoglycemia has been used to argue that β-cell secretion of insulin is required for the full glucagon counterregulatory response. For years, the concept has been that insulin from the β-cell core flows downstream to suppress glucagon secretion from the α-cells in the islet mantle. This core–mantle relationship has been supported
-
Specialized Retinal Endothelial Cells Modulates Blood-Retina- Barrier in Diabetic Retinopathy Diabetes (IF 7.7) Pub Date : 2023-11-17 Xuyang Yao, Ziyan Zhao, Wenhui Zhang, Ruixin Liu, Tianwen Ni, Bohao Cui, Yi Lei, Jie Du, Ding Ai, Hongfeng Jiang, Huizhen Lv, Xiaorong Li
Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent
-
Methylglyoxal adducts are prognostic biomarkers for diabetic kidney disease in patients with type 1 diabetes Diabetes (IF 7.7) Pub Date : 2023-11-15 Seigmund Wai Tsuen Lai, Carlos Hernandez-Castillo, Edwin De Jesus Lopez Gonzalez, Tala Zoukari, Min Talley, Nadia Paquin, Zhuo Chen, Bart O. Roep, John S. Kaddis, Rama Natarajan, John Termini, Sarah C. Shuck
Over 30% of patients with type 1 diabetes develop diabetic kidney disease (DKD), significantly increasing mortality risk. The Diabetes Control and Complications Trial (DCCT) and follow-up study Epidemiology of Diabetes Interventions and Complications (EDIC) established that glycemic control measured by HbA1c predicts DKD risk. However, the continued high incidence of DKD reinforces the urgent need
-
METTL3-mediated m6A Methylation Controls Pancreatic Bipotent Progenitor Fate and Islet Formation Diabetes (IF 7.7) Pub Date : 2023-11-14 Jiajun Sun, Yanqiu Wang, Hui Fu, Fuyun Kang, Jiaxi Song, Min Xu, Guang Ning, Jian Wang, Weiqing Wang, Qidi Wang
The important role of m6A RNA modification on β cell function has been established, yet how it regulates pancreas development and endocrine differentiation remains unknown. Here, we generated transgenic mice lacking RNA methyltransferase-like 3 (Mettl3) specifically in Pdx1+ pancreatic progenitor cells and found the mutant mice developed hyperglycemia and hypo-insulinemia at 2 weeks of age, with atrophic
-
Adipocyte glucocorticoid receptor activation with high glucocorticoid doses impairs healthy adipose tissue expansion by repressing angiogenesis Diabetes (IF 7.7) Pub Date : 2023-11-14 Anna Vali, Héloïse Dalle, Alya Loubaresse, Jérôme Gilleron, Emmanuelle Havis, Marie Garcia, Carine Beaupère, Clémentine Denis, Natacha Roblot, Karine Poussin, Tatiana Ledent, Benjamin Bouillet, Mireille Cormont, Jean-François Tanti, Jacqueline Capeau, Camille Vatier, Bruno Fève, Alexandra Grosfeld, Marthe Moldes
In Human, glucocorticoids (GC) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GC often lead to adverse side effects including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion
-
Role of glycosuria in SGLT2 inhibitor-induced cardio-renal protection: a mechanistic analysis of the CREDENCE trial. Diabetes (IF 7.7) Pub Date : 2023-11-08 Ele Ferrannini, Anna Solini, Simona Baldi, Tiziana Scozzaro, David Polidori, Andrea Natali, Michael K. Hansen
SGLT2 inhibitors have been shown to provide pronounced reductions in cardio-renal outcomes, including cardiovascular death, heart failure, and renal failure. The mechanisms underlying these benefits remain uncertain. We hypothesized that the effects could be attributed to the elevated glycosuria induced by these drugs. Urine concentrations of glucose, creatinine, and ketones were measured at baseline
-
Erythritol as a potential causal contributor to cardiometabolic disease: A Mendelian randomization study Diabetes (IF 7.7) Pub Date : 2023-11-08 Rana Khafagy, Satya Dash, Andrew D. Paterson
People with type 2 diabetes frequently use low-calorie sweeteners to manage glycemia and reduce caloric intake. Use of erythritol, a low-calorie sweetener, has increased recently. Higher circulating concentration associates with major cardiac events and metabolic disease in observational data, prompting some concern. As observational data may be prone to confounding and reverse causality, we undertook
-
