Treatment of Type 2 Diabetes by Adenoviral-Mediated Overexpression of the Glucokinase Regulatory Protein

Abstract

The enzyme glucokinase (GK) plays a central role in glucose homeostasis. Hepatic GK activity is acutely controlled by the action of the GK regulatory protein (GKRP). In vitro evidence suggests that GKRP reversibly binds to GK and inhibits its activity; however, less is known about the in vivo function of GKRP. To further explore the physiological role of GKRP in vivo, we used an E1/E2a/E3-deficient adenoviral vector containing the cDNA encoding human GKRP (Av3hGKRP). High fat diet-induced diabetic mice were administered Av3hGKRP or a control vector lacking a transgene (Av3Null). Surprisingly, the Av3hGKRP-treated mice showed a significant improvement in glucose tolerance and had lower fasting blood glucose levels than Av3Null-treated mice. A coincident decrease in insulin levels indicated that the Av3hGKRP-treated mice had sharply improved insulin sensitivity. These mice also exhibited lower leptin levels, reduced body weight, and decreased liver GK activity. In vitro experiments indicated that GKRP was able to increase both GK protein and enzymatic activity levels, suggesting that another role for GKRP is to stabilize and/or protect GK. These data are the first to indicate the ability of GKRP to treat type 2 diabetes and therefore have significant implications for future therapies of this disease.

The Common P446L Polymorphism in GCKR Inversely Modulates Fasting Glucose and Triglyceride Levels and Reduces Type 2 Diabetes Risk in the DESIR Prospective General French Population

“…This suggests, for the first time, a molecular mechanism by which these two components of the so-called metabolic syndrome can be dissociated. Based on rodent models, such as the adenoviral-mediated hepatic overexpression of GCK or GCKR in mice with diet-induced diabetes (5,19), more active GCKR may result in improved interaction with GCK, leading to more efficiently releasable pools of GCK enzyme, with subsequent beneficial effects on glucose metabolism but otherwise with a concomitant alteration of lipid profile.…”

“…Adenoviral-mediated hepatic overexpression of GCKR in mice with high-fat diet-induced diabetes improves fasting and glucoseinduced glycemia and leads to a concomitant increase in insulin sensitivity and triglyceride levels and a decrease in leptin levels (5). Heterozygous mutations in GCK resulting in a reduction of enzymatic activity are responsible for a subtype of monogenic diabetes (maturity-onset diabetes of the young-2) (1,6).…”

The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population

“…1,2 In the presence of fructose-1-phosphate, GCKR permits GCK to exert its activity in the cytoplasm. GCKR-deficient mice have reduced GCK expression and show impaired glycemic control, 3 suggesting that the GCK pool in the nucleus maintained by GCKR is critical for GCK function in glucose metabolism. In contrast, the adenoviral-mediated hepatic overexpression of GCKR in mice was reported to improve fasting plasma glucose (FPG) levels and insulin sensitivity, and increased plasma triglyceride (TG) levels.…”

Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

“…GCKR-deficient mice have reduced GCK expression but maintain nearly normal GCK activity and show impaired glucose clearance (4). Furthermore, adenoviral-mediated overexpression of GCKR in mouse liver increased GCK activity and lowered fasting blood glucose (5) and overexpression of GCK in liver led to lowered blood glucose and increased triglyceride concentrations (6,7). Thus, experimental evidence suggests that perturbation of the GCKR pathway has opposing effects of triglyceride and glucose metabolism.…”