, Volume 20, Issue 11, pp 1420–1432 | Cite as

Curcumin attenuates palmitate-induced apoptosis in MIN6 pancreatic β-cells through PI3K/Akt/FoxO1 and mitochondrial survival pathways

  • Feng Hao
  • Jinsen Kang
  • Yajun Cao
  • Shengjun Fan
  • Haopeng Yang
  • Yu An
  • Yan Pan
  • Lu TieEmail author
  • Xuejun LiEmail author
Original Paper


Lipotoxicity plays a vital role in development and progression of type 2 diabetes. Prolonged elevation of free fatty acids especially the palmitate leads to pancreatic β-cell dysfunction and apoptosis. Curcumin (diferuloylmethane), a polyphenol from the curry spice turmeric, is considered to be a broadly cytoprotective agent. The present study was designed to determine the protective effect of curcumin on palmitate-induced apoptosis in β-cells and investigate underlying mechanisms. Our results showed that curcumin improved cell viability and enhanced glucose-induced insulin secretory function in MIN6 pancreatic β-cells. Palmitate incubation evoked chromatin condensation, DNA nick end labeling and activation of caspase-3 and -9. Curcumin treatment inhibited palmitate-induced apoptosis, relieved mitochondrial depolarization and up-regulated Bcl-2/Bax ratio. Palmitate induced the generation of reactive oxygen species and inhibited activities of antioxidant enzymes, which could be neutralized by curcumin treatment. Moreover, curcumin could promote rapid phosphorylation of Akt and nuclear exclusion of FoxO1 in MIN6 cells under lipotoxic condition. Phosphatidylinositol 3-kinase and Akt specific inhibitors abolished the anti-lipotoxic effect of curcumin and stimulated FoxO1 nuclear translocation. These findings suggested that curcumin protected MIN6 pancreatic β-Cells against apoptosis through activation of Akt, inhibition of nuclear translocation of FoxO1 and mitochondrial survival pathway.


