TY - JOUR
T1 - Hypoxia-inducible factor-1 mediates pancreatic b-cell dysfunction by intermittent hypoxia
AU - Wang, Ning
AU - Shi, Xue Feng
AU - Khan, Shakil A.
AU - Wang, Benjamin
AU - Semenza, Gregg L.
AU - Prabhakar, Nanduri R.
AU - Nanduri, Jayasri
N1 - Publisher Copyright:
Copyright © 2020 the American Physiological Society
PY - 2020/11
Y1 - 2020/11
N2 - The role of hypoxia-inducible factor (HIF)-1 in pancreatic b-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1a heterozygous (HET), b-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic b-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1a HET mice. IH increased HIF-1a expression and elevated reactive oxygen species (ROS) levels in b-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1a HET mice as well as in b -HIF-1-/- mice. IH-evoked b-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1a. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1a protein expression, and these effects were abolished with genetic silencing of HIF-1a. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic b-cell dysfunction.
AB - The role of hypoxia-inducible factor (HIF)-1 in pancreatic b-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1a heterozygous (HET), b-cell-specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic b-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1a HET mice. IH increased HIF-1a expression and elevated reactive oxygen species (ROS) levels in b-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1a HET mice as well as in b -HIF-1-/- mice. IH-evoked b-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1a. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1a protein expression, and these effects were abolished with genetic silencing of HIF-1a. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2O2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2O2 contribute to IH-induced pancreatic b-cell dysfunction.
KW - Glucose-stimulated insulin secretion
KW - Hypoxia-inducible factor
KW - NADPH oxidases
KW - Obstructive sleep apnea
KW - Reactive oxygen species
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U2 - 10.1152/ajpcell.00309.2020
DO - 10.1152/ajpcell.00309.2020
M3 - Article
C2 - 32936698
AN - SCOPUS:85095798858
SN - 0363-6143
VL - 319
SP - C922-C932
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 5
ER -