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 glucokinase (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 various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before 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 with ZCL rats have lower hepatic GK activity (11.6 Ϯ 1.9 vs. 32.5 Ϯ 3.2 mU/mg protein), marked hyperglycemia (23.9 Ϯ 1.2 vs. 7.4 Ϯ 0.3 mmol/l), higher endogenous glucose production (80 Ϯ 3 vs. 38 Ϯ 3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), increased glucose-6-phosphatase flux (150 Ϯ 11 vs. 58 Ϯ 8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 Ϯ 7 vs. Ϫ7 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and promote glucose incorporation into glycogen (15 Ϯ 5 vs. 43 Ϯ 3 mol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.CONCLUSIONS-Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.

Targeting Hepatic Glucokinase in Type 2 Diabetes

“…At 20 weeks the ZDF rat has very marked hypertriglyceridemia (15). In this model, glucokinase overexpression was associated with markedly raised lactate concentrations and a trend toward elevated plasma triglycerides (15). It is noteworthy, however, that in 20-week ZDF rats, impaired clearance of triglycerides is an important contributing factor to excessive triglyceridemia (16).…”

“…in [3]). At 20 weeks the ZDF rat has very marked hypertriglyceridemia (15). In this model, glucokinase overexpression was associated with markedly raised lactate concentrations and a trend toward elevated plasma triglycerides (15).…”

“…Torres et al (15) report a detailed study of the effect of overexpression of glucokinase in liver on glucose turnover in the Zucker diabetic fatty (ZDF) rat (20 weeks old) in basal conditions and during a hyperglycemic clamp. The ZDF rat is characterized by increased body weight and progressive insulin resistance, beginning at ϳ7 weeks and leading to development of overt diabetes after 10 weeks.…”

“…Torres et al (15) overexpressed glucokinase in the liver of ZDF rats by treatment with an adenoviral vector at 19 -20 weeks. The viral titers used enabled selection of two groups of treated diabetic rats: one with glucokinase activity that was restored to the level of nondiabetic controls (threefold increase) and another with activity twice that of nondiabetic controls (sixfold increase).…”

Liver Glucokinase and Lipid Metabolism

“…Animal diabetic models linked to obesity, show that GK deficiency in the liver occurs only in the case of obesity, and in severe or long-term forms of the disease. Although hepatic GK expression is different depending on disease stage, some strategies www.intechopen.com based on increasing GK activity in the liver have been tested in some models of high fat diet induced type 2 diabetes & Ferre, 2003 , in obesity models (Wu, 2005& Torres, 2009) and in transgenic mice with hepatic insulin resistance (Okamoto, 2007). All these studies have in common that the increase in hepatic GK activity produces glycaemia normalization.…”