Curcumin Palmitate Lipotoxicity Apoptosis β-Cells FoxO1 



This work was supported by the National Natural Science Foundation of China No. 81473235, 91129727, 81020108031, 81270049 to X.-J. Li, No. 81373405 and 30901803 to L. Tie, Research Fund from Ministry of Education of China (111 Projects No. B07001), Beijing Higher Education Young Elite Teacher Project (No. YETP0053), Leading Academic Discipline Project of Beijing Education Bureau (No. BMU20110254) and the Fund of Janssen Research Council China (JRCC2011).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Haendeler J, Dimmeler S (2006) Inseparably tied: functional and antioxidative capacity of endothelial progenitor cells. Circ Res 98:157–158CrossRefPubMedGoogle Scholar
  2. 2.
    Savage DB, Petersen KF, Shulman GI (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507–520PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Elks ML (1993) Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology 133:208–214PubMedGoogle Scholar
  4. 4.
    Kelpe CL, Moore PC, Parazzoli SD, Wicksteed B, Rhodes CJ, Poitout V (2003) Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem 278:30015–30021CrossRefPubMedGoogle Scholar
  5. 5.
    Bollheimer LC, Kemptner DM, Kagerbauer SM, Kestler TM, Wrede CE, Buettner R (2003) Intracellular depletion of insulin: a comparative study with palmitate, oleate and elaidate in INS-1 cells. Eur J Endocrinol 148:481–486CrossRefPubMedGoogle Scholar
  6. 6.
    Elks ML (1994) Divergent effects of arachidonate and other free fatty acids on glucose-stimulated insulin release from rat islets. Cell Mol Biol 40:761–768PubMedGoogle Scholar
  7. 7.
    Lupi R, Dotta F, Marselli L et al (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51:1437–1442CrossRefPubMedGoogle Scholar
  8. 8.
    Wrede CE, Dickson LM, Lingohr MK, Briaud I, Rhodes CJ (2003) Fatty acid and phorbol ester-mediated interference of mitogenic signaling via novel protein kinase C isoforms in pancreatic beta-cells (INS-1). J Mol Endocrinol 30:271–286CrossRefPubMedGoogle Scholar
  9. 9.
    Wrede CE, Buettner R, Wobser H, Ottinger I, Bollheimer LC (2007) Systematic analysis of the insulinotropic and glucagonotropic potency of saturated and monounsaturated fatty acid mixtures in rat pancreatic islets. Hormon Metab Res 39:482–488CrossRefGoogle Scholar
  10. 10.
    Maestre I, Jordan J, Calvo S et al (2003) Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal and fatty acids in the beta-cell line INS-1. Endocrinology 144:335–345CrossRefPubMedGoogle Scholar
  11. 11.
    El-Assaad W, Buteau J, Peyot ML et al (2003) Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144:4154–4163CrossRefPubMedGoogle Scholar
  12. 12.
    Wang W, Liu Y, Chen Y et al (2010) Inhibition of Foxo1 mediates protective effects of ghrelin against lipotoxicity in MIN6 pancreatic beta-cells. Peptides 31:307–314CrossRefPubMedGoogle Scholar
  13. 13.
    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 57:846–859CrossRefPubMedGoogle Scholar
  14. 14.
    Wang HW, Mizuta M, Saitoh Y, Noma K, Ueno H, Nakazato M (2011) Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic beta-cells. Metabolism 60:1081–1089CrossRefPubMedGoogle Scholar
  15. 15.
    Higa M, Shimabukuro M, Shimajiri Y, Takasu N, Shinjyo T, Inaba T (2006) Protein kinase B/Akt signalling is required for palmitate-induced beta-cell lipotoxicity. Diabetes Obes Metab 8:228–233CrossRefPubMedGoogle Scholar
  16. 16.
    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 277:49676–49684CrossRefPubMedGoogle Scholar
  17. 17.
    Kitamura T, Nakae J, Kitamura Y et al (2002) The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 110:1839–1847PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Huang H, Tindall DJ (2006) FOXO factors: a matter of life and death. Future Oncol 2:83–89CrossRefPubMedGoogle Scholar
  19. 19.
    Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75:787–809CrossRefPubMedGoogle Scholar
  20. 20.
    Kang C, Kim E (2010) Synergistic effect of curcumin and insulin on muscle cell glucose metabolism. Food Chem Toxicol 48:2366–2373CrossRefPubMedGoogle Scholar
  21. 21.
    Best L, Elliott AC, Brown PD (2007) Curcumin induces electrical activity in rat pancreatic beta-cells by activating the volume-regulated anion channel. Biochem Pharmacol 73:1768–1775CrossRefPubMedGoogle Scholar
  22. 22.
    Rouse M, Younes A, Egan JM (2014) Resveratrol and curcumin enhance pancreatic beta-cell function by inhibiting phosphodiesterase activity. J Endocrinol 223:107–117PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Li JM, Li YC, Kong LD, Hu QH (2010) Curcumin inhibits hepatic protein-tyrosine phosphatase 1B and prevents hypertriglyceridemia and hepatic steatosis in fructose-fed rats. Hepatology 51:1555–1566CrossRefPubMedGoogle Scholar
  24. 24.
    Pari L, Murugan P (2007) Antihyperlipidemic effect of curcumin and tetrahydrocurcumin in experimental type 2 diabetic rats. Ren Fail 29:881–889CrossRefPubMedGoogle Scholar
  25. 25.
    Seo KI, Choi MS, Jung UJ et al (2008) Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. Mol Nutr Food Res 52:995–1004CrossRefPubMedGoogle Scholar
  26. 26.
