Chlorogenic Acid, a Potential Glucose-6-Phosphatase Inhibitor: An Approach to Develop a Pre-Clinical Glycogen Storage Disease Type I Model

Abstract:

Introduction: Gluconeogenesis and glycogenolysis are highly regulated metabolic processes that are critical in maintaining blood glucose levels within the physiological range. Any aberration in the regulation of these processes can lead to an inadequate repository or accumulation of excess glycogen in hepatocytes. Glycogen Storage Disease type I (GSD type I), also known as Von Gierke’s disease, is categorized under inborn errors of metabolism caused due to either inactivity or complete absence of the Glucose-6-phosphatase enzyme (G6Pase). Objectives: This study's focus is to suppress G6Pase, hepatic glucose synthesis, and induce the symptoms of GSD type I in experimental rats. Materials and Methods: The in silico approach using Chlorogenic Acid (CGA) and G6Pase exhibited a good docking score (-8.9), and promising binding patterns, molecular dynamic simulation studies (at 100 nanoseconds) also confirmed the stability of the docked complex. Based on this in silico speculation, the in vivo study was designed, where, in the pilot study varying doses (50, 100, 200, 400 mg/kg) and CGA-liposome formulation were scrutinized, Results: It was corroborated that the CGA can cause hypoglycemia, hence CGA (200 mg/kg) was chosen for the study, to further augment the other major GSD type I manifestations, metformin (500 mg/kg) was included in the study for 49 days, manifestations like hypoglycemia, suppressed G6Pase activity, elevated hepatic glycogen and lactate dehydrogenase were evident. Conclusion: The observations suggest that chlorogenic acid has the potential to induce GSD type I manifestations along with metformin, which can be an alternative animal model to match the genetically modified disease models.

Keywords: Chlorogenic acid, Metformin, Fasting blood glucose, Glucose-6-phosphatase, Glycogen storage disease type I, Glycogenolysis.