Restoration of Hepatic Glucokinase Expression Corrects Hepatic Glucose Flux and Normalizes Plasma Glucose in Zucker Diabetic Fatty Rats.

Abstract

Objective: We examined in 20-week old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic GK expression would alter hepatic glucose flux and improve hyperglycemia.

Research Design and Methods: ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose-dependently and compared various metabolic parameters with that of nondiabetic lean littermates (ZCL rats) prior to and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.

Results: ZDF rats compared to ZCL rats have lower hepatic GK activity (11.6 ± 1.9 vs 32.5 ± 3.2 mU/mg protein), marked hyperglycemia (23.9 ± 1.2 vs 7.4 ± 0.3 mM), higher endogenous glucose production (80 ± 3 vs 38 ± 3 μmol·kg⁻¹·min⁻¹), increased glucose-6-phosphatase flux (150 ± 11 vs 58 ± 8 μmol·kg⁻¹·min⁻¹), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 ± 7 vs −7 ± 4 μmol·kg⁻¹·min⁻¹) and promote glucose incorporation into glycogen (15 ± 5 vs 43 ± 3 μmol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to 1-2x that of ZCL rats, normalized plasma glucose levels and endogenous glucose production, and during a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.

Conclusions: Alterations of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.