Glucose-Induced beta-Cell Dysfunction In Vivo: Evidence for a Causal Role of C-jun N-terminal Kinase Pathway

摘要

Prolonged elevation of glucose can adversely affect beta-cell function. Oxidative stress, which has been implicated in glucose-induced beta-cell dysfunction, can activate c-jun N-terminal kinase (JNK). However, whether JNK is causal in glucose-induced beta-cell dysfunction in vivo is unclear. Therefore, we aimed at investigating the causal role of JNK activation in in vivo models of glucose-induced beta-cell dysfunction. Glucose-induced beta-cell dysfunction was investigated in the presence or absence of JNK inhibition. JNK inhibition was achieved using either (i) the JNK-specific inhibitor SP600125 or (ii) JNK-1-null mice. (i) Rats or mice were infused intravenously with saline or glucose with or without SP600125. (ii) JNK-1 null mice and their littermate wild-type controls were infused intravenously with saline or glucose. Following the glucose infusion periods in rats and mice, beta-cell function was assessed in isolated islets or in vivo using hyperglycemic clamps. Forty-eight-hour hyperglycemia at similar to 20 mM in rats or 96-hour hyperglycemia at similar to 13 mM in mice impaired beta-cell function in isolated islets and in vivo. Inhibition of JNK using either SP600125 or JNK-1-null mice prevented glucose-induced beta-cell dysfunction in isolated islets and in vivo. Islets of JNK-1-null mice exposed to hyperglycemia in vivo showed an increase in Pdx-1 and insulin 2 mRNA, whereas islets of wild-type mice did not. Together, these data show that JNK pathway is involved in glucose-induced beta-cell dysfunction in vivo and is thus a potential therapeutic target for type 2 diabetes.