Foxj3 regulates thermogenesis of brown and beige fat via induction of PGC-1α Diabetes (IF 7.7) Pub Date : 2023-11-08 Jincan Huang, Yujie Zhang, Xuenan Zhou, Jiani Song, Yueyao Feng, Tongtong Qiu, Sufang Sheng, Menglin Zhang, Xi Zhang, Jingran Hao, Lei Zhang, Yinliang Zhang, Xiaorong Li, Ming Liu, Yongsheng Chang
Enhancing the development and thermogenesis in brown and beige fat represents a potential treatment for obesity. In the present study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impairs the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice display
-
Leptin Reduction as a Required Component for Weight Loss Diabetes (IF 7.7) Pub Date : 2023-11-07 Shangang Zhao, Na Li, Wei Xiong, Guannan Li, Sijia He, Zhuzhen Zhang, Qingzhang Zhu, Nisi Jiang, Christian Ikejiofor, Yi Zhu, May-Yun Wang, Xianlin Han, Ningyang Zhang, Carolina Herrera-Solis, Christine Kusminski, Zhiqiang An, Joel K. Elmquist, Philipp E. Scherer
Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism
-
GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice Diabetes (IF 7.7) Pub Date : 2023-11-07 Ellen C Furber, Karissa Hyatt, Kyla Collins, Xinxin Yu, Brian A Droz, Adrienne Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L Konkol, Libbey S O’Farrell, Hana E Baker, Tamer Coskun, Philipp E Scherer, Christine M Kusminski, Michael E Christe, Kyle W Sloop, Ricardo J Samms
Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic
-
Roles of Activin A and Gpnmb in metabolic dysfunction-associated steatotic liver disease (MASLD) Diabetes (IF 7.7) Pub Date : 2023-11-07 Huan Liu, Armen Yerevanian, Maria Westerhoff, Margaret H. Hastings, Justin Ralph Baldovino Guerra, Meng Zhao, Katrin J. Svensson, Bishuang Cai, Alexander A. Soukas, Anthony Rosenzweig
Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD)) and metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis (NASH)) are leading chronic liver diseases, driving cirrhosis, hepatocellular carcinoma, and mortality. MASLD/MASH is associated with increased senescence proteins, including
-
Genetic analysis of obesity-induced diabetic nephropathy in BTBR mice Diabetes (IF 7.7) Pub Date : 2023-11-07 Mark P. Keller, Chris O’Connor, Markus Bitzer, Kathryn L. Schueler, Donald S. Stapleton, Christopher H. Emfinger, Aimee Teo Broman, Jeffrey B. Hodgin, Alan D. Attie
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States and has a significant impact on human suffering. Leptin-deficient BTBR mice (BTBRob/ob) develop hallmark features of obesity-induced diabetic nephropathy, whereas leptin-deficient C57BL/6J (B6ob/ob) mice do not. To identify genetic loci that underlie this strain difference, we constructed an F2 intercross
-
Plasma neuronal growth regulator 1 may link physical activity to reduced risk of type 2 diabetes: a proteome-wide study of ARIC participants Diabetes (IF 7.7) Pub Date : 2023-11-07 Brian T. Steffen, Daniel J. McDonough, James S. Pankow, Weihong Tang, Mary R. Rooney, Ryan T. Demmer, Pamela L. Lutsey, Weihua Guan, Kelley Pettee Gabriel, Priya Palta, Ethan D. Moser, Mark A. Pereira
Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach in Atherosclerosis Risk in Communities Study participants, we aimed to identify plasma proteins associated with PA and determine which of these may be causally related to lower T2D risk. PA was associated with 92 plasma proteins in discovery
-
Exocrine pancreas in type 1 and type 2 diabetes: different patterns of fibrosis, metaplasia, angiopathy, and adiposity Diabetes (IF 7.7) Pub Date : 2023-10-26 Jordan J Wright, Adel Eskaros, Annika Windon, Rita Bottino, Regina Jenkins, Amber M Bradley, Radhika Aramandla, Sharon Philips, Hakmook Kang, Diane C Saunders, Marcela Brissova, Alvin C Powers
The endocrine and exocrine compartments of the pancreas are spatially related but functionally distinct. Multiple diseases affect both compartments, including type 1 diabetes (T1D), pancreatitis, cystic fibrosis, and pancreatic cancer. To better understand how the exocrine pancreas changes with age, obesity, and diabetes, we performed systematic analysis of wellpreserved tissue sections from the pancreatic