Zhang Y, Zhen W, Maechler P, et al.. Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB

Faculty of Life Science, Northwestern Polytechnical University, Xi'an, 710072, China
The Journal of nutritional biochemistry (Impact Factor: 3.79). 07/2012; 24(4). DOI: 10.1016/j.jnutbio.2012.03.008
Source: PubMed


Chronic hyperlipidemia causes β-cell apoptosis and dysfunction, thereby contributing to the pathogenesis of type 2 diabetes (T2D). Thus, searching for agents to promote pancreatic β-cell survival and improve its function could be a promising strategy to prevent and treat T2D. We investigated the effects of kaempferol, a small molecule isolated from ginkgo biloba, on apoptosis and function of β-cells and further determined the mechanism underlying its actions. Kaempferol treatment promoted viability, inhibited apoptosis and reduced caspase-3 activity in INS-1E cells and human islets chronically exposed to palmitate. In addition, kaempferol prevented the lipotoxicity-induced down-regulation of antiapoptotic proteins Akt and Bcl-2. The cytoprotective effects of kaempferol were associated with improved insulin secretion, synthesis, and pancreatic and duodenal homeobox-1 (PDX-1) expression. Chronic hyperlipidemia significantly diminished cyclic adenosine monophosphate (cAMP) production, protein kinase A (PKA) activation, cAMP-responsive element binding protein (CREB) phosphorylation and its regulated transcriptional activity in β-cells, all of which were restored by kaempferol treatment. Disruption of CREB expression by transfection of CREB siRNA in INS-1E cells or adenoviral transfer of dominant-negative forms of CREB in human islets ablated kaempferol protection of β-cell apoptosis and dysfunction caused by palmitate. Incubation of INS-1E cells or human islets with kaempferol for 48h induced PDX-1 expression. This effect of kaempferol on PDX-1 expression was not shared by a host of structurally related flavonoid compounds. PDX-1 gene knockdown reduced kaempferol-stimulated cAMP generation and CREB activation in INS-1E cells. These findings demonstrate that kaempferol is a novel survivor factor for pancreatic β-cells via up-regulating the PDX-1/cAMP/PKA/CREB signaling cascade.

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    • "Inhibition of PKA or AKT ablated the anti-apoptotic effect of kaempferol, indicating that its action relies on these kinases. Similar cytoprotective effects of kaempferol were observed after long-term exposure of INS-1E cells and human islets to lipotoxicity (0.5 mM palmitate for 4 days) (Zhang et al. 2013). Moreover, b-cell treatment with kaempferol rescued chronic hyperlipidaemia-mediated decreases of PDX-1 protein expression , PKA activation and CREB transcriptional activity at 1 and 10 lM, but not at the lower concentration of 0.1 lM. "

    Phytochemistry Reviews 07/2015; DOI:10.1007/s11101-015-9429-x · 2.41 Impact Factor
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    Kaempferol: Chemistry, Natural Occurrences and Health Benefits, Edited by Garion Villers, Yves Fougere, 01/2013: chapter Metal Complexes of Kaempferol and Their Speciation in Human Plasma: pages 187 - 202; Nova Science Publishers., ISBN: 978-1-62618-515-9
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    ABSTRACT: With the worldwide increase in diabetes prevalence there is a pressing unmet need for novel antidiabetic therapies. Insufficient insulin production due to impaired β‐cell function and apoptotic reduction of β‐cell mass is a common denominator in the pathogenesis of diabetes. Current treatments are directed at improving insulin sensitivity, and stimulating insulin secretion or replacing the hormone, but do not target progressive apoptotic β‐cell loss. Here we review the current development of small‐molecule inhibitors designed to rescue β‐cells from apoptosis. Several distinct classes of small molecules have been identified that protect β‐cells from inflammatory, oxidative and/or metabolically induced apoptosis. Although none of these have yet reached the clinic, β‐cell protective small molecules alone or in combination with current therapies provide exciting opportunities for the development of novel treatments for diabetes.
    Diabetes Obesity and Metabolism 09/2013; 15(s3). DOI:10.1111/dom.12158 · 6.36 Impact Factor
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