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Type 2 diabetes (T2D) affects an escalating percentage of populations in both the developed and developing parts of the world. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 20.8 million Americans (~7% of the population) have diabetes, and nearly one-third of these cases are undiagnosed. Another 41 million have insulin resistance or pre-diabetes. Worldwide figures are especially astounding: in 2003 the World Health Organization (WHO) reported a global incidence of 194 million diabetes patients and this figure may possibly double by 2025. The underlying principle pathological origins of T2D include: (i) attenuated glucose-induced insulin release from pancreatic p-cells; (ii) insulin resistance in adipose tissue, skeletal muscle and liver; and (iii) disproportionate hepatic glucose production.

Evidence gathered over the previous 40 years has ascertained an essential function for glucokinase (GK), also known as hexokinase IV or hexokinase D, in regulating glucose homeostasis. GK is expressed mainly in two tissues of high importance to glucose homeostasis and therapeutic strategies to treat T2D, pancreatic b-cells and hepatocytes. The mechanism of GK has been thoroughly studied and is well established [1-4]. In the liver, GK functions as a high-capacity enzyme that removes glucose from the blood and reacts it with adenosine triphosphate (ATP) to form glucose-6-phosphate (G-6-P), the first biosynthetic step in the

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 41 ISSN: 0065-7743 DOI 10.1016/S0065-7743(06)41008-3

© 2006 Elsevier Inc. All rights reserved conversion of glucose to its storage form, glycogen. In pancreatic p-cells, through its ability to sense glucose concentrations, GK operates as a glucose sensor to determine the threshold for glucose-stimulated insulin release (GSIR).

Because GK has a central role in glucose homeostasis, many researchers have attempted to develop drugs that augment GK activity to treat T2D. It is reasoned that an activator of GK would serve dual purposes of firstly decreasing blood glucose levels by increasing hepatic glucose uptake, and secondly, increasing insulin secretion by lowering the threshold of GSIR. In this review, the mechanism of enzymatic catalysis by GK, its function in the liver and pancreatic p-cells, key publications on small-molecule GK activators (GKAs) that report full characterization, and key compound disclosures from patents will be discussed.

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