Role of pancreatic beta-cells in the process of beta-cell death.

Pipeleers, Daniël; Hoorens, Anne; Marichal-Pipeleers, M; Casteele, Mark Van de; Bouwens, Luc; Ling, Zong Chao

doi:10.2337/diabetes.50.2007.s52

Cited by 52 publications

(49 citation statements)

References 32 publications

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“…We examined whether isolated postnatal human duct-cell preparations have this property when transplanted under the kidney capsule of normal mice. A duct cell-containing fraction was obtained during the islet-cell isolation procedure that is conducted for our clinical trial on beta-cell transplantation, and is further enriched during suspension culture [19,20,21,22,23]. Grafts are then prepared that contain approximately 0.5 million cells and mainly consist of CK 19 marked duct cells (80%) with acinar cells as major contaminant (18%); endocrine and insulin-positive cells were rare (<2%) but consistently present.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proposed that addition of an extracellular matrix and selected agents might induce differentiation of duct cells to islet cells [18]. It is important to know whether a similar process can occur in human islet grafts which are known to be heavily contaminated by pancreatic duct cells [19,20,21]. To investigate this possibility we prepared human pancreatic duct cells [22,23] and followed their cellular composition and cell population volumes over 10 weeks after transplantation in nude mice.…”

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confidence: 99%

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Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

et al. 2003

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Aims/hypothesis. Pancreatic ducts are considered as potential sites for neogenesis of beta cells. In vitro studies have reported formation of islets from postnatal human and rodent duct tissue. We examined whether postnatal human duct-cell preparations can generate new beta cells after transplantation. Methods. Pancreatic duct cells were prepared from the non-endocrine fraction of human donor pancreases that were processed for islet-cell isolation. Grafts containing 0.5 million duct cells with 1% contaminating insulin-positive cells were implanted under the kidney capsule of normoglycaemic nude mice. At 0.5 and 10 weeks post-transplantation, implants were examined for their cellular composition and for the volumes of their composing cell populations, i.e. cytokeratin 19-positive duct cells, synaptophysin-, insulin-and glucagon-positive endocrine cells. Results. Between week 0.5 and 10, duct-cell volume decreased by at least 90% whereas the change in insulin-positive cell volume depended on donor age. Implants from donors over10 years had a threefold decrease in their insulin-positive cell volume, while those from donors under 10 years had a 2.5-fold increase. After 10 weeks, the implants from the younger donors consisted of 19% insulin-positive cells occurring as single units or small cell clusters. Three percent of these insulin-positive cells also expressed the ductal marker CK 19 and were consistently found in conjunction with ductal epithelia; up to 1% was positive for the proliferation marker BrdU and located in small endocrine cell clusters. Conclusions/interpretation. These data indicate that duct cell preparations from donors under 10 years can generate insulin-positive cells. This process might involve differentiation of CK 19-positive-insulin cells that are formed at the duct epithelia as well as proliferation of insulin-positive cells within endocrine cell aggregates. [Diabetologia (2003) 46:830-838]

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

et al. 2003

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“…Clearly, other factors are playing a role. These could include noxious products of the beta cells themselves [43] or lack of positive/protective factors normally contributed by the non-beta cells of human isolated islets. These must now be addressed in further studies and appropriate intervention conceived to block entirely cell death and restore glucose-sensitivity.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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Aims/hypothesis. Human islet cells survive poorly in culture and are overgrown by non-endocrine cells. The aims of this study were to sort human beta cells and to develop approaches for their improved survival in culture. Methods. Human islets were infected with recombinant adenovirus expressing green fluorescent protein (GFP) under the control of the rat insulin promoter such that only beta cells expressed GFP. GFP-positive beta cells were sorted by flow cytometry, and expression of select integrins evaluated by RT-PCR. Beta cells were cultured on different extracellular matrices for up to 15 days. Apoptosis was measured by annexin V binding and ELISA. Insulin secretion was measured by ELISA. Results. Sorted beta cells survived less well in culture than unsorted islet cells. This did not appear to be due to adenoviral infection and/or GFP expression. Purified beta cells expressed the integrins α3, α5, α6, αV, β1, but not β4. Of the various matrices tested, sorted beta cells attached and spread best on a lawn of lysed human bladder carcinoma cells (5637 cells). However, survival remained poor. Cell death was decreased but not prevented by continued presence of 10 mmol/l nicotinamide and apoptosis decreased by 24 h incubation with 20 µmol/l Z-VAD. Insulin secretion was maintained over 6 days following treatment with both agents. Conclusions/interpretation. Purification of human beta cells induces marked apoptosis limiting their function and survival in vitro. This was improved by matching the extracellular matrix to the specific expression of integrins and by addition of nicotinamide and Z-VAD. [Diabetologia (2002) 45:841-850]

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“…Earlier studies have shown that Ucp2-KO macrophages have increased MAPK activation in response to LPS and therefore produce more NO (8). NO and IL-1␤ are two important mediators in inflammation and ␤-cell death (20,21). To investigate whether MLDS treatment differentially affected macrophage activity in Ucp2-KO and Ucp2-WT mice, peritoneal macrophages were isolated from both types of mice.…”

Section: Increased No and Cytokine Production Of Macrophages From Mlds-mentioning

confidence: 99%

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

Emre

Hurtaud

Karaca

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting ␤-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1␤ and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.inflammation ͉ nitric oxide M itochondria are important organelles for cellular functions, including ATP synthesis. Oxidative glucose metabolism in pancreatic ␤-cells increases the ATP/ADP ratio, leading to insulin release. Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein expressed in pancreatic ␤-cells (1, 2) and immune cells (3,4).In pancreatic ␤-cells, UCP2 was reported to alter the yield of ATP synthesis from glucose, and it has been proposed as a negative regulator of glucose-stimulated insulin secretion (2). In other respects, there is much evidence for the influence of UCP2 on immune responses. First, Ucp2-KO mice exhibit increased resistance to a Toxoplasma gondii or Listeria monocytogenes infection (4, 5). Second, in an LDL receptor-null background, Ucp2-KO mice develop greater and more unstable atherosclerotic plaques than WT mice (6). Third, in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, Ucp2-KO mice develop higher disease scores than Ucp2-WT mice (7). We showed that UCP2 regulates LPS-induced reactive oxygen species (ROS) signaling in macrophages (8). MAPK activation in Ucp2-KO macrophages is quicker and stronger than in WT macrophages (8), leading to increased nitric oxide (NO), cytokine production, and migration ability (8, 9). Consistent with these findings, overexpression of UCP2 in macrophages is associated with diminished NO production (10) and decreased migration capacity (11).Given the evidence for a role of UCP2 in the immune system, in macrophages, and in ␤-cell function, we investigated whether UCP2 affects the development of autoimmune diabetes by using the model of multiple low-dose of streptozotocin (STZ). In this report, we show that the absence of UCP2 renders animals more sensitive to the onset of diabetes in mice....

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Role of pancreatic beta-cells in the process of beta-cell death.

Cited by 52 publications

References 32 publications

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

Formation of insulin-positive cells in implants of human pancreatic duct cell preparations from young donors

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

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

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