TY - JOUR
T1 - Insulin withdrawal induces apoptosis via a free radical-mediated mechanism
AU - Ricci, Craig
AU - Pastukh, Viktor
AU - Mozaffari, Mahmood S
AU - Schaffer, Stephen W.
PY - 2007/3/1
Y1 - 2007/3/1
N2 - Diabetes is characterized by chronic hyperglycemia as well as insulin deficiency or resistance. However, the majority of research has focused on the consequences of hyperglycemia in development of diabetic complications, whereas the effects of insulin deficiency or resistance, independent of hyperglycemia, have received little attention. Since insulin is a well known cytoprotective factor, we hypothesized that its removal could significantly impact cell survival. To examine this possibility, cultured neonatal cardiomyocytes were subjected to insulin withdrawal and examined for apoptosis. Insulin deficient cells succumbed to apoptosis, an effect associated with impaired PI3-kinase/Akt signaling and reduction in the Bc1-2 to Bax ratio. Perhaps more importantly, superoxide generation was altered in cells subjected to insulin withdrawal. Removal of insulin caused a significant increase in reactive oxygen species production and resulted in oxidative mitochondrial DNA damage the latter effect is associated with impaired expression of mitochondrially encoded proteins that make up the electron transport chain. Significantly, the effects of insulin withdrawal could be mitigated by treatment with the antioxidant, Tiron. Collectively, these data demonstrate that insulin deficiency leads to apoptosis and suggest a role for ox-idative mitochondrial DNA damage in this cascade.
AB - Diabetes is characterized by chronic hyperglycemia as well as insulin deficiency or resistance. However, the majority of research has focused on the consequences of hyperglycemia in development of diabetic complications, whereas the effects of insulin deficiency or resistance, independent of hyperglycemia, have received little attention. Since insulin is a well known cytoprotective factor, we hypothesized that its removal could significantly impact cell survival. To examine this possibility, cultured neonatal cardiomyocytes were subjected to insulin withdrawal and examined for apoptosis. Insulin deficient cells succumbed to apoptosis, an effect associated with impaired PI3-kinase/Akt signaling and reduction in the Bc1-2 to Bax ratio. Perhaps more importantly, superoxide generation was altered in cells subjected to insulin withdrawal. Removal of insulin caused a significant increase in reactive oxygen species production and resulted in oxidative mitochondrial DNA damage the latter effect is associated with impaired expression of mitochondrially encoded proteins that make up the electron transport chain. Significantly, the effects of insulin withdrawal could be mitigated by treatment with the antioxidant, Tiron. Collectively, these data demonstrate that insulin deficiency leads to apoptosis and suggest a role for ox-idative mitochondrial DNA damage in this cascade.
KW - Akt
KW - Apoptosis
KW - Bax
KW - Bc1-2
KW - Insulin
KW - Superoxide
KW - mtDNA damage
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U2 - 10.1139/Y07-029
DO - 10.1139/Y07-029
M3 - Article
C2 - 17612655
AN - SCOPUS:34547891556
SN - 0008-4212
VL - 85
SP - 455
EP - 464
JO - Canadian Journal of Physiology and Pharmacology
JF - Canadian Journal of Physiology and Pharmacology
IS - 3-4
ER -