Central K_ATP Channels Modulate Glucose Effectiveness

Glucose effectiveness describes the restraining effect of hyperglycemia on endogenous glucose production (EGP), which is lost in type 2 diabetes (T2D). Since central nervous system K_ATP channels likely regulate EGP in humans and rats, we examined whether these channels contribute to glucose effectiveness. Paired 4-hour hyperglycemic ’pancreatic clamp’ studies were performed in 9 healthy humans (age 37 ± 15 years; BMI 26 ± 4 kg/m²) 3 hours following glyburide 10 mg (GLB) or placebo (PLC). With PLC, hyperglycemia suppressed EGP by 59% (euglycemia: 2.38 ± 0.229 vs. hyperglycemia: 0.98 ± 0.17, p < 0.001). GLB resulted in 46% less suppression of EGP by hyperglycemia from baseline euglycemia compared to PLC (GLB: 1.56 ± 0.29 mg/kg/min vs. PLC: 0.98 ± 0.17 mg/kg/min, p = 0.047). To confirm that GLB’s effects were centrally mediated, parallel hyperglycemic studies were conducted in normal rats after oral gavage of normal saline (NS) (n=8), GLB (n=14), and oral GLB with intracerebroventricular (ICV) infusion of K_ATP channel agonist diazoxide (DZX) (n=8). GLB attenuated hyperglycemia’s suppressive effect on EGP (GLB: 9.4 ± 0.3 mg/kg/min vs. NS: 6.9 ± 0.3 mg/kg/min; p = 0.047), while ICV DZX abolished the effects of GLB (DZX + GLB: 5.5 ± 0.5 mg/kg/min vs. GLB, p = 0.003)(Figure 1). This suggests that ∼50% of the suppression of EGP by hyperglycemia is mediated by central K_ATP channels. Targeting these channels may offer a new therapeutic approach to improve glycemic control in T2D.

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