TY - JOUR
T1 - Divergent antioxidant capacity of human islet cell subsets
T2 - A potential cause of beta-cell vulnerability in diabetes and islet transplantation
AU - Miki, Atsushi
AU - Ricordi, Camillo
AU - Sakuma, Yasunaru
AU - Yamamoto, Toshiyuki
AU - Misawa, Ryosuke
AU - Mita, Atsuyoshi
AU - Molano, Ruth D.
AU - Vaziri, Nosratola D.
AU - Pileggi, Antonello
AU - Ichii, Hirohito
N1 - Funding Information:
This work was supported in part by NIH-NCRR, GCRC MO1RR16587, NIDDK R01-DK55347-IU42RR016603, 5R01DK25802, ICR 5U42RR016603, UL1 TR000153, KL2 TR000147, NIH-NCRR UL1 TR000153, KL2 TR000147; the Juvenile Diabetes Research Foundation International 4-200-946, 4-2004-361, and 17-2011-609, JSPS KAKENHI Grant Number JP This article was prepared while Dr. Pileggi was employed at the University of Miami. He is currently employed at National Institutes of Health/Center for Scientific Review. The opinions expressed in this article are the author?s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
PY - 2018/5
Y1 - 2018/5
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0196570
DO - 10.1371/journal.pone.0196570
M3 - Article
C2 - 29723228
AN - SCOPUS:85046653300
VL - 13
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 5
M1 - e0196570
ER -