Publications by authors named "Thilo Speckmann"

4 Publications

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Friend and foe: β-cell Ca signaling and the development of diabetes.

Mol Metab 2019 03 24;21:1-12. Epub 2018 Dec 24.

Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Background: The divalent cation Calcium (Ca) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca-regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis.

Scope Of Review: This review aims to briefly highlight canonical Ca signaling pathways in β-cells and how β-cells regulate the movement of Ca across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca signaling pathways for β-cell function and health.

Major Conclusions: Acute increases in intracellular Ca stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.
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http://dx.doi.org/10.1016/j.molmet.2018.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407368PMC
March 2019

Neuronal PAS Domain Protein 4 Suppression of Oxygen Sensing Optimizes Metabolism during Excitation of Neuroendocrine Cells.

Cell Rep 2018 01;22(1):163-174

Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Depolarization of neuroendocrine cells results in calcium influx, which induces vesicle exocytosis and alters gene expression. These processes, along with the restoration of resting membrane potential, are energy intensive. We hypothesized that cellular mechanisms exist to maximize energy production during excitation. Here, we demonstrate that NPAS4, an immediate early basic helix-loop-helix (bHLH)-PAS transcription factor, acts to maximize energy production by suppressing hypoxia-inducible factor 1α (HIF1α). As such, knockout of Npas4 from insulin-producing β cells results in reduced OXPHOS, loss of insulin secretion, β cell dedifferentiation, and type 2 diabetes. NPAS4 plays a similar role in the nutrient-sensing cells of the hypothalamus. Its knockout here results in increased food intake, reduced locomotor activity, and elevated peripheral glucose production. In conclusion, NPAS4 is critical for the coordination of metabolism during the stimulation of electrically excitable cells; its loss leads to the defects in cellular metabolism that underlie the cellular dysfunction that occurs in metabolic disease.
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http://dx.doi.org/10.1016/j.celrep.2017.12.033DOI Listing
January 2018

SOX4 Allows Facultative β-Cell Proliferation Through Repression of .

Diabetes 2017 08 11;66(8):2213-2219. Epub 2017 May 11.

BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada

The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in are associated with an increased risk of developing type 2 diabetes. We used an inducible β-cell knockout mouse model to test the hypothesis that is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease in β-cell mass in knockout mice that was caused by a 39% reduction in β-cell proliferation. Gene expression studies revealed that induction of the cell cycle inhibitor was responsible for the decreased proliferation in the knockout animals. Altogether, this study demonstrates that SOX4 is necessary for adult β-cell replication through direct regulation of the β-cell cycle.
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http://dx.doi.org/10.2337/db16-1074DOI Listing
August 2017

Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells.

J Biol Chem 2016 Feb 9;291(6):2682-95. Epub 2015 Dec 9.

From the Diabetes Research Program, Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada and the Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada

Cytosolic calcium influx activates signaling pathways known to support pancreatic beta cell function and survival by modulating gene expression. Impaired calcium signaling leads to decreased beta cell mass and diabetes. To appreciate the causes of these cytotoxic perturbations, a more detailed understanding of the relevant signaling pathways and their respective gene targets is required. In this study, we examined the calcium-induced expression of the cytoprotective beta cell transcription factor Npas4. Pharmacological inhibition implicated the calcineurin, Akt/protein kinase B, and Ca(2+)/calmodulin-dependent protein kinase signaling pathways in the regulation of Npas4 transcription and translation. Both Npas4 mRNA and protein had high turnover rates, and, at the protein level, degradation was mediated via the ubiquitin-proteasome pathway. Finally, beta cell cytotoxicity of the calcineurin inhibitor and immunosuppressant tacrolimus (FK-506) was prevented by Npas4 overexpression. These results delineate the pathways regulating Npas4 expression and stability and demonstrate its importance in clinical settings such as islet transplantation.
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http://dx.doi.org/10.1074/jbc.M115.704098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742737PMC
February 2016
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