Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents

Abstract

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 ∼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.

Figure 1

Effect of K_ATP channel inhibition on the ability of glucose effectiveness to regulate EGP and glucose disposal in humans. A: Schematic of the hyperglycemic pancreatic clamp protocol used in humans (n = 9). B: Blood glucose levels during the clamps. C: Atom percent enrichment (APE) during the steady-state period. D: Time course of EGP at the euglycemic baseline (t = −30 to 0 min) and during the hyperglycemic clamp (t = 0–240 min). E: Mean EGP during the final hour of the hyperglycemic clamp studies (“Hyperglycemic”) and at the euglycemic baseline (“Euglycemic”). F: R_d during the final hour of the hyperglycemic clamp. *P < 0.05, repeated-measures ANOVA (D) or two-way Student t test (E and F). Data are the mean ± SEM. GLB, glyburide; PLC, placebo.

Figure 2

Effect of K_ATP channel inhibition on the ability of glucose effectiveness to regulate EGP and glucose disposal in rodents. A: Schematic of the hyperglycemic pancreatic clamp protocol used in rats (n = 19). B: Schematic of the opposing actions of glyburide and diazoxide at various sites within the same K_ATP channel. C: Time course of EGP at the euglycemic baseline (t = 60–120 min) and during the hyperglycemic clamp (t = 180–240 min). D: Mean EGP during the hyperglycemic clamp studies and at the euglycemic baseline. E: R_d during the final hour of the hyperglycemic clamp. F and G: Expression of Pepck (F) and G6Pase (G) in the rodents receiving normal saline (NS) (n = 7), glyburide (GLB) (n = 7), or glyburide and ICV diazoxide (GLB+DZX) (n = 5). *P < 0.05, ANOVA with Bonferroni correction. Data are the mean ± SEM. Glucose 6P, glucose-6-phosphate; PEP, phosphoenolpyruvate.