The Fas pathway is involved in pancreatic β cell secretory function

Schumann, Desiree M.; Maedler, Kathrin; Franklin, Isobel; Konrad, Daniel; Størling, Joachim; Böni-Schnetzler, Marianne; Gjinovci, Asllan; Kurrer, Michael; Gauthier, Benoit R.; Bosco, Domenico; Andrès, Axel; Berney, Thierry; Greter, Melanie; Becher, Burkhard; Chervonsky, Alexander V.; Halban, Philippe A.; Mandrup-Poulsen, Thomas; Wollheim, Claes B.; Donath, Marc Y.

doi:10.1073/pnas.0611487104

Cited by 74 publications

(60 citation statements)

References 46 publications

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“…Human islets were cultured in CMRL-1066 medium containing 5.5 mmol/l glucose and 100 units/ml penicillin, 100 g/ml streptomycin, and 10% FCS (Invitrogen, Carlsbad, CA). Mouse islets were isolated using Collagenase type 4 (Worthington, Lakewood, NJ) as described previously (17) and cultured in RPMI 1640 containing 11.1 mmol/l glucose. In culture, a glucose concentration of 11.1 mmol/l accomplishes the lowest frequency of ␤-cell apoptosis in mouse islets (18 -20).…”

Section: Methodsmentioning

confidence: 99%

Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

et al. 2008

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OBJECTIVE-Type 2 diabetes is characterized by impaired insulin secretion in response to increased metabolic demand. This defect in ␤-cell compensation seems to result from the interplay between environmental factors and genetic predisposition. Genome-wide association studies reveal that common variants in transcription factor 7-like 2 (TCF7L2) are associated with increased risk of type 2 diabetes. The aim of the present study was to establish whether TCF7L2 plays a role in ␤-cell function and/or survival. RESEARCH DESIGN AND METHODS-To investigate the effects of TCFL7L2 depletion, isolated islets were exposed to TCF7L2 small interfering RNA (siRNA) versus scrambled siRNA, and ␤-cell survival and function were examined. For TCF7L2 overexpression, islets were cultured in glucose concentrations of 5.5-33.3 mmol/l and the cytokine mix interleukin-1␤/␥-interferon with or without overexpression of TCF7L2. Subsequently, glucose-stimulated insulin secretion (GSIS), ␤-cell apoptosis [by transferase-mediated dUTP nick-end labeling assay and Western blotting for poly(ADP-ribose) polymerase and Caspase-3 cleavage], and ␤-cell proliferation (by Ki67 immunostaining) were analyzed. RESULTS-DepletingTCF7L2 by siRNA resulted in a 5.1-fold increase in ␤-cell apoptosis, 2.2-fold decrease in ␤-cell proliferation (P Ͻ 0.001), and 2.6-fold decrease in GSIS (P Ͻ 0.01) in human islets. Similarly, loss of TCF7L2 resulted in impaired ␤-cell function in mouse islets. In contrast, overexpression of TCF7L2 protected islets from glucose and cytokine-induced apoptosis and impaired function. CONCLUSIONS-TCF7L2is required for maintaining GSIS and ␤-cell survival. Changes in the level of active TCF7L2 in ␤-cells from carriers of at-risk allele may be the reason for defective insulin secretion and progression of type 2 diabetes. Diabetes 57: [645][646][647][648][649][650][651][652][653] 2008

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Section: Methodsmentioning

confidence: 99%

Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

et al. 2008

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“…This bimodal effect was shown to involve the Fas signalling pathway, which can switch from a mitogenic signal to induction of apoptosis when the FLICE-inhibitory protein (FLIP) is inactive (Maedler et al 2006). This pathway was also found to be important in sustaining the secretory function of b-cells, as Fas-deficient mice exhibited impaired glucose-induced insulin secretion (Schumann et al 2007). It would therefore appear that Pax4 is an integrated factor of the Fas/FLIP signal transduction pathway, which relays either the positive or negative effects of IL-1b pending levels of the cytokine.…”

