Divergent antioxidant capacity of human islet cell subsets: A potential cause of beta-cell vulnerability in diabetes and islet transplantation

Atsushi Miki, Camillo Ricordi, Yasunaru Sakuma, Toshiyuki Yamamoto, Ryosuke Misawa, Atsuyoshi Mita, Ruth D. Molano, Nosratola D. Vaziri, Antonello Pileggi, Hirohito Ichii

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) are caused by beta(β)-cell loss and functional impairment. Identification of mechanisms of β-cell death and therapeutic interventions to enhance β-cell survival are essential for prevention and treatment of diabetes. Oxidative stress is a common feature of both T1DM and T2DM; elevated biomarkers of oxidative stress are detected in blood, urine and tissues including pancreas of patients with DM. Islet transplantation is a promising treatment for diabetes. However, exposure to stress (chemical and mechanical) and ischemia-reperfusion during isolation and transplantation causes islet loss by generation of reactive oxygen species (ROS). Human intracellular antioxidant enzymes and related molecules are essential defenses against ROS. Antioxidant enzyme levels including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) have been shown to be low in islet cells. However, little is known about the expression and function of antioxidant enzymes within islet cell subsets. We evaluated the expression of the key antioxidant enzymes in β- and alpha(α)-cell and accessed effects of oxidative stress, islet isolation and transplantation on β/α-cell ratio and viability in human islets. Methods Human pancreata from T1DM, T2DM and non-diabetic deceased donors were obtained and analyzed by confocal microscopy. Isolated islets were (I) transplanted in the renal sub-capsular space of streptozotocin-induced diabetic nude mice (in vivo bioassay), or (II) exposed to oxidative (H2O2) and nitrosative (NO donor) stress for 24 hrs in vitro. The ratio, % viability and death of β- and α-cells, and DNA damage (8OHdG) were measured. Results and conclusions Catalase and GPX expression was much lower in β- than α-cells. The β/α-cell ratio fells significantly following islet isolation and transplantation. Exposure to oxidative stress caused a significantly lower survival and viability, with higher DNA damage in β- than α-cells. These findings identified the weakness of β-cell antioxidant capacity as a main cause of vulnerability to oxidative stress. Potential strategies to enhance β-cell antioxidant capacity might be effective in prevention/treatment of diabetes.

Original languageEnglish (US)
Article numbere0196570
JournalPloS one
Volume13
Issue number5
DOIs
StatePublished - May 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Miki, A., Ricordi, C., Sakuma, Y., Yamamoto, T., Misawa, R., Mita, A., Molano, R. D., Vaziri, N. D., Pileggi, A., & Ichii, H. (2018). Divergent antioxidant capacity of human islet cell subsets: A potential cause of beta-cell vulnerability in diabetes and islet transplantation. PloS one, 13(5), [e0196570]. https://doi.org/10.1371/journal.pone.0196570