    Weisberg SP, Leibel R, Tortoriello DV (2008) Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology 149:3549–3558PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Han J, Pan XY, Xu Y et al (2012) Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy 8:812–825CrossRefPubMedGoogle Scholar
  28. 28.
    Wang W, Zhang D, Zhao H et al (2010) Ghrelin inhibits cell apoptosis induced by lipotoxicity in pancreatic beta-cell line. Regul Pept 161:43–50CrossRefPubMedGoogle Scholar
  29. 29.
    Karaskov E, Scott C, Zhang L, Teodoro T, Ravazzola M, Volchuk A (2006) Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology 147:3398–3407CrossRefPubMedGoogle Scholar
  30. 30.
    Wang Z, Tang X, Li Y et al (2008) 20-Hydroxyeicosatetraenoic acid inhibits the apoptotic responses in pulmonary artery smooth muscle cells. Eur J Pharmacol 588:9–17CrossRefPubMedGoogle Scholar
  31. 31.
    Tie L, Yang HQ, An Y et al (2012) Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes. Cell Physiol Biochem 29:583–594CrossRefPubMedGoogle Scholar
  32. 32.
    Tie L, Xu Y, Lin YH et al (2008) Down-regulation of brain-pancreas relative protein in diabetic rats and by high glucose in PC12 cells: prevention by calpain inhibitors. J Pharmacol Sci 106:28–37CrossRefPubMedGoogle Scholar
  33. 33.
    Wehinger S, Ortiz R, Diaz MI et al (2015) Phosphorylation of caveolin-1 on tyrosine-14 induced by ROS enhances palmitate-induced death of beta-pancreatic cells. Biochim Biophys Acta 1852:693–708CrossRefPubMedGoogle Scholar
  34. 34.
    Abdel Aziz MT, El-Asmar MF, El Nadi EG et al (2010) The effect of curcumin on insulin release in rat-isolated pancreatic islets. Angiology 61:557–566CrossRefPubMedGoogle Scholar
  35. 35.
    Meghana K, Sanjeev G, Ramesh B (2007) Curcumin prevents streptozotocin-induced islet damage by scavenging free radicals: a prophylactic and protective role. Eur J Pharmacol 577:183–191CrossRefPubMedGoogle Scholar
  36. 36.
    Kanitkar M, Gokhale K, Galande S, Bhonde RR (2008) Novel role of curcumin in the prevention of cytokine-induced islet death in vitro and diabetogenesis in vivo. Br J Pharmacol 155:702–713PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Kanitkar M, Bhonde RR (2008) Curcumin treatment enhances islet recovery by induction of heat shock response proteins, Hsp70 and heme oxygenase-1, during cryopreservation. Life Sci 82:182–189CrossRefPubMedGoogle Scholar
  38. 38.
    Laybutt DR, Preston AM, Akerfeldt MC et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763CrossRefPubMedGoogle Scholar
  39. 39.
    Robertson RP, Harmon J, Tran PO, Poitout V (2004) Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53(Suppl 1):S119–S124CrossRefPubMedGoogle Scholar
  40. 40.
    Supale S, Li N, Brun T, Maechler P (2012) Mitochondrial dysfunction in pancreatic beta cells. Trends Endocrinol Metab 23:477–487CrossRefPubMedGoogle Scholar
  41. 41.
    Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY (2003) Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52:726–733CrossRefPubMedGoogle Scholar
  42. 42.
    Koshkin V, Dai FF, Robson-Doucette CA, Chan CB, Wheeler MB (2008) Limited mitochondrial permeabilization is an early manifestation of palmitate-induced lipotoxicity in pancreatic beta-cells. J Biol Chem 283:7936–7948CrossRefPubMedGoogle Scholar
  43. 43.
    Lei X, Zhang S, Bohrer A, Ramanadham S (2008) Calcium-independent phospholipase A2 (iPLA2 beta)-mediated ceramide generation plays a key role in the cross-talk between the endoplasmic reticulum (ER) and mitochondria during ER stress-induced insulin-secreting cell apoptosis. J Biol Chem 283:34819–34832PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Gurzov EN, Eizirik DL (2011) Bcl-2 proteins in diabetes: mitochondrial pathways of beta-cell death and dysfunction. Trends Cell Biol 21:424–431CrossRefPubMedGoogle Scholar
  45. 45.
    Cheng Q, Dong W, Qian L, Wu J, Peng Y (2011) Visfatin inhibits apoptosis of pancreatic beta-cell line, MIN6, via the mitogen-activated protein kinase/phosphoinositide 3-kinase pathway. J Mol Endocrinol 47:13–21CrossRefPubMedGoogle Scholar
  46. 46.
    Rashid K, Sil PC (2015) Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats. Toxicol Appl Pharmacol 282:297–310CrossRefPubMedGoogle Scholar
  47. 47.
    Biden TJ, Boslem E, Chu KY, Sue N (2014) Lipotoxic endoplasmic reticulum stress, beta cell failure, and type 2 diabetes mellitus. Trends Endocrinol Metab 25:389–398CrossRefPubMedGoogle Scholar
  48. 48.
    Lai E, Bikopoulos G, Wheeler MB, Rozakis-Adcock M, Volchuk A (2008) Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic beta-cells. Am J Physiol Endocrinol Metab 294:E540–E550CrossRefPubMedGoogle Scholar
  49. 49.
    Kajimoto Y, Kaneto H (2004) Role of oxidative stress in pancreatic beta-cell dysfunction. Ann N Y Acad Sci 1011:168–176CrossRefPubMedGoogle Scholar
  50. 50.
    Chen L, Na R, Gu M et al (2008) Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging Cell 7:866–878PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Matheny RW Jr, Adamo ML (2009) Current perspectives on Akt Akt-ivation and Akt-ions. Exp Biol Med 234:1264–1270CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems BiologyPeking UniversityBeijingPeople’s Republic of China

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