br Glucose metabolism and diet Glucokinase is essential for
Glucose metabolism and diet Glucokinase is essential for sensing blood glucose levels, thus controls metabolism (Iynedjian, 1993, Iynedjian, 2009, Postic et al., 2001, Agius, 2008). Loss of glucokinase activity in humans and mice leads to diabetes (Printz et al., 1993b, Postic et al., 2001, Agius, 2008, Iynedjian, 2009); however, this does not appear to be the case for all vertebrate species. Several mammals, and other vertebrate species, have been reported to be deficient in liver glucokinase activity (reviewed in Ureta, 1982). The initial reports of liver glucokinase deficiency were based largely on the electrophoretic separation of hexokinase isozymes (see Ureta, 1982). More recent investigations that used more sensitive approaches have often detected low levels of glucokinase in the livers of many of these species (e.g., Panserat et al., 2000a, Berradi et al., 2005, Hiskett et al., 2009), but confirm, at least in some species, that the levels of glucokinase in their liver are low. It has been argued that low levels of glucokinase in the liver of these species is unlikely to be due to inactivating mutations in the glucokinase gene, as these mutations would likely disrupt essential glucokinase function (i.e., regulating insulin secretion) in the pancreas (Cárdenas et al., 1998, Wang et al., 2013). These observations raise several questions, including what is the genetic basis for the low levels of glucokinase in the liver and what are functional consequences of the low level of activity (Cárdenas et al., 1998). Reduced liver glucokinase levels, without changes in pancreatic levels, were observed in GCKR knockout mice (Farrelly et al., 1999, Grimsby et al., 2000). This result suggested that GCKR not only has a role in regulating glucokinase activity, via subcellular localization, but also enhances the stability of the enzyme. GCKR is also absent from the livers of the cat, a species who are deficient in liver glucokinase activity (Hiskett et al., 2009). These observations prompted searches for glucokinase and GCKR Demethoxycurcumin receptor from the genomes of diverse vertebrate species, including those that do and do not have reported liver glucokinase activity (Wang et al., 2012, Wang et al., 2013). Potentially intact glucokinase genes could be found in every genome searched, however, mutated GCKR genes were found in the genomes of multiple species (Wang et al., 2012, Wang et al., 2013). GCKR genes that contain mutations that should prevent function (i.e., frame-shift or splicing mutations) were found in species that were previously reported to lack (or have low) glucokinase activity in the liver; while potentially intact (i.e., have complete open reading frames and splice consensus sequences) GCKR genes were found in species that were reported to have activity (Wang et al., 2013). The correlation between the possessing an intact GCKR gene with glucokinase activity (and mutated gene with loss of activity) suggests that the loss of the GCKR may be the main molecular mechanism for deficiency of liver glucokinase activity. Intriguingly, loss of liver-specific glucokinase activity must have occurred multiple times, as neither loss of liver glucokinase activity nor disrupted GCKR genes are monophyletic, where both intact and mutated GCKR genes as well as presence and absence of liver glucokinase activity are interspersed in the vertebrate phylogeny (Wang et al., 2013). Why would glucokinase activity, and thus GCKR genes, be dispensable? The liver only needs glucokinase activity if blood glucose levels can exceed the preferred level, and glucose levels would only exceed this level if too much is made by gluconeogenesis or if too much is absorbed from the diet. Since gluconeogenesis is a regulated process (Postic et al., 2001, Agius, 2008), this should not cause excess blood glucose levels. Acquiring glucose from the diet is not a regulated process, therefore it can lead to elevated blood glucose levels, but only if the diet is high in carbohydrate as they are broken down to sugars in the digestive tract. Species that lack liver glucokinase activity have a ruminant lifestyle that ferments plant material to generate short-chain fatty acids (e.g., cow and sheep), have elevated blood glucose levels (e.g., birds), or are carnivores (e.g., cat) (Hiskett et al., 2009, Aschenbach et al., 2010, Polakof et al., 2011, Verbrugghe et al., 2012). These species, though, will still require glucose sensing in pancreatic islets, as well as gut and neuronal cells, to prevent hypoglycemia, therefore must retain a intact glucokinase gene to function in those cells. The loss of a requirement for glucokinase in ruminants can be explained by the fact that these animals derive almost all of their energy needs from short chain fatty acids (Aschenbach et al., 2010). Very little glucose is acquired from the ruminant diet, thus they do not need to remove excess glucose from the blood. Birds have the highest blood glucose levels of any vertebrate group (Braun and Sweazea, 2008, Polakof et al., 2011). The lower levels of glucocokinase activity in the liver of birds may contribute to this, with the increased blood glucose levels contributing to the high metabolic rates required for flight. Further studies are needed to understand how birds cope with high blood glucose levels. Carnivores derive most of their energy from protein, thus one might expect to be similar to ruminants and not require glucose uptake by the liver. The cat provides an example of a carnivore that has lost GCKR and thus glucokinase activity (Hiskett et al., 2009, Verbrugghe et al., 2012). However, there are many other carnivores, such as the dog that have glucokinase activity (Tanaka et al., 2005) and have retained both GCKR and glucokinase genes (Wang et al., 2012, Wang et al., 2013). The retention of glucokinase activity in the liver may allow dogs (Batchelor et al., 2011) or carnivorous fish (Panserat et al., 2000b, Polakof et al., 2011) to eat more varied diets or to regulate blood glucose levels when glucose is synthesized from other substrates. Species that have lost GCKR function may be more restricted in their diets.