Different Effects of FK506, Rapamycin, and Mycophenolate Mofetil on Glucose-Stimulated Insulin Release and Apoptosis in Human Islets

Johnson, James D.; Ao, Ziliang; Ao, Peter; Li, Hong; Dai, Long‐Jun; He, Zehua; Tee, May C.; Potter, Kathryn; Klimek, Agnieszka M.; Meloche, R. M.; Thompson, David M.; Verchere, C. Bruce; Warnock, Garth L.

doi:10.3727/096368909x471198

Cited by 141 publications

(122 citation statements)

References 57 publications

(92 reference statements)

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“…However, upon removal of many negative or insignificant first screen factors (such as FBS, IGF-1, retinoic acid and gastrin17) from the second screen, these synergies were lost, but new synergies between nicotinamide and activin A or insulin were uncovered. While previous studies have generally shown beneficial effects of exendin-4 on beta cell function and survival [33,34], we observed a significant negative effect of exendin-4 on beta cell maturity.…”

Section: Discussioncontrasting

confidence: 94%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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Section: Discussioncontrasting

confidence: 94%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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“…We determined that media containing these factors could differentiate ADSCs into cells having a beta cell phenotype. After 30 days of differentiation, DTZ-positive clusters were observed, which were 50 -400 μm in diameter and were similar in shape to human isolated islets (Johnson et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Production of islet-like insulin-producing cell clusters in vitro from adiposederived stem cells

Dang¹,

Bui²,

Pham³

et al. 2015

Biomed Res Ther

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Abstract-Diabetes mellitus is a high incidence disease that has increased rapidly in recent years. Many new therapies are being studied and developed in order to find an effective treatment. An ideal candidate is stem cell therapy. In this study, we investigated the differentiation of adipose derived stem cells (ADSCs) into pseudo-islets in defined medium in vitro, to produce large quantities of insulin-producing cells (IPCs) for transplantation. ADSCs isolated from adipose tissue were induced to differentiate into islet-like insulin-producing cell clusters in vitro by inducing medium DMEM/F12 containing nicotinamide, N2, B27, bFGF, and insulin-transferrin-selenite (ITS). Differentiated cells were analyzed for properties of IPCs, including storage of Zn 2+ by dithizone staining, insulin production by ELISA and immunochemistry, and beta cell-related gene expression by reverse transcriptase PCR. The results showed that after 2 weeks of differentiation, the ADSCs aggregated into cell clusters, and after 4 weeks they formed islets, 50-400 micrometers in diameter. These islet cells exhibited characteristics of pancreatic beta cells as they were positive for dithizone staining, expressed insulin in vitro and C-peptide in the cytoplasm, and expressed pancreatic beta cellspecific genes, including Pdx-1, NeuroD, and Ngn3. These results demonstrate that ADSCs can be used to produce a large number of functional islets for research as well as application.

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“…Rapamycin treatment has been shown to have mixed effects on insulin secretion, depending on the experimental conditions. [56][57][58][59] The role of mTORC1 in β-cell proliferation using rapamycin has been explored in multiple studies, which have resulted in five important observations. (1) Rapamycin treatment blocks β-cell expansion, cell size and proliferation induced by an activation of AKT in β cells.…”

Section: Proliferation Cell Size and Massmentioning

confidence: 99%

mTORC1 signaling and regulation of pancreatic β-cell mass

et al. 2012

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T he capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of β-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in β cells. This review will discuss recent advances in the understanding of how this pathway regulates β-cell mass and present data on the role of TSC1 in modulation of β-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic β cells results in improved glucose tolerance, hyperinsulinemia and expansion of β-cell mass that persists with aging.

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Different Effects of FK506, Rapamycin, and Mycophenolate Mofetil on Glucose-Stimulated Insulin Release and Apoptosis in Human Islets

Cited by 141 publications

References 57 publications

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Production of islet-like insulin-producing cell clusters in vitro from adiposederived stem cells

mTORC1 signaling and regulation of pancreatic β-cell mass

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