Abstract
Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / chemistry*
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Animals
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Area Under Curve
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Blood Glucose / metabolism
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Catalysis
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Diabetes Mellitus, Experimental / drug therapy
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Enzyme Activators / chemistry*
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Glucokinase / metabolism*
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Glucose / metabolism
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Glucose Tolerance Test
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Hepatocytes / metabolism
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Homeostasis
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / cytology
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Kinetics
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Liver / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Obesity / drug therapy
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Phosphorylation
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Rats
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Rats, Sprague-Dawley
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Thiadiazoles / chemistry*
Substances
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1-(5-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol
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Aminopyridines
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Blood Glucose
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Enzyme Activators
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Insulin
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Thiadiazoles
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Glucokinase
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Glucose
Grants and funding
This study was supported by Amgen Inc., which played a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.