Hyperglycemia resulting from
type 2 diabetes mellitus (T2DM) is the main cause of
diabetic complications such as retinopathy and neuropathy. A reduction in
hyperglycemia has been shown to prevent these associated complications supporting the importance of
glucose control.
Glucokinase converts
glucose to
glucose-6-phosphate and determines
glucose flux into the β-cells and hepatocytes. Since activation of
glucokinase in β-cells is associated with increased risk of
hypoglycemia, we hypothesized that selectively activating hepatic
glucokinase would reduce fasting and postprandial
glucose with minimal risk of
hypoglycemia. Previous studies have shown that hepatic
glucokinase overexpression is able to restore
glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic
glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic
glucokinase is an effective strategy to reduce
hyperglycemia without causing adverse hepatic
lipids changes. To test this hypothesis, we evaluated a hepatoselective
glucokinase activator,
PF-04991532, in Goto-Kakizaki rats. In these studies,
PF-04991532 reduced plasma
glucose concentrations independent of changes in
insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the
glucose infusion rate was increased approximately 5-fold with
PF-04991532. This increase in
glucose infusion can be partially attributed to the 60% reduction in endogenous
glucose production. While
PF-04991532 induced dose-dependent increases in plasma
triglyceride concentrations it had no effect on hepatic
triglyceride concentrations in Goto-Kakizaki rats. Interestingly,
PF-04991532 decreased intracellular
AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective
glucokinase activation may offer
glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.