Mammalian glucokinase was identified 30 years ago as a distinct form of hexokinase in rat liver. The hexokinases (ATP: hexose 6-phosphotransferases, EC 2.7. 1.1) constitute a family of evo-lutionarily and stucturally related enzymes present in eukaryotic cells from yeast to mammals. In the cells of higher organisms, the physiologically significant substrate for these enzymes is D-glucose. The reaction catalysed by the hexokinases, ATP+ D-glucose-+ ADP+D-glucose 6-phosphate, is the first and obligatory step for glucose utilization after transport of the sugar into the cell. Mammalian tissues contain four different hexokinases which can be isolated by conventional protein separation tech-niques and for which cDNAs have been cloned. The isoenzymes of the rat have been designated hexokinases type I-IV or AD in order of increasing negative net charge. The subject of this Review is hexokinase type IV or D, usually called glucokinase. Glucokinase stands apart from all the other hexokinases by a number of criteria. The first and most striking is its low affinity for glucose. The enzyme is half-saturated with glucose at 6 mM, compared with Km values in the micromolar range for the three other mammalian hexokinases. This feature led to the discovery of the enzyme and underlies its key role in the physiology of glucose homeostasis. The second hallmark of mammalian glucokinase is its highly typical tissue distribution. The glucokinase gene is transcribed and the mRNA translated into active enzyme only in hepatocytes and insulin-secreting f-cells ofthe pancreatic islets of Langerhans, reflecting the great functional specialization of this isoenzyme. A third outstanding feature is the developmental and multihormonal regulation of the enzyme, illustrated most dramatically by the transcriptional induction of the glucokinase gene by insulin in the liver. The distinctive kinetics of glucokinase, its tissue-specific ex-pression and its hormonal regulation were recognized within a few years of the discovery of the enzyme. However, our understanding of these particular characteristics has remained super-ficial until recently. The main reason for limited progresswas the difficulty of purifying the enzyme, hence of raising specific antibodies or obtaining peptide sequence for the isolation of cDNA clones. Once this obstacle was surmounted, studies on glucokinase became a very fertile field of research. The most recent and medically rewarding outcome of this research has been the discovery of mutations of the glucokinase geneas the cause ofone subtype of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this article is to review the recent developments on the structure and function of the glucokinase gene and its gene products, as they relate to our understanding of blood glucose homeostasis. The reader interested in historical perspectives and a complete background on the biochemistry of glucokinase should refer to the classical reviews of Walker [1], Weinhouse [2] and Colowick [3]. Recent commentaries on topical aspects are also available [4-8].

The glucokinase genewas first clonedfrom the rat and the structure of the gene in this species can serve as the standard of reference (Figure 1 a). The most remarkable feature is the presence of alternative promoters, responsible for the initiation of tran-scription at different sites on the DNA in hepatic and endocrine cells. The first clue to theexistence of cell-type-specific promoters came from the sequences oftwo quasi-full-length cDNAs isolated from rat liver and insulinoma libraries [9, 10]. The sequences were essentially identical for more than 2000nucleotides starting from the 3'ends of the cDNAs, but segments of …