Adiponectin-induced Inhibition of Intrinsic and Extrinsic Apoptotic Pathways Protects Pancreatic β-Cells Against Apoptosis

 

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Abstract

Apoptosis is the main form of β-cell death in type 2 diabetes mellitus. There are 2 major pathways leading to apoptosis, ‘intrinsic and extrinsic pathways’. Adiponectin is an adipocyte-derived hormone, which plays an important role in glucose and lipid metabolism. The main aims of this study were to investigate related apoptotic pathways in diabetes and the anti-apoptosis effects of adiponectin on pancreatic β-cell and the underlying mechanisms. Diabetic mice were generated by intraperitoneal injection of streptozotocin (STZ, 50 mg/kg/d for 5 days) and high-fat diet. Adiponectin overexpressing mice were developed by injecting lentivirus expressing mouse full length adiponectin (plenti-acdc-EGFP) through tail vein. Fourteen days after plenti-acdc-EGFP lentivirus injection, plasma adiponectin protein levels were increased 2-fold. Plasma triglyceride and glucose levels, but not total cholesterol, were significantly reduced in plenti-acdc-EGFP-treated mice. Pancreatic β-cell apoptotic numbers and the expression of caspase-8, -9, -3 in islet increased in diabetic mice, which was reversed by elevated adiponectin in plenti-acdc-EGFP-treated mice. These results suggest that both intrinsic and extrinsic apoptotic pathways have an important role in diabetic β-cell apoptosis. Adiponectin has antidiabetic and anti-apoptotic effects by regulating glucose and lipid metabolisms and inhibiting intrinsic and extrinsic apoptotic pathway in pancreatic β-cells.

• References

• 1 Bonner-Weir S. Perspective: Postnatal pancreatic beta cell growth. Endocrinology 2000; 141: 1926-1929
  CrossrefPubMedGoogle Scholar
• 2 Ulukayal E, Acilan C, Yilmaz Y. Apoptosis: why and how does it occur in biology?. Cell Biochem Funct 2011; 29: 468-480
  CrossrefPubMedGoogle Scholar
• 3 Sayers TJ. Targeting the extrinsic apoptosis signaling pathway for cancer therapy. Cancer Immunol Immunother 2011; 60: 1173-1180
  CrossrefPubMedGoogle Scholar
• 4 Ferrín G, Linares CI, Muntané J. Mitochondrial drug targets in cell death and cancer. Curr Pharm Des 2011; 17: 2002-2016
  CrossrefPubMedGoogle Scholar
• 5 Niu K, Asada M, Okazaki T, Yamanda S, Ebihara T, Guo H, Zhang D, Nagatomi R, Arai H, Kohzuki M, Ebihara S. Adiponectin pathway attenuates malignant mesothelioma cell growth. Am J Respir Cell Mol Biol 2011; 46: 515-523
  PubMedGoogle Scholar
• 6 Zhang D, Guo M, Zhang W, Lu XY. Adiponectin stimulates proliferation of adult hippocampal neural stem/progenitor cells through activation of p38 mitogen-activated protein kinase (p38MAPK)/glycogen synthase kinase 3b (GSK-3b)/b-catenin signaling cascade. J Biol Chem 2011; 286: 44913-44920
  CrossrefPubMedGoogle Scholar
• 7 Zhao HY, Zhao M, Yi TN, Zhang J. Globular adiponectin protects human umbilical vein endothelial cells against apoptosis through adiponectin receptor 1/adenosine monophosphate-activated protein kinase pathway. Chin Med J (Engl) 2011; 124: 2540-2547
  PubMedGoogle Scholar
• 8 Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB. Adiponectin-induced ERK and Akt Phosphorylation Protects against Pancreatic Beta Cell Apoptosis and Increases Insulin Gene Expression and Secretion. J Biol Chem 2010; 285: 33623-33631
  CrossrefPubMedGoogle Scholar
• 9 Rakatzi I, Mueller H, Ritzeler O, Tennagels N, Eckel J. Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia 2004; 47: 249-258
  CrossrefPubMedGoogle Scholar
• 10 Lin P, Chen L, Li D, Liu J, Yang N, Sun Y, Xu Y, Fu Y, Hou X. Adiponectin reduces glucotoxicity-induced apoptosis of INS-1 rat insulin-secreting cells on a microfluidic chip. Tohoku J Exp Med 2009; 217: 59-65
  CrossrefPubMedGoogle Scholar
• 11 Srinivasan K, Ramarao P. Animal models in type 2 diabetes research: An overview. Indian J Med Res 2007; 125: 451-472
  PubMedGoogle Scholar
• 12 Dropulić B. Lentiviral vectors: their molecular design, safety, and use in laboratory and preclinical research. Hum Gene Ther 2011; 22: 649-657
  CrossrefPubMedGoogle Scholar
• 13 Khare R, Chen CY, Weaver EA, Barry MA. Advances and future challenges in adenoviral vector pharmacology and targeting. Curr Gene Ther 2011; 11: 241-258
  CrossrefPubMedGoogle Scholar
• 14 Satoh H, Nguyen MT, Trujillo M, Nguyen A, Trujillo M, Imamura T, Usui I, Scherer PE, Olefsky JM. Adenovirus-mediated adiponectin expression augments skeletal muscle insulin sensitivity in male Wistar rats. Diabetes 2005; 54: 1304-1313
  CrossrefPubMedGoogle Scholar
• 15 Brochu-Gaudreau K, Rehfeldt C, Blouin R, Bordignon V, Murphy BD, Palin MF. Adiponectin action from head to toe. Endocrine 2010; 37: 11-32
  CrossrefPubMedGoogle Scholar
• 16 Lee YH, Magkos F, Mantzoros CS, Kang ES. Effects of leptin and adiponectin on pancreatic β-cell function. Metabolism 2011; 60: 1664-1672
  CrossrefPubMedGoogle Scholar
• 17 Zhang Y, Zhou P, Kimondo JW. Adiponectin and osteocalcin: relation to insulin sensitivity. Biochem Cell Biol 2012; 90: 613-620
  CrossrefPubMedGoogle Scholar
• 18 Luo N, Liu J, Chung BH, Yang Q, Klein RL, Garvey WT, Fu Y. Macrophage Adiponectin Expression Improves Insulin Sensitivity and Protects Against Inflammation and Atherosclerosis. Diabetes 2010; 59: 791-799
  CrossrefPubMedGoogle Scholar
• 19 Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T. Globular Adiponectin Protected ob/ob Mice from Diabetes and ApoE-deficient Mice from Atherosclerosis. J Biol Chem 2003; 278: 2461-2468
  CrossrefPubMedGoogle Scholar
• 20 Shklyaev S, Aslanidi G, Tennant M, Prima V, Kohlbrenner E, Kroutov V, Campbell-Thompson M, Crawford J, Shek EW, Scarpace PJ, Zolotukhin S. Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci USA 2003; 100: 14217-14222
  CrossrefPubMedGoogle Scholar
• 21 Sulpice T, Prunet-Marcassus B, Molveaux C, Cani PD, Vitte PA, Graber P, Dreano M, Burcelin R. An adiponectin-like molecule with antidiabetic properties. Endocrinology 2009; 150: 4493-4501
  CrossrefPubMedGoogle Scholar
• 22 Johnson JD, Luciani DS. Mechanisms of pancreatic beta-cell apoptosis in diabetes and its therapies. Adv Exp Med Biol 2010; 654: 447-462
  PubMedGoogle Scholar