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Published By American Diabetes Association

0012-1797, 0012-1797

Diabetes ◽  
2022 ◽  
Author(s):  
Qianxing Hu ◽  
Jinming Mu ◽  
Yuhong Liu ◽  
Yue Yang ◽  
Yue Liu ◽  
...  

Pancreatic β-cell adapt to compensate for increased metabolic demand during obesity. Although the microRNA (miRNA) pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly-A tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.


Diabetes ◽  
2022 ◽  
Author(s):  
Naiara G. Bediaga ◽  
Alexandra L. Garnham ◽  
Gaetano Naselli ◽  
Esther Bandala-Sanchez ◽  
Natalie L. Stone ◽  
...  

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4+ and CD8+ T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4+ T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (‘Progressors’) compared to five children matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ T cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.


Diabetes ◽  
2022 ◽  
Author(s):  
Braxton L. Jamison ◽  
James E. DiLisio ◽  
K. Scott Beard ◽  
Tobias Neef ◽  
Brenda Bradley ◽  
...  

The induction of antigen (Ag)-specific tolerance and replacement of islet β-cells are major ongoing goals for the treatment of Type 1 Diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the non-obese diabetic (NOD) mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and to the expansion of Foxp3+ regulatory T cells specific for the same antigen. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other β-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with a hybrid insulin peptide can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.


Diabetes ◽  
2021 ◽  
Vol 71 (1) ◽  
pp. 172-172

Diabetes ◽  
2021 ◽  
Vol 71 (1) ◽  
pp. e1-e2
Author(s):  
Gary Tse ◽  
Tong Liu ◽  
Leonardo Roever ◽  
Sharen Lee
Keyword(s):  

Diabetes ◽  
2021 ◽  
Vol 71 (1) ◽  
pp. 23-30
Author(s):  
Korbyn J.V. Dahlquist ◽  
Christina D. Camell

Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest for their well-known roles in metabolic disease. Recent literature reveals that adipose tissue is an organ in which signs of initial aging occur, including immune cell activation. Aged adipose tissue reveals changes in many innate and adaptive immune cell subsets, revealing a complex interaction that contributes to inflammation, increased senescence, impaired catecholamine-induced lipolysis, and impaired insulin sensitivity. Here, we will describe current knowledge surrounding age-related changes in immune cells while relating those findings to recent discoveries regarding immune cells in aged adipose tissue.


Diabetes ◽  
2021 ◽  
pp. db210545
Author(s):  
Mark J. O'Connor ◽  
Philip Schroeder ◽  
Alicia Huerta-Chagoya ◽  
Paula Cortés-Sánchez ◽  
Silvía Bonàs-Guarch ◽  
...  

Diabetes ◽  
2021 ◽  
pp. db210289
Author(s):  
Prasanna K. R. Allu ◽  
Malapaka Kiranmayi ◽  
Sromona D. Mukherjee ◽  
Venkat R. Chirasani ◽  
Richa Garg ◽  
...  

Diabetes ◽  
2021 ◽  
pp. db210281
Author(s):  
Tal Israeli ◽  
Yael Riahi ◽  
Perla Garzon ◽  
Ruy Andrade Louzada ◽  
Joao Pedro Werneck-de-Castro ◽  
...  
Keyword(s):  

Diabetes ◽  
2021 ◽  
pp. db210638
Author(s):  
Xiaoxi Xu ◽  
Yumeng Huang ◽  
Xin Li ◽  
Peter Arvan ◽  
Ming Liu

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