Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Onset of Type 2 diabetes occurs when the pancreatic β-cell fails to adapt to the increased insulin demand caused by insulin resistance. Morphological and therapeutic intervention studies have uncovered an inflammatory process in islets of patients with Type 2 diabetes characterized by the presence of cytokines, immune cells, β-cell apoptosis, amyloid deposits, and fibrosis. This insulitis is due to a pathological activation of the innate immune system by metabolic stress and governed by IL-1 signaling. We propose that this insulitis contributes to the decrease in β-cell mass and the impaired insulin secretion observed in patients with Type 2 diabetes.

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A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development

eLife ◽

10.7554/elife.20145 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 46

Author(s):

Jennifer Hampton Hill ◽

Eric A Franzosa ◽

Curtis Huttenhower ◽

Karen Guillemin

Keyword(s):

Cell Proliferation ◽

Cell Expansion ◽

Bacterial Species ◽

Pancreatic Beta Cell ◽

Fecal Microbiota ◽

Pancreatic Β Cell ◽

Β Cell ◽

Larval Zebrafish ◽

Low Diversity ◽

Early Larval Development

Resident microbes play important roles in the development of the gastrointestinal tract, but their influence on other digestive organs is less well explored. Using the gnotobiotic zebrafish, we discovered that the normal expansion of the pancreatic β cell population during early larval development requires the intestinal microbiota and that specific bacterial members can restore normal β cell numbers. These bacteria share a gene that encodes a previously undescribed protein, named herein BefA (β Cell Expansion Factor A), which is sufficient to induce β cell proliferation in developing zebrafish larvae. Homologs of BefA are present in several human-associated bacterial species, and we show that they have conserved capacity to stimulate β cell proliferation in larval zebrafish. Our findings highlight a role for the microbiota in early pancreatic β cell development and suggest a possible basis for the association between low diversity childhood fecal microbiota and increased diabetes risk.

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Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-cell Proliferation Through the CPEB1/CDKN1B Pathway

10.2337/figshare.17189177 ◽

2022 ◽

Author(s):

Ada Admin ◽

Qianxing Hu ◽

Jinming Mu ◽

Yuhong Liu ◽

Yue Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Expansion ◽

Binding Protein ◽

Pancreatic Β Cell ◽

Loss Of Function ◽

Metabolic Demand ◽

Β Cell ◽

Element Binding Protein ◽

Mirna Pathway

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.

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Recent progress in studies of factors that elicit pancreatic β-cell expansion

Protein & Cell ◽

10.1007/s13238-014-0123-3 ◽

2014 ◽

Vol 6 (2) ◽

pp. 81-87 ◽

Cited By ~ 5

Author(s):

Qiu Li ◽

Zhi-Chun Lai

Keyword(s):

Cell Expansion ◽

Recent Progress ◽

Pancreatic Β Cell ◽

Β Cell

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JUND regulates pancreatic β cell survival during metabolic stress

Molecular Metabolism ◽

10.1016/j.molmet.2019.04.007 ◽

2019 ◽

Vol 25 ◽

pp. 95-106 ◽

Cited By ~ 6

Author(s):

Austin L. Good ◽

Corey E. Cannon ◽

Matthew W. Haemmerle ◽

Juxiang Yang ◽

Diana E. Stanescu ◽

...

Keyword(s):

Cell Survival ◽

Metabolic Stress ◽

Pancreatic Β Cell ◽

Β Cell

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NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

Cells ◽

10.3390/cells10071573 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1573

Author(s):

Suma Elumalai ◽

Udayakumar Karunakaran ◽

Jun-Sung Moon ◽

Kyu-Chang Won

Keyword(s):

Nadph Oxidase ◽

Cell Function ◽

Negative Impact ◽

Redox Homeostasis ◽

Metabolic Stress ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Therapeutic Benefits

In type 2 diabetes, metabolic stress has a negative impact on pancreatic β-cell function and survival (T2D). Although the pathogenesis of metabolic stress is complex, an imbalance in redox homeostasis causes abnormal tissue damage and β-cell death due to low endogenous antioxidant expression levels in β-cells. Under diabetogenic conditions, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to contributing to β-cell dysfunction. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions by NADPH oxidase, as well as the therapeutic benefits of NOX inhibitors, which may provide clues for understanding the pathomechanisms and developing strategies aimed at the treatment or prevention of metabolic stress associated with β-cell failure.

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Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-cell Proliferation Through the CPEB1/CDKN1B Pathway

Diabetes ◽

10.2337/db21-0134 ◽

2022 ◽

Author(s):

Qianxing Hu ◽

Jinming Mu ◽

Yuhong Liu ◽

Yue Yang ◽

Yue Liu ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Expansion ◽

Binding Protein ◽

Pancreatic Β Cell ◽

Loss Of Function ◽

Metabolic Demand ◽

Β Cell ◽

Element Binding Protein ◽

Mirna Pathway

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.

Download Full-text