Insulin withdrawal induces apoptosis via a free radical-mediated mechanism

Craig Ricci, Viktor Pastukh, Mahmood S Mozaffari, Stephen W. Schaffer

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)455-464
Number of pages10
JournalCanadian Journal of Physiology and Pharmacology
Volume85
Issue number3-4
DOIs
StatePublished - Mar 1 2007

Fingerprint

Free Radicals
Insulin
Apoptosis
Hyperglycemia
Mitochondrial DNA
DNA Damage
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Diabetes Complications
Electron Transport
Phosphatidylinositol 3-Kinases
Cardiac Myocytes
Superoxides
Reactive Oxygen Species
Cell Survival
Antioxidants
Research

Keywords

  • Akt
  • Apoptosis
  • Bax
  • Bc1-2
  • Insulin
  • Superoxide
  • mtDNA damage

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

Insulin withdrawal induces apoptosis via a free radical-mediated mechanism. / Ricci, Craig; Pastukh, Viktor; Mozaffari, Mahmood S; Schaffer, Stephen W.

In: Canadian Journal of Physiology and Pharmacology, Vol. 85, No. 3-4, 01.03.2007, p. 455-464.

Research output: Contribution to journalArticle

Ricci, Craig ; Pastukh, Viktor ; Mozaffari, Mahmood S ; Schaffer, Stephen W. / Insulin withdrawal induces apoptosis via a free radical-mediated mechanism. In: Canadian Journal of Physiology and Pharmacology. 2007 ; Vol. 85, No. 3-4. pp. 455-464.
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