Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells in vitro

Ris, Frédéric; Hammar, Eva; Bosco, Domenico; Pilloud, C.; Maedler, Kathrin; Donath, Marc Y.; Oberholzer, José; Zeender, E.; Morel, Philippe; Rouiller, D.; Halban, Philippe A.

doi:10.1007/s00125-002-0840-7

Cited by 86 publications

(86 citation statements)

References 50 publications

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“…We showed that two cell surface proteins (PVR and integrin αvβ3), both of which act as enterovirus receptors in established cell lines, are also expressed in primary human islets and especially in beta cells. Recently, expression of integrin subunits including αv and β3 in purified human beta cells was shown by semi-quantitative RT-PCR [61]. In contrast, no evidence was found for expression of DAF, which acts as a receptor for several of the islet cell replicating EVs in established cell lines, although different highly reactive DAF-specific monoclonal antibodies [51] were used.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells

Ylipaasto

Klingel

Lindberg³

et al. 2004

Diabetologia

265

248

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Aims/hypothesis. It is thought that enterovirus infections cause beta-cell damage and contribute to the development of Type 1 diabetes by replicating in the pancreatic islets. We sought evidence for this through autopsy studies and by investigating known enterovirus receptors in cultured human islets. Methods. Autopsy pancreases from 12 newborn infants who died of fulminant coxsackievirus infections and from 65 Type 1 diabetic patients were studied for presence of enteroviral ribonucleic acid by in situ hybridisation. Forty non-diabetic control pancreases were included in the study. The expression and role of receptor candidates in cultured human islets were investigated with receptor-specific antibodies using immunocytochemistry and functional assays. Results. Enterovirus-positive islet cells were found in some of both autopsy specimen collections, but not in control pancreases. No infected cells were seen in exocrine tissue. The cell surface molecules, poliovirus receptor and integrin αvβ 3 , which act as enterovirus receptors in established cell lines, were expressed in beta cells. Antibodies to poliovirus receptor, human coxsackievirus and adenovirus receptor and integrin αvβ 3 protected islets and beta cells from adverse effects of poliovirus, coxsackie B viruses, and several of the arginine-glycine-aspartic acid motifs containing enteroviruses and human parechovirus 1 respectively. No evidence was found for expression of the decay-accelerating factor which acts as a receptor for several isletcell-replicating echoviruses in established cell lines. Conclusions/interpretation. The results show a definite islet-cell tropism of enteroviruses in the human pancreas. Some enteroviruses seem to use previously identified cell surface molecules as receptors in beta cells, whereas the identity of receptors used by other enteroviruses remains unknown. [Diabetologia (2004) 47:225-239]

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Section: Discussionmentioning

confidence: 99%

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells

Ylipaasto

Klingel

Lindberg³

et al. 2004

Diabetologia

265

248

View full text Add to dashboard Cite

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“…Specifically, the gastrointestinal hormones gastrin, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) have been shown to induce beta cell proliferation in different in vitro models [11,[38][39][40]. However, it is difficult to directly translate these findings to the in vivo situation in adult humans, because the peptide concentrations used in those experiments were often far above the tolerable plasma concentrations in humans, and because the mitotic capacity of beta cells in culture is much higher than that of beta cells under in vivo conditions [41,42]. In the present studies, Fig.…”

Section: Discussionmentioning

confidence: 99%

Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans

Meier¹,

Butler²,

Galasso³

et al. 2006

Diabetologia

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Aims/hypothesis Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases? Methods Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy. Results Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour. Conclusions/interpretationOne or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumourdistant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.

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“…Previous studies have also demonstrated high levels of cell death in dispersed islet cultures [40,44]. One explanation for the increase in cell death upon dispersion of islets into single cells is the loss of contact with the extracellular matrix (ECM), which is mediated by the integrin receptor family.…”

Section: Discussionmentioning

confidence: 99%

Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. Methods In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. Results We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. Conclusions/interpretation Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

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Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells in vitro

Cited by 86 publications

References 50 publications

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells

Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells

Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans

Autocrine insulin action activates Akt and increases survival of isolated human islets

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