Section: Pax4 As a Master Regulator Of Islet Developmentmentioning

confidence: 99%

A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

Brun¹,

Gauthier

2007

Journal of Molecular Endocrinology

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Blood glucose homeostasis is achieved by the regulation of insulin and glucagon secretion from the pancreatic islet b-and a-cells. Diabetes mellitus, which comprises a heterogeneous group of hyperglycaemic disorders, results mainly from inadequate mass and function of islet b-cells. Autoimmune destruction of b-cells causes type 1 diabetes, while type 2 is characterized by impaired insulin secretion and is often associated with diminished insulin action on its target tissues. Interestingly, similar to type 1 diabetes, a gradual loss of b-cell mass is observed in type 2 diabetes often requiring insulin therapy. Understanding the molecular mechanism that governs b-cell mass plasticity may provide a means to develop strategies to countera,ct b-cell death while increasing replication. Of particular interest is the islet-specific transcription factor paired box4 (Pax4) that was previously shown to be indispensable for the establishment of the b-cell lineage during development. However, recent accumulating evidence now suggest that Pax4 is also crucial for mature b-cell expansion and survival in response to physiological cues and that mutations or polymorphisms are associated with both type 1 and type 2 diabetes. In contrast, aberrant expression of Pax4 confers protection against apoptosis to insulinomas, whereas it promotes cell growth in lymphocytes. This review summarizes promising new published results supporting the important function of Pax4 in mature islet b-cell physiology and its contribution to pathophysiology when deregulated.

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“…Since DEDD Ϫ/Ϫ mice revealed glucose intolerance, it might be worthwhile to assess whether any dysfunction of DEDD is present, either in the whole body or in specific tissues, in a subset of type 2 diabetes patients. Schumann et al (39) reported that the Fas pathway, where many DED-containing elements are associated, is involved in ␤ cell secretory function. Thus, DED-containing proteins might also influence metabolic homeostasis through apoptosis cascades, although DEDD Ϫ/Ϫ cells or mice showed no apparent defect in apoptosis (10,11).…”

Section: Dedd Prevents Inhibitory Phosphorylation Of Mitotic S6k1mentioning

confidence: 99%

The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation

Kurabe

Arai

Nishijima

et al. 2009

Journal of Biological Chemistry

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؊/؊ cells and tissues. Consequently, as in S6K1 ؊/؊ mice, the insulin mass within pancreatic islets was reduced in DEDD ؊/؊ mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.Cell size is closely related to specialized cell function and to the specific patterning of tissues in the body. Cell sizing is regulated mainly by two mechanisms: cell cycle control and the biochemical response to nutrients and/or growth factors (1-5). During cell cycle progression, both the G 1 (which is believed to be dominant) and the G 2 periods are important for cells to increase their volume (6 -9). In addition, we recently provided evidence that the mitotic period (M phase) also influences cell size, through analysis of DEDD-deficient mice (10, 11). The DEDD molecule was initially described as a member of the death effector domain (DED) 2 -containing protein family (12). Although the absence of DEDD did not apparently influence progression of apoptosis (10), we found that during mitosis, DEDD is associated with Cdk1-cyclin B1 and that it decreases the kinase activity of Cdk1. This response impedes the Cdk1-dependent mitotic program to shut off synthesis of ribosomal RNA (rRNA) and protein and is consequently useful in gaining sufficient cell growth prior to cell division. Depletion of DEDD consistently results in a shortened mitotic duration and an overall reduction in the amount of cellular rRNA and protein and, furthermore, in cell and body size (10,11).Of the biochemical responses responsible for cell sizing, the signaling cascade involving phosphatydilinositol 3-kinase (PI3K) and its downstream target of rapamycin (TOR) is most crucial (13)(14)(15). In mammals, upon stimulation by growth factors, including insulin, the mammalian TOR (mTOR) cooperates with PI3K-dependent effectors to activate S6K1, thereby phosphorylating the 40 S ribosomal protein S6, and subsequently enhances translation of the 5Ј-terminal oligopyrimidine sequences that encode components of the translational machinery. This reaction increases the number of ribosomes and the efficacy of protein synthesis, thus critically promoting cell growth (16 -18). Therefore, mice deficient for S6K1 (S6K1 Ϫ/Ϫ ) had reduced cell and body size (19 -23). This effect also involves S6K1 in maintenance of glucose tolerance. S6K1 * This work was supported, in whole or in part, by National Institutes of Health Grant 5RO1AI50948-05. This work was also supported by grants-in-aid from the Ministry of Education, Sports, Culture, Science, and Technology, Japan, the Takeda Science Foundation (to T. M. and S. A.), the Mitsubishi Pharma Research Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Danone Institute of Nutrition for Health, the Uehara Memorial Fou...

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The Fas pathway is involved in pancreatic β cell secretory function

Cited by 74 publications

References 46 publications

Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets

A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease

The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation

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