Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

Nakayama, Shiho; Arakawa, Masayuki; Uchida, Toyoyoshi; Ogihara, Takeshi; Kanno, Rei; Ikeda, Fuki; Azuma, Kosuke; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

doi:10.1007/s00125-008-1080-2

Cited by 19 publications

(21 citation statements)

References 39 publications

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“…The expression profiles of hedgehog signaling markers, stem cell markers, and pancreatic A-cell markers at day 8 (PTC), day 14 (PTC, PDX-1, Glut3, and GK), day 17 (IHH, SHH, PTC, PDX-1, Glut2, GK), and day 21 (IHH, PTC, PDX-1, Glut3, GK, and insulin) can be a valuable fundamental model for understanding the time-dependent differentiation process. It has been reported that hedgehog signaling pathway plays an important role in determining the fate of the mesoderm of the gut tube in early pancreatic development, 45 in islet cell function, 46 in pancreatic cancer, and in chronic pancreatitis. 47 Three mammalian hedgehog genes, SHH, IHH, and DHH, have been identified, and their products are found as secreted morphogenetic proteins.…”

Section: Discussionmentioning

confidence: 99%

Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways

Hui¹,

Tang²,

Zhu³

et al. 2010

Pancreas

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Section: Discussionmentioning

confidence: 99%

Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways

Hui¹,

Tang²,

Zhu³

et al. 2010

Pancreas

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“…Immunohistochemistry was applied for measurement of the relative area of ␤-cells in the pancreas using the method described previously (19). The following primary antibodies were used: guinea pig antihuman insulin antibody (Linco Research), chicken antihuman insulin antibody (Abcam), guinea pig antip62 antibody (PROGEN), rabbit anticleaved caspase-3 antibody (Cell Signaling Technology), and mouse antihuman Ki67 Ab (BD Biosciences).…”

Section: Immunohistochemical Analysis and Quantification Of ␤-Cell Areamentioning

confidence: 99%

Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

et al. 2013

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Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

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“…Indeed, genetic deletion of the Shh mediator Smo in the pancreas epithelium induces delayed expansion of the early pancreatic epithelium and delayed b-cell mass development (113). Several other studies demonstrate a role of hedgehog signaling in the growth of the pancreas (31,33,34,(114)(115)(116)(117)(118). These seemingly conflicting studies may be consolidated by taking into account the different mechanisms of hedgehog signaling modulation, such as ligand overexpression or Smo deletion.…”

Section: Shh Signaling In Neural and Pancreatic Developmentmentioning

confidence: 99%

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

et al. 2016

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Loss of insulin-producing pancreatic islet β-cells is a hallmark of type 1 diabetes. Several experimental paradigms demonstrate that these cells can, in principle, be regenerated from multiple endogenous sources using signaling pathways that are also used during pancreas development. A thorough understanding of these pathways will provide improved opportunities for therapeutic intervention. It is now appreciated that signaling pathways should not be seen as “on” or “off” but that the degree of activity may result in wildly different cellular outcomes. In addition to the degree of operation of a signaling pathway, noncanonical branches also play important roles. Thus, a pathway, once considered as “off” or “low” may actually be highly operational but may be using noncanonical branches. Such branches are only now revealing themselves as new tools to assay them are being generated. A formidable source of noncanonical signal transduction concepts is neural stem cells because these cells appear to have acquired unusual signaling interpretations to allow them to maintain their unique dual properties (self-renewal and multipotency). We discuss how such findings from the neural field can provide a blueprint for the identification of new molecular mechanisms regulating pancreatic biology, with a focus on Notch, Hes/Hey, and hedgehog pathways.

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Dose-dependent requirement of patched homologue 1 in mouse pancreatic beta cell mass

Cited by 19 publications

References 39 publications

Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways

Glucagon Like Peptide-1-Directed Human Embryonic Stem Cells Differentiation Into Insulin-Producing Cells Via Hedgehog, cAMP, and PI3K Pathways

Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

Endocrine Pancreas Development and Regeneration: Noncanonical Ideas From Neural Stem Cell Biology

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