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.
Highlights
Type 2 diabetes is preceded by insulin resistance, the impaired ability of tissues to take up and store glucose in response to insulin [1]
Human genetic mutations in GK further underscore its role in controlling metabolic homeostasis: activating mutations result in hyperinsulinemia and hypoglycemia, and loss-of-function mutations result in a form of diabetes known as maturity onset diabetes of the young, type 2 (MODY2) [8]
We show that in rats GKA23 improved glucose homeostasis due to increased b cell insulin secretion and decreased hepatic glucose production
Summary
Type 2 diabetes is preceded by insulin resistance, the impaired ability of tissues to take up and store glucose in response to insulin [1] To compensate for this reduced responsiveness, the pancreatic b cells over-secrete insulin, causing hyperinsulinemia. Compared to other hexokinases, GK has a lower affinity for glucose, displays substrate cooperativity, and is not inhibited by its product, glucose-6-phophate [5]. These characteristics allow GK to serve as a glucose sensor to regulate cellular metabolism in response to changes in glucose concentration [7]. Human genetic mutations in GK further underscore its role in controlling metabolic homeostasis: activating mutations result in hyperinsulinemia and hypoglycemia, and loss-of-function mutations result in a form of diabetes known as maturity onset diabetes of the young, type 2 (MODY2) [8]
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