Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells.

Department of Medicine, College of Medicine, Institute of Basic Science and Department of Biology, College of Natural Science, Cheju National University, Ara-1, Cheju, 690-756, South Korea.
European Journal of Endocrinology (Impact Factor: 3.14). 02/2003; 148(1):147-55. DOI: 10.1530/eje.0.1480147
Source: PubMed

ABSTRACT Insulin has well-known activities in controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Recently, several studies have suggested that insulin may protect cells from apoptosis in different cell lines; however, little is known about the nature of its anti-apoptotic activity. In many clinical disorders, including type 2 diabetes mellitus, oxidative stress and the production of reactive oxygen species (ROS) is increased. With these facts as a background, we examined here whether insulin protects HepG2 cells from apoptosis by decreasing oxidative stress and, if so, which signaling steps are involved in this process.
Intracellular DNA content, the degree of nuclear condensation or poly(ADP-ribose) polymerase hydrolysis was measured to verify the occurrence of apoptotic events. Caspase-3 activity and ROS accumulation within cells were also measured. Western blot analysis was performed to identify signaling molecules activated in response to insulin.
Serum starvation resulted in a marked accumulation of ROS, activation of caspase-3, and subsequent apoptotic cell death which were, in turn, markedly blocked by the addition of insulin. The anti-apoptotic activity of insulin was sensitive to blockade of two different signaling steps, activations of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated protein kinase (ERK).
Insulin exerts an anti-apoptotic activity by suppressing the excessive accumulation of ROS within cells through signaling pathways including stimulation of PI3 kinase and ERK in HepG2 cells.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence indicates that Alzheimer's disease, one of the most diffused aging pathologies, and diabetes may be related. Here, we demonstrate that insulin signalling protects LAN5 cells by amyloid-β42 (Aβ)-induced toxicity. Aβ affects both activation of insulin receptors and the levels of phospho-Akt, a critical signalling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro-apoptotic transcription factor activated by reactive oxygen species generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show that the recovery of the organelle integrity recruits active Akt translocation to the mitochondrion. Here, it plays a role both by maintaining unimpaired the permeability transition pore through increase in HK-II levels and by blocking apoptosis through phosphorylation of Bad, coming from cytoplasm after Aβ stimulus. Together, these results indicate that the Akt survival signal antagonizes the Aβ cell death process by balancing the presence and modifications of common molecules in specific cellular environments.
    Aging cell 05/2011; 10(5):832-43. · 7.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well-known that insulin acts as an important hormone, controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Over the past few years, intensive insulin therapy has been believed to be benefit for the outcome of diabetic patients, in which the suppression of oxidative stress plays a role. Moreover, insulin is accepted as a key component of glucose-insulin-potassium, a treatment which has been believed to exert significant cardiovascular protective effect via the reduction of oxidative stress. Furthermore, accumulating evidence has suggested that insulin exerts important redox-regulating actions in various insulin-sensitive target organs, implying the systematic antioxidative role of insulin as a hormone. It is time for us to revisit insulin effects, through summarizing and evaluating the novel functions of insulin and their mechanisms. This review focuses on the antioxidative effect of insulin and highlights insulin-induced regulation of various antioxidant enzymes via insulin signaling pathways and the cross talk between key transcription factors, including nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB) which are responsible for the transcription of antioxidant enzymes, leading to reduced generation of reactive oxygen species (ROS) and the enhancement of the elimination of ROS.
    Molecular and Cellular Endocrinology 08/2011; 349(2):111-27. · 4.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin is a cytokine which promotes cell growth. Recently, a few published reports on insulin in different cell lines support the antiapoptotic effect of insulin. But the reports fail to explain the role of insulin in modulating glutamate-mediated neuronal cell death through excitotoxicity. Thus, we examined the neuroprotective effect of insulin on glutamate-induced toxicity on differentiated SH-SY5Y neuronal cells. Changes in cell viability were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) based assay, while apoptotic damage was detected by acridine orange/ethidium bromide and Hoechst staining. Intracellular reactive oxygen species (ROS) accumulation and morphological alterations were also measured. Treatment with glutamate induced apoptosis, elevated ROS levels and caused damage to neurons. Insulin was able to attenuate the glutamate-induced excitotoxic damage to neuronal cells.
    Behavioural neurology 06/2014; 2014. · 1.25 Impact Factor


1 Download
Available from