Regulation of pancreatic β-cell insulin secretion by actin cytoskeleton remodelling: role of gelsolin and cooperation with the MAPK signalling pathway

Tomás, Alejandra; Yermen, Barbara; Min, Le; Pessin, Jeffrey E.; Halban, Philippe A.

doi:10.1242/jcs.02942

Cited by 145 publications

(170 citation statements)

References 52 publications

(81 reference statements)

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“…We have shown that the IRS-2/ Akt/AS160 pathway is involved in GSIS in primary beta cells (9), and a recent report indicates that an IGF-2/IGF-1 receptor autocrine loop underlies the glucose effect on insulin signaling mediated by IRS-2 (17). Moreover, IRS-2 is indispensable for normal beta cell function (12,43), while ERK activation is involved in GSIS (44,45). Our present data indicate that TNF-␣ treatment blocks glucose action on IR, Akt, ERK, and AS160 as well as other Akt substrates.…”

Section: Discussionmentioning

confidence: 57%

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Bouzakri

Ribaux

Halban

2009

Journal of Biological Chemistry

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Obesity and type 2 diabetes present partially overlapping phenotypes with systemic inflammation as a common feature, raising the hypothesis that elevated cytokine levels may contribute to peripheral insulin resistance as well as the decreased beta cell functional mass observed in type 2 diabetes. In healthy humans, TNF-␣ infusion induces skeletal muscle insulin resistance. We now explore the impact of TNF-␣ on primary beta cell function and the underlying signaling pathways. Human and rat primary beta cells were sorted by FACS and cultured for 24 h ؎ 20 ng/ml TNF-␣ to explore the impact on apoptosis, proliferation, and short-term insulin secretion (1 h, 2.8 mM glucose followed by 1 h, 16.7 mM glucose at the end of the 24-h culture period) as well as key signaling protein phosphorylation and expression. Prior exposure to TNF-␣ for 24 h inhibits glucose-stimulated insulin secretion from primary beta cells. This is associated with a decrease in glucose-stimulated phosphorylation of key proteins in the insulin signaling pathway including Akt, AS160, and other Akt substrates, ERK as well as the insulin receptor. Strikingly, TNF-␣ treatment decreased IRS-2 protein level by 46 ؎ 7% versus control, although mRNA expression was unchanged. While TNF-␣ treatment increased MAP4K4 mRNA expression by 33 ؎ 5%, knockdown of MAP4K4 by siRNA-protected beta cells against the detrimental effects of TNF-␣ on both insulin secretion and signaling. We thus identify MAP4K4 as a key upstream mediator of TNF-␣ action on the beta cell, making it a potential therapeutic target for preservation of beta cell function in type 2 diabetes.

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Section: Discussionmentioning

confidence: 57%

Silencing Mitogen-activated Protein 4 Kinase 4 (MAP4K4) Protects Beta Cells from Tumor Necrosis Factor-α-induced Decrease of IRS-2 and Inhibition of Glucose-stimulated Insulin Secretion

Bouzakri

Ribaux

Halban

2009

Journal of Biological Chemistry

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“…Supporting this view, we observed altered levels of proteins involved in remodeling the cortical cytoskeleton network-the depolymerizing enzymes Villin 1 and Gelsolin are up and inhibitory enzymes Capza 1 and 2 are down-regulated. Gelsolin's role in this process has already been demonstrated (33). Moreover, ␣-actinin-1 and 4 were up-regulated.…”

Section: Resultsmentioning

confidence: 79%

Quantitative proteomic analysis of single pancreatic islets

Waanders

Chwalek

Monetti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

201

213

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Technological developments make mass spectrometry (MS)-based proteomics a central pillar of biochemical research. MS has been very successful in cell culture systems, where sample amounts are not limiting. To extend its capabilities to extremely small, physiologically distinct cell types isolated from tissue, we developed a high sensitivity chromatographic system that measures nanogram protein mixtures for 8 h with very high resolution. This technology is based on splitting gradient effluents into a capture capillary and provides an inherent technical replicate. In a single analysis, this allowed us to characterize kidney glomeruli isolated by laser capture microdissection to a depth of more than 2,400 proteins. From pooled pancreatic islets of Langerhans, another type of ''miniorgan,'' we obtained an in-depth proteome of 6,873 proteins, many of them involved in diabetes. We quantitatively compared the proteome of single islets, containing 2,000 -4,000 cells, treated with high or low glucose levels, and covered most of the characteristic functions of beta cells. Our ultrasensitive analysis recapitulated known hyperglycemic changes but we also find components up-regulated such as the mitochondrial stress regulator Park7. Direct proteomic analysis of functionally distinct cellular structures opens up perspectives in physiology and pathology.hyperglycemia ͉ liquid chromatography-mass spectrometry ͉ quantitative proteomics ͉ replay technology

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“…The selective reduction of the second phase of GSIS in Dnm2 KO mice shows striking parallel with the reduced insulin secretion after perturbations of actin remodeling (13)(14)(15)81), a key factor that selectively contributes to the second phase (10,11). Accordingly, enhanced actin disassembly by PPARβ/δ (17) or the actin-capping protein gelsolin (81) increases the second phase.…”

Section: Discussionmentioning

confidence: 99%