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Hepatic glycogen cycling contributes to glucose lowering effects of the glucokinase activator LCZ960

Laurent, Didier and Yerby, Brittany and Zhang, Bailin and Chen, Xiao-Hui and Gounarides, John and Gao, Jiaping and Duttaroy, Alokesh (2013) Hepatic glycogen cycling contributes to glucose lowering effects of the glucokinase activator LCZ960. European Journal Of Pharmacology, 715 (1-3). pp. 89-95.

Abstract

Aims/Hypothesis Glucokinase (GK) acts as a glucose sensor by facilitating glucose phosphorylation into glucose-6-phosphate (G6P) in the liver and pancreas, the two key target tissues. LCZ960, a small molecule glucokinase activator (GKA) exerts a stimulatory effect on GK activity in hepatocyte in vitro. The current study was aimed to verify in vivo that LCZ960 stimulates glucose uptake primarily through a mechanism involving hepatic GK activation.
Methods Acute and chronic LCZ960 treatment-induced changes in glycemia and hepatic glucose turnover were measured in high fat diet-induced obese (DIO) mice and rats, respectively. G6P production and glycogen cycling were quantified by 13C-MR spectroscopy during a 120-min [1-13C]glucose infusion, followed by a 60-min pulse-chase with [12C]glucose to mimic postprandial conditions in rats.
Results Acute treatment with LCZ960 dose-dependently reduced blood glucose without hypoglycemic effect in DIO mice. Chronic LCZ960 treatment maintained normoglycemia and improved glucose tolerance without increased insulin secretion in DIO mice and rats. In rats, LCZ960 stimulated a 240% increase in the glycogen synthase flux. However, due to a much higher glycogen breakdown (LCZ960: 47.8±15.2 vs control: 3.9±1.0 mol/kg/min), this translated to a much smaller increase (46%) in glycogen storage (Vsyn net 64.3±8.6 mol/kg/min). Despite a 4-fold increase in hepatic glycogen turnover (LCZ960: 36.0±5.5% vs. control: 8.3±2.0%), LCZ960 did not impact glucose-stimulated G6P accumulation.
Conclusions/Interpretation LCZ960 maintains normoglycemia without causing hypoglycemia in rodents. Under hyperglycemic conditions, LCZ960 caused a robust increase in hepatic glycogen cycling. Because net hepatic glycogen storage is diminished in poorly controlled patients with type 2 diabetes, stimulation of glycogen synthesis may contribute to antihyperglycemic properties of GKA.

Item Type: Article
Additional Information: Abbreviations 13C-MRS: 13C magnetic resonance spectroscopy GKA: Glucokinase activator G6P: Glucose-6-Phosphate MODY2: maturity-onset diabetes of young type 2 T2D: Type 2 diabetes
Keywords: 13C-MRS, Diabetes, Glucokinase activator, Glucose-6-phosphate, Glycogen
Date Deposited: 28 Apr 2018 00:45
Last Modified: 28 Apr 2018 00:45
URI: https://oak.novartis.com/id/eprint/1995

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