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H Shibata, M Kanzaki, T Takeuchi, J-i Miyazaki and I Kojima

ABSTRACT

Activin A stimulates insulin secretion in pancreatic β-cells by a calcium-dependent mechanism. The present study was conducted to further characterize the effects of activin A in two glucose-responsive insulinoma cell lines, MIN6 and HIT-T15 cells. In HIT-T15 cells, activin A evoked an increase in cytoplasmic free calcium concentration, stimulated insulin secretion, maintained glucose responsiveness of the cells and inhibited DNA synthesis. However, activin A did not have any effect in MIN6 cells. Measurement of 125I-labeled activin A binding in MIN6 cells revealed that the number of binding sites was markedly reduced, suggesting that the refractoriness was due, at least partly, to the reduced numbers of the activin receptor. Stable transfectants of MIN6 cells that overexpressed the type II activin receptor were then developed. The transfected cells (MIN6-ActR cells) expressed ten times more 125I-labeled activin A-binding sites than parental cells and the apparent K d was 1·15 nm, which was nearly identical to that in parental cells. Affinity cross-linking in MIN6-ActR cells showed that a 90 kDa type II receptor as well as a 52 kDa protein, presumably follistatin, was markedly labeled with 125I-labeled activin A. Although MIN6-ActR cells expressed significant numbers of activin receptors, activin A did not induce immediate calcium-dependent responses in these cells. In contrast, activin A was capable of inducing long-term effects in MIN6-ActR cells; thus, reduction of the glucose concentration in culture medium from 25 to 5·5 mm for 4 days resulted in a remarkable loss of insulin response to glucose stimulation but this decline in response to glucose was prevented by the addition of activin A during culture. In addition, activin A inhibited DNA synthesis in MIN6-ActR cells. Hence, although activin A did not induce calcium-dependent responses, it evoked some calcium-independent effects in MIN6-ActR cells. Taken together, activin A elicits various effects in β-cells by both calcium-dependent and -independent mechanisms.

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William J Stanley, Prerak M Trivedi, Andrew P Sutherland, Helen E Thomas and Esteban N Gurzov

NOD8.3 CD8 + T-cells overnight at an effector:target ratio of 20:1. Result is representative of two independent experiments and shows 51 Cr release measurement in triplicate. Discussion Pancreatic β-cells are sensitive to the

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M. Welsh, D. L. Eizirik and E. Strandell

ABSTRACT

To elucidate the role of thermal stress on the function of pancreatic β cells, isolated mouse pancreatic islets were incubated for 30 min at 42°C. This resulted in decreased glucose-stimulated insulin secretion, inhibited total protein and pro-insulin synthesis and the induction of heat-shock proteins with molecular weights of 64 and 88 kDa. Six days later, the islets exposed to heat shock showed a lower DNA content, indicating islet cell death. However, the insulin secretory response and rates of oxygen consumption in the presence of glucose were normal. It is suggested that the induction of heat-shock proteins does not permanently impair β-cell function, but rather protects these cells from lasting damage.

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Talitha van der Meulen and Mark O Huising

Introduction The pancreatic islets consist of several endocrine cell types including insulin-producing β cells, glucagon-producing α cells, somatostatin-producing δ cells, pancreatic polypeptide-producing PP cells, and ghrelin-producing ϵ cells. The

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M Blandino-Rosano, G Perez-Arana, J M Mellado-Gil, C Segundo and M Aguilar-Diosdado

Introduction Autoimmune diabetes mellitus type 1 (DM1) is due to a selective death of pancreatic islet β cells, mainly by apoptosis ( Castano & Eisenbarth 1990 ). Pro-inflammatory cytokines such as IL-1β, alone or in combination with IFN-γ and

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Shinobu Shimizu, Tetsuya Hosooka, Tomokazu Matsuda, Shun-ichiro Asahara, Maki Koyanagi-Kimura, Ayumi Kanno, Alberto Bartolome, Hiroaki Etoh, Megumi Fuchita, Kyoko Teruyama, Hiroaki Takahashi, Hiroyuki Inoue, Yusuke Mieda, Naoko Hashimoto, Susumu Seino and Yoshiaki Kido

Introduction Pancreatic β cell failure is a fundamental pathogenic feature of type 2 diabetes, and the progressive decline in β cell function and mass over the course of type 2 diabetes development is well known ( Weyer et al . 1999 , Butler et

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Wataru Nishimura, Naoko Ishibashi, Koki Eto, Nobuaki Funahashi, Haruhide Udagawa, Harukata Miki, Souichi Oe, Yasuko Noda and Kazuki Yasuda

Introduction Diabetes mellitus results from dysfunction of pancreatic β-cells, although the mechanism of impaired secretion of insulin from β-cells is not fully understood. Recent studies suggest that a subpopulation of β-cells in diabetic humans

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Riccarda Granata, Marco Volante, Fabio Settanni, Carlotta Gauna, Corrado Ghé, Marta Annunziata, Barbara Deidda, Iacopo Gesmundo, Thierry Abribat, Aart-Jan van der Lely, Giampiero Muccioli, Ezio Ghigo and Mauro Papotti

2 diabetes ( Donath et al . 2003 ). We recently reported that AG and UAG promote proliferation and inhibit serum starvation- and cytokine-induced apoptosis of β-cells and human pancreatic islets ( Granata et al . 2006 , 2007 ). Furthermore, both

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Riccarda Granata, Alessandra Baragli, Fabio Settanni, Francesca Scarlatti and Ezio Ghigo

will summarize the newest findings on AG, UAG, and Ob expression and their effects in endocrine pancreatic cells. In particular, we will consider the implication of these peptides for pancreatic β-cell development, survival, and secretory activity. AG

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Holger Steinbrenner, Anna-Lena Hotze, Bodo Speckmann, Antonio Pinto, Helmut Sies, Matthias Schott, Margret Ehlers, Werner A Scherbaum and Sven Schinner

Introduction Insulin resistance is a hallmark in the pathogenesis of type 2 diabetes mellitus (T2DM). Pancreatic β-cells have the capacity to compensate for insulin resistance by a reactive increase in insulin secretion over a long period. However