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Diabetologia

Erschienen in:

01.06.2015 | Article

Forkhead box O1 mediates defects in palmitate-induced insulin granule exocytosis by downregulation of calcium/calmodulin-dependent serine protein kinase expression in INS-1 cells

verfasst von: Yao Wang, Haiyan Lin, Nana Hao, Zhengqiu Zhu, Dong Wang, Yuan Li, Hong Chen, Yunxia Zhu, Xiao Han

Erschienen in: Diabetologia | Ausgabe 6/2015

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Abstract

Aims/hypothesis

The transcription factor forkhead box O1 (FOXO1) induces pancreatic islet beta cell endoplasmic reticulum stress and is involved in fatty-acid-induced insulin-secretion defects. Cask is a downstream target gene of FOXO1. Using INS-1 cells with palmitate-induced insulin-release defects, we investigated the relationship between FOXO1 and Cask.

Methods

The expression levels and location of calcium/calmodulin-dependent serine protein kinase (CASK) and FOXO1 were evaluated by real-time PCR, western blotting and immunofluorescence. The regulation of Cask by FOXO1 was examined using chromatin immunoprecipitation (ChIP) and luciferase assays. Potassium-stimulated insulin-secretion assays were used to verify the function of INS-1 cells and islets. Electron microscopy was used to establish the anchoring process of the insulin granules after CASK knockdown in islets.

Results

Palmitic acid reduced CASK levels and increased FOXO1 levels. ChIP and luciferase assays demonstrated FOXO1 binding with the Cask promoter, which was enhanced by palmitate treatment. CASK knockdown reduced insulin release in INS-1 cells and primary islets, and Cask overexpression reversed the palmitate-induced insulin reduction. CASK knockdown attenuated forskolin-enhanced insulin release, but Cask overexpression did not change the insulin-secretion suppression induced by nifedipine. In pancreatic islet beta cells, CASK knockdown reduced the anchoring of insulin vesicles to cell membranes.

Conclusions/interpretation

The induction of beta cell insulin-secretion defects by fatty acids is mediated, at least in part, by FOXO1 via downregulation of Cask expression. It is characterised mainly as an obstruction of the anchoring of insulin granules to beta cell membranes.

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Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625CrossRefPubMed

Donath MY, Storling J, Maedler K, Mandrup-Poulsen T (2003) Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med (Berl) 81:455–470CrossRef

Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A (2001) Beta-cell adaptation and decompensation during the progression of diabetes. Diabetes 50(Suppl 1):S154–S159CrossRefPubMed

Seidell JC (2000) Obesity, insulin resistance and diabetes – a worldwide epidemic. Br J Nutr 83(Suppl 1):S5–S8PubMed

Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787CrossRefPubMed

Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481CrossRefPubMedCentralPubMed

Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE (2000) Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498–1506CrossRefPubMed

Saltiel AR (2001) New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104:517–529CrossRefPubMed

Tang ED, Nunez G, Barr FG, Guan KL (1999) Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274:16741–16746CrossRefPubMed

10.

Martinez SC, Tanabe K, Cras-Meneur C, Abumrad NA, Bernal-Mizrachi E, Permutt MA (2008) Inhibition of Foxo1 protects pancreatic islet beta-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes 57:846–859CrossRefPubMed

11.

Glauser DA, Schlegel W (2007) The emerging role of FOXO transcription factors in pancreatic beta cells. J Endocrinol 193:195–207CrossRefPubMed

12.

Lin HY, Yin Y, Zhang JX et al (2012) Identification of direct forkhead box O1 targets involved in palmitate-induced apoptosis in clonal insulin-secreting cells using chromatin immunoprecipitation coupled to DNA selection and ligation. Diabetologia 55:2703–2712CrossRefPubMed

13.

Slawson JB, Kuklin EA, Ejima A, Mukherjee K, Ostrovsky L, Griffith LC (2011) Central regulation of locomotor behavior of Drosophila melanogaster depends on a CASK isoform containing CaMK-like and L27 domains. Genetics 187:171–184CrossRefPubMedCentralPubMed

14.

Najm J, Horn D, Wimplinger I et al (2008) Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40:1065–1067CrossRefPubMed

15.

Chung WC, Huang TN, Hsueh YP (2011) Targeted deletion of CASK-interacting nucleosome assembly protein causes higher locomotor and exploratory activities. Neurosignals 19:128–141CrossRefPubMed

16.

