Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide?streptozotocin G�ttingen minipig after oral glucose in vivo and in the perfused pancreas

AbstractExpanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice. We show that Wisp1 promotes endogenous and transplanted adult beta cell proliferation in vivo. We validate these findings using isolated mouse and human islets and find that the beta cell trophic effect of Wisp1 is dependent on Akt signaling. In summary, our study reveals the role of Wisp1 as an inducer of beta cell replication, supporting the idea that the use of young blood factors may be a useful strategy to expand adult beta cell mass.

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In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass

Nuclear Medicine and Biology ◽

10.1016/j.nucmedbio.2009.12.004 ◽

2010 ◽

Vol 37 (3) ◽

pp. 357-363 ◽

Cited By ~ 44

Author(s):

Olof Eriksson ◽

Mahabuba Jahan ◽

Peter Johnström ◽

Olle Korsgren ◽

Anders Sundin ◽

...

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

In Vitro Characterization

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In vivo expression of GLP-1/IgG-Fc fusion protein enhances beta-cell mass and protects against streptozotocin-induced diabetes

Gene Therapy ◽

10.1038/sj.gt.3302944 ◽

2007 ◽

Vol 14 (12) ◽

pp. 981-988 ◽

Cited By ~ 43

Author(s):

N Soltani ◽

M Kumar ◽

Y Glinka ◽

G J Prud'Homme ◽

Q Wang

Keyword(s):

Fusion Protein ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Fc Fusion Protein ◽

In Vivo Expression ◽

Streptozotocin Induced Diabetes

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Defective exocytosis and processing of insulin in a cystic fibrosis mouse model

Journal of Endocrinology ◽

10.1530/joe-18-0570 ◽

2019 ◽

Vol 241 (1) ◽

pp. 45-57 ◽

Cited By ~ 2

Author(s):

A Edlund ◽

M Barghouth ◽

M Hühn ◽

M Abels ◽

J S E Esguerra ◽

...

Keyword(s):

Cystic Fibrosis ◽

Mouse Model ◽

Beta Cell ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Hormone Secretion ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Number

Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine alpha and beta cell function in the Cftr tm1 EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild type (WT) mice aged 7–10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in (1) reduced number of docked insulin granules and reduced exocytosis and (2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.

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The Harmine and Exendin-4 Combination Markedly Expands Human Beta Cell Mass In Vivo: Quantification and Visualization By iDISCO+ 3D Imaging

10.1101/2020.07.24.220244 ◽

2020 ◽

Author(s):

Carolina Rosselot ◽

Alexandra Alvarsson ◽

Peng Wang ◽

Yansui Li ◽

Kunal Kumar ◽

...

Keyword(s):

Cell Proliferation ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Mass ◽

Beta Cell Mass ◽

Beta Cell Proliferation ◽

Light Sheet Microscopy ◽

Human Beta Cell

AbstractSince all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

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Development of Radiotracers for the Determination of the Beta-Cell Mass In Vivo

Current Pharmaceutical Design ◽

10.2174/138161210791164126 ◽

2010 ◽

Vol 16 (14) ◽

pp. 1561-1567 ◽

Cited By ~ 33

Author(s):

Maarten Brom ◽

Karolina Andraojc ◽

Wim J.G. Oyen ◽

Otto C. Boerman ◽

Martin Gotthardt

Keyword(s):

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass

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Exendin-4 Promotes Beta Cell Proliferation via PI3k/Akt Signalling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000374027 ◽

2015 ◽

Vol 35 (6) ◽

pp. 2223-2232 ◽

Cited By ~ 15

Author(s):

Chaoxun Wang ◽

Xiaopan Chen ◽

Xiaoying Ding ◽

Yanju He ◽

Chengying Gu ◽

...

Keyword(s):

Cell Proliferation ◽

Beta Cell ◽

Molecular Mechanisms ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Number ◽

Beta Cell Proliferation ◽

Proliferation In Vitro

Background/Aims: Prevention of diabetes requires maintenance of a functional beta-cell mass, the postnatal growth of which depends on beta cell proliferation. Past studies have shown evidence of an effect of an incretin analogue, Exendin-4, in promoting beta cell proliferation, whereas the underlying molecular mechanisms are not completely understood. Methods: Here we studied the effects of Exendin-4 on beta cell proliferation in vitro and in vivo through analysing BrdU-incorporated beta cells. We also analysed the effects of Exendin-4 on beta cell mass in vivo, and on beta cell number in vitro. Then, we applied specific inhibitors of different signalling pathways and analysed their effects on Exendin-4-induced beta cell proliferation. Results: Exendin-4 increased beta cell proliferation in vitro and in vivo, resulting in significant increases in beta cell mass and beta cell number, respectively. Inhibition of PI3K/Akt signalling, but not inhibition of either ERK/MAPK pathway, or JNK pathway, significantly abolished the effects of Exendin-4 in promoting beta cell proliferation. Conclusion: Exendin-4 promotes beta cell proliferation via PI3k/Akt signaling pathway.

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