br Conclusion In conclusion SHP was

Conclusion In conclusion, SHP289-04 was demonstrated as a potent glucokinase activator. It could normalize the blood glucose level and lipid level in spontaneous type 2 diabetes model KKAy mice. At the same time, it ameliorated the function of islets and liver in KKAy mice. It had been proved to have the potential for type 2 diabetes treatment.
Mammalian glucose metabolism Glucose is an essential energy molecule for many species as it can readily be metabolized to generate ATP by either aerobic on SB 203580 respiration. In mammals, several tissues, such as the brain, depend upon glucose for the generation of ATP for cellular functions (Wasserman, 2009, Thorens, 2011). To supply these tissues, glucose is distributed by the blood stream, and complex systems have evolved to maintain appropriate blood glucose levels in the face of changes due to the availability of food and the expenditures of energy (Suh et al., 2007, Wasserman, 2009, Polakof et al., 2011, Thorens, 2011). The diet is the ultimate source of glucose in mammals, where it is either directly absorbed from the digested food in the intestine or is generated by gluconeogenesis (generally from amino acids) from precursors obtained from the diet. Whether glucose comes directly from the diet, or is synthesized via gluconeogenesis, depends upon the carbohydrate content of the diet. Counter-regulatory hormone systems have evolved to maintain blood glucose within a narrow range. Insulin promotes glucose uptake from the blood by diverse tissues when blood glucose levels are high; e.g., after feeding, while glucagon induces gluconeogenesis by the liver to release glucose and prevent hypoglycemia (Bansal and Wang, 2008, Wasserman, 2009). Additional physiological systems, including other hormones and the central nervous system, contribute to the regulation of blood glucose levels (Polakof et al., 2011, Thorens, 2011, Grayson et al., 2013). Excess energy obtained from the diet is stored as glycogen in the liver and muscle and as lipid in adipose tissue (Klover and Mooney, 2004). Glycogen in muscle can be rapidly broken down to release glucose when it is needed by muscle tissue (Jensen and Richter, 2012); similarly, glycogen is a source for the production of glucose that can be released by the liver to maintain blood glucose levels (Klover and Mooney, 2004). While glucose can be dispersed to distant tissues of the body through the blood, it still must enter cells, as it cannot cross the lipid membranes of cells by simple diffusion, as it is hydrophilic. In mammals, glucose is transported across the cell membrane by transporters, which belong to one of two families: the glucose transporters (SLC2 or GLUT gene family) (Augustin, 2010, Wilson-O’Brien et al., 2010, Mueckler and Thorens, 2013) and the sodium-coupled glucose transporters (SGLT or SLC5 gene family) (Wright et al., 2011, Wright, 2013). Members of the SGLT are expressed in the kidney and intestine where they actively transport glucose and allow reabsorption against a concentration gradient (Wright et al., 2011, Wright, 2013). The SLC2 family members (or GLUT proteins) are facilitative transports and only move glucose in the direction of a concentration gradient (Augustin, 2010, Mueckler and Thorens, 2013). The diverse members of the SLC2 family have varying substrate specificities, kinetics, and expression profiles allowing cells to have tissue-specific differences in their glucose uptake (Augustin, 2010, Mueckler and Thorens, 2013).
Glucokinase and the vertebrate hexokinase gene family Once glucose (or other simple sugars, e.g., fructose) enter cells it is phosphorylated. Phosphorylation has two purposes: (1) the first step in metabolism, and (2) decreasing the intracellular concentration of the unphosphorylated form of the sugar, thus driving the uptake of the sugar from the external environment. Enzymes, called hexokinases, phosphorylate glucose, and other six-carbon sugars. In mammals, and other vertebrates, four hexokinase isozymes have been identified (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). The different isozymes of hexokinase were initially distinguished by letters (i.e., hexokinase (HK) A, B, C, and D) based on their elution time from DEAE cellulose columns (González et al., 1964), but subsequently given numbers (i.e., hexokinase I, II, III, and IV) based on their migration in electrophoretic gels (Katzen et al., 1965). Hexokinase IV (or D) is most often called glucokinase (GCK), although it is not specific for glucose (Cárdenas et al., 1998, Wilson, 2004). Genes encoding these hexokinases use Arabic numbers; e.g., HK1 encodes hexokinase I. Mammalian hexokinases have been extensively characterized, with possibly their most striking difference being their molecular weights (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). Hexokinases I, II, and III have a molecular weight of approximately 100kD, while glucokinase has a molecular mass of about 50kD. Hexokinases having a molecular weight of 50kD, but not 100kD, have also been found, and characterized, in many other eukaryotes species, including non-vertebrate animals, plants, and yeast (Ureta, 1982, Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). In some of these non-mammalian species multiple isozymes have been characterized (Wilson, 1995, Wilson, 2004, Cárdenas et al., 1998). While enzymes that phosphorylate sugars have also found in bacteria, these sequences show no significant sequence similarity to the eukaryotic hexokinases. However there is some similarity in the three-dimensional structures of hexokinases from bacteria and eukaryotes, which has been used to suggest that they share a common ancestor (Bork et al., 1993, Cárdenas et al., 1998, Kawai et al., 2005).