Suckow AT, Comoletti D, Waldrop MA et al (2008) Expression of neurexin, neuroligin, and their cytoplasmic binding partners in the pancreatic beta-cells and the involvement of neuroligin in insulin secretion. Endocrinology 149:6006–6017CrossRefPubMedCentralPubMed

17.

Hori Y, Gu X, Xie X, Kim SK (2005) Differentiation of insulin-producing cells from human neural progenitor cells. PLoS Med 2:e103CrossRefPubMedCentralPubMed

18.

Han X, Sun Y, Scott S, Bleich D (2001) Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. Diabetes 50:1047–1055CrossRefPubMed

19.

Wrede CE, Dickson LM, Lingohr MK, Briaud I, Rhodes CJ (2002) Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells (INS-1). J Biol Chem 277:49676–49684CrossRefPubMed

20.

Zhu ZQ, Wang D, Xiang D, Yuan YX, Wang Y (2014) Calcium/calmodulin-dependent serine protein kinase is involved in exendin-4-induced insulin secretion in INS-1 cells. Metabolism 63:120–126CrossRefPubMed

21.

Meng Z, Lv J, Luo Y et al (2009) Forkhead box O1/pancreatic and duodenal homeobox 1 intracellular translocation is regulated by c-Jun N-terminal kinase and involved in prostaglandin E2-induced pancreatic beta-cell dysfunction. Endocrinology 150:5284–5293CrossRefPubMed

22.

Zhang X, Yong W, Lv J et al (2009) Inhibition of forkhead box O1 protects pancreatic beta-cells against dexamethasone-induced dysfunction. Endocrinology 150:4065–4073CrossRefPubMed

23.

Zhang HJ, Walseth TF, Robertson RP (1989) Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes 38:44–48CrossRefPubMed

24.

Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145:5087–5096CrossRefPubMed

25.

Mottis A, Mouchiroud L, Auwerx J (2013) Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev 27:819–835CrossRefPubMedCentralPubMed

26.

Newsholme P, Brennan L, Rubi B, Maechler P (2005) New insights into amino acid metabolism, beta-cell function and diabetes. Clin Sci (Lond) 108:185–194CrossRef

27.

Li G, Rungger-Brandle E, Just I, Jonas JC, Aktories K, Wollheim CB (1994) Effect of disruption of actin filaments by Clostridium botulinum C2 toxin on insulin secretion in HIT-T15 cells and pancreatic islets. Mol Biol Cell 5:1199–1213CrossRefPubMedCentralPubMed

28.

He TT, Cao XP, Chen RZ et al (2011) Down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha expression in fatty acid-induced pancreatic beta-cell apoptosis involves nuclear factor-kappaB pathway. Chin Med J (Engl) 124:3657–3663

29.

Tuo Y, Wang D, Li S, Chen C (2011) Long-term exposure of INS-1 rat insulinoma cells to linoleic acid and glucose in vitro affects cell viability and function through mitochondrial-mediated pathways. Endocrine 39:128–138CrossRefPubMed

30.

Kitamura T (2013) The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol 9:615–623CrossRefPubMed

31.

Hsueh YP (2006) The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem 13:1915–1927CrossRefPubMed

32.

Rulifson EJ, Kim SK, Nusse R (2002) Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296:1118–1120CrossRefPubMed

33.

Kozlova EN, Jansson L (2009) Differentiation and migration of neural crest stem cells are stimulated by pancreatic islets. Neuroreport 20:833–838CrossRefPubMed

34.

Andrali SS, Sampley ML, Vanderford NL, Ozcan S (2008) Glucose regulation of insulin gene expression in pancreatic beta-cells. Biochem J 415:1–10CrossRefPubMed

35.

Li J, Luo R, Kowluru A, Li G (2004) Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 beta-cells. Am J Physiol Endocrinol Metab 286:E818–E827CrossRefPubMed

Titel: Forkhead box O1 mediates defects in palmitate-induced insulin granule exocytosis by downregulation of calcium/calmodulin-dependent serine protein kinase expression in INS-1 cells
verfasst von: Yao Wang
Haiyan Lin
Nana Hao
Zhengqiu Zhu
Dong Wang
Yuan Li
Hong Chen
Yunxia Zhu
Xiao Han
Publikationsdatum: 01.06.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 6/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3561-4

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