scholarly journals The Tetracycline-Controlled Transactivator (Tet-On/Off) System in Beta Cells Reduces Insulin Expression and Secretion in Mice

Diabetes ◽  
2021 ◽  
pp. db210147
Author(s):  
Nathalie Jouvet ◽  
Khalil Bouyakdan ◽  
Scott A. Campbell ◽  
Cindy Baldwin ◽  
Shannon E. Townsend ◽  
...  
Keyword(s):  
Beta Cells ◽  
Insulin Expression

scholarly journals An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Jeffrey Babad ◽  
Riyasat Ali ◽  
Jennifer Schloss ◽  
Teresa P. DiLorenzo
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cells ◽  
Immune Cell ◽  
Regulatory Region ◽  
Islet Autoimmunity ◽  
Positive Type ◽  
Insulin Expression ◽  
Pancreatic Islet Beta Cells

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Multiple genetic loci contribute to disease susceptibility in humans, with the most responsible locus being the major histocompatibility complex (MHC). Certain MHC alleles are predisposing, including the common HLA-A∗02:01. After the MHC, the locus conferring the strongest susceptibility to T1D is the regulatory region of the insulin gene, and alleles associated with reduced thymic insulin expression are predisposing. Mice express two insulin genes,Ins1andIns2. While both are expressed in beta cells, onlyIns2is expressed in the thymus. We have developed an HLA-A∗02:01-transgenic NOD-based T1D model that is heterozygous for a functionalIns2gene. These mice exhibit reduced thymic insulin expression and accelerated disease in both genders. Immune cell populations are not grossly altered, and the mice exhibit typical signs of islet autoimmunity, including CD8 T cell responses to beta cell peptides also targeted in HLA-A∗02:01-positive type 1 diabetes patients. This model should find utility as a tool to uncover the mechanisms underlying the association between reduced thymic insulin expression and T1D in humans and aid in preclinical studies to evaluate insulin-targeted immunotherapies for the disease.

scholarly journals Clinical and Functional Characteristics of a Novel KLF11 Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yujing Sun ◽  
Jingru Qu ◽  
Jing Wang ◽  
Ruxing Zhao ◽  
Chuan Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Luciferase Reporter ◽  
Maturity Onset Diabetes ◽  
Insulin Expression ◽  
Insulin Promoter ◽  
Impaired Insulin ◽  
Reporter Assays

Background. Mutations in human KLF11 may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel KLF11 mutation c.1061G > T have not yet been reported. Methods. Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the KLF11 variant. Luciferase reporter assays were used to investigate whether the KLF11 variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the KLF11 variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels. Results. Mutation screening for the whole exon genes identified a heterozygous KLF11 (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the KLF11 (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake ( p < 0.05 ). Conclusions. Herein, for the first time, we report a novel KLF11 (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband.

scholarly journals Dysregulation of Dicer1 in Beta Cells Impairs Islet Architecture and Glucose Metabolism

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Amitai D. Mandelbaum ◽  
Tal Melkman-Zehavi ◽  
Roni Oren ◽  
Sharon Kredo-Russo ◽  
Tomer Nir ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Beta Cell ◽  
Beta Cells ◽  
Endocrine Pancreas ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Pancreas Development ◽  
Wild Type ◽  
Insulin Expression ◽  
E Cadherin

microRNAs (miRNAs) play important roles in pancreas development and in regulation of insulin expression in the adult. Here we show that loss of miRNAs activity in beta-cells during embryonic development results in lower beta-cell mass and in impaired glucose tolerance. Dicer1-null cells initially constitute a significant portion of the total beta-cell population. However, during postnatal development, Dicer1-null cells are depleted. Furthermore, wild-type beta cells are repopulating the islets in complex compensatory dynamics. Because loss of Dicer1 is also associated with changes in the distribution of membranous E-cadherin, we hypothesized that E-cadherin activity may play a role in beta cell survival or islet architecture. However, genetic loss of E-cadherin function does not impair islet architecture, suggesting that miRNAs likely function through other or redundant effectors in the endocrine pancreas.

scholarly journals Integrin αvβ5 heterodimer is a specific marker of human pancreatic beta cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacqueline V. Schiesser ◽  
Thomas Loudovaris ◽  
Helen E. Thomas ◽  
Andrew G. Elefanty ◽  
Edouard G. Stanley
Keyword(s):  
Cell Surface ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Specific Marker ◽  
Human Pancreas ◽  
Cell Type ◽  
Immunofluorescence Analysis ◽  
Insulin Expression ◽  
Rnaseq Data

AbstractThe identification of cell surface markers specific to pancreatic beta cells is important for both the study of islet biology and for investigating the pathophysiology of diseases in which this cell type is lost or damaged. Following analysis of publicly available RNAseq data, we identified specific integrin subunits, integrin αv and integrin β5, that were expressed in beta cells. This finding was further elaborated using immunofluorescence analysis of histological sections derived from donor human pancreas. Despite the broad expression of specific integrin subunits, we found that expression of integrin αvβ5 heterodimers was restricted to beta cells and that this complex persisted in islet remnants of some type 1 diabetic individuals from which insulin expression had been lost. This study identifies αvβ5 heterodimers as a novel cell surface marker of human pancreatic beta cells, a finding that will aid in the identification and characterisation of this important cell type.

scholarly journals GLIS3 binds pancreatic beta cell regulatory regions alongside other islet transcription factors

2019 ◽  
Vol 243 (1) ◽  
pp. 1-14 ◽  
Author(s):  
David W Scoville ◽  
Kristin Lichti-Kaiser ◽  
Sara A Grimm ◽  
Anton M Jetten
Keyword(s):  
Transcription Factors ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Critical Role ◽  
Regulatory Regions ◽  
Insulin Expression

The Krüppel-like zinc finger transcription factor Gli-similar 3 (GLIS3) plays a critical role in the regulation of pancreatic beta cells, with global Glis3-knockout mice suffering from severe hyperglycemia and dying by post-natal day 11. In addition, GLIS3 has been shown to directly regulate the early endocrine marker Ngn3, as well as Ins2 gene expression in mature beta cells. We hypothesize that GLIS3 regulates several other genes critical to beta cell function, in addition to Ins2, by directly binding to regulatory regions. We therefore generated a pancreas-specific Glis3 deletion mouse model (Glis3Δ panc ) using a Pdx1-driven Cre mouse line. Roughly 20% of these mice develop hyperglycemia by 8 weeks and lose most of their insulin expression. However, this did not appear to be due to loss of the beta cells themselves, as no change in cell death was observed. Indeed, presumptive beta cells appeared to persist as PDX1+/INS−/MAFA−/GLUT2− cells. Islet RNA-seq analysis combined with GLIS3 ChIP-seq analysis revealed apparent direct regulation of a variety of diabetes-related genes, including Slc2a2 and Mafa. GLIS3 binding near these genes coincided with binding for other islet-enriched transcription factors, indicating these are distinct regulatory hubs. Our data indicate that GLIS3 regulates not only insulin expression, but also several additional genes critical for beta cell function.

Endodermal progenitor cells (EPCs) as an extensive source for human endocrine beta-cells

2014 ◽  
Vol 52 (08) ◽  
Author(s):  
A Illing ◽  
M Hohwieler ◽  
T Seufferlein ◽  
A Kleger
Keyword(s):  
Progenitor Cells ◽  
Beta Cells
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