MAP Kinase cross talks in oxidative stress-induced impairment of insulin secretion. Involvement in the protective activity of quercetin.
Insulin secretion preservation is a major issue for the prevention or treatment of type 2 diabetes. We previously showed on β-cells that quercetin (Q), but not resveratrol (R) or N-acetyl cysteine (NAC), amplified glucose-induced insulin secretion in a calcium- and ERK1/2-dependent manner. Quercetin, but not resveratrol or NAC, also protected β-cell function and hyperamplified ERK1/2 phosphorylation in oxidative stress conditions. As quercetin may interfere with other stress-activated protein kinases (JNK and p38 MAPK), we further explored MAPK cross talks and their relationships with the mechanism of the protective effect of quercetin against oxidative stress. In INS-1 insulin-secreting β-cells, using pharmacological inhibitors of MAPK pathways, we found that under oxidative stress (50 μm H2O2) and glucose-stimulating insulin secretion conditions: (i) p38 MAPK phosphorylation was increased and regulated by ERK1/2 (positively) and JNK (negatively), although p38 MAPK activation did not seem to play any significant role in oxidative stress-induced insulin secretion impairment; (ii) the JNK pathway appeared to inhibit both ERK1/2 activation and insulin secretion, although JNK phosphorylation was not significantly changed in our experimental conditions; (iii) the functionality of β-cell in the presence of oxidative stress was closely linked to the level of ERK1/2 activation, (iv) quercetin, resveratrol, or NAC inhibited H2O2 -induced p38 MAPK phosphorylation. The preservation of β-cell function against oxidative stress appears dependent on the balance between ERK1/2 and JNK activation. The protecting effect of quercetin appears due to ERK1/2 hyperactivation, possibly induced by L-type calcium channel opening as we recently showed.
Institut des Biomolécules Max Mousseron (IBMM), UMR CNRS-5247, Universités Montpellier 1 et 2, Ecole Nationale Supérieure de Chimie de Montpellier, BP 14491, 34093, Montpellier Cedex 5, France.
Estelle
E
Youl
Richard
R
Magous
Gérard
G
Cros
Catherine
C
Oiry
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002460:Cell Line; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D007328:Insulin; D013267:Stilbenes; D011794:Quercetin; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol
MAP kinase cross talks; insulin secretion; oxidative stress; quercetin; β-cells