Abstract

Background Prolonged elevation of glucose can adversely affect β-cell function. In vitro studies have linked glucose-induced β-cell dysfunction to oxidative stress, however whether oxidative stress plays a role in vivo is unclear.

Objective To investigate the role of oxidative stress in an in vivo model of glucose-induced β-cell dysfunction.

Methods Wistar rats were infused i.v. with glucose for 48h to achieve 20mM hyperglycemia with/out coinfusion of one of the following antioxidants: Taurine (TAU), an aldehyde scavenger, N-acetylcysteine (NAC), a precursor of glutathione, or tempol (TPO), a superoxide dismutase mimetic. This was followed by islet isolation or hyperglycemic clamp.

Results 48h glucose infusion decreased glucose stimulated insulin secretion (GSIS), and elevated ROS, total superoxide and mitochondrial superoxide in freshly isolated islets. TPO prevented the increase in total and mitochondrial superoxide, and the β-cell dysfunction induced by high glucose. However, TAU and NAC despite completely normalizing H₂DCF-DA-measured ROS, did not prevent the increase in superoxide and the decrease in β-cell function induced by high glucose. TPO but not TAU also prevented β-cell dysfunction induced by less extreme hyperglycemia (15mM) for a longer period of time (96h). To further investigate whether TPO is effective in vivo, a hyperglycemic clamp was performed. Similar to the findings in isolated islets, prolonged glucose elevation (20mmol/l for 48h) decreased β-cell function as assessed by the disposition index (insulin secretion adjusted for insulin sensitivity) and co-infusion of TPO with glucose completely restored β-cell function.

Conclusion These findings implicate superoxide generation in β-cell dysfunction induced by prolonged hyperglycemia.