Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this glucose effectiveness is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). K-ATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central K-ATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by similar to 50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of K-ATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the K-ATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central K-ATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.