Abstract

The low-affinity glucose-phosphorylating enzyme glucokinase (GK) is the flux-limiting glucose sensor in liver and β-cells of the pancreas. Furthermore, GK is also expressed in various neuroendocrine cell types. This review describes the complex network of GK regulation, which shows fundamental differences in liver and pancreatic β-cells. Tissue-specific GK promoters determine a higher gene expression level and glucose phosphorylation capacity in liver than in pancreatic β-cells. The second hallmark of tissue-specific GK regulation is based on posttranslational mechanisms in which the high-affinity regulatory protein in the liver undergoes glucose- and fructose-dependent shuttling between cytoplasm and nucleus. In β-cells, GK resides outside the nucleus but has been reported to interact with insulin secretory granules. The unbound diffusible GK fraction likely determines the glucose sensor activity of insulin-producing cells. The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) has been identified as an activating binding partner of β-cell GK, increasing the V_max value of the enzyme, while the S_0.5 value for glucose remains unchanged. This effect is likely due to stabilization of a catalytically active enzyme conformation. The identification of chemical activators of GK paved the way to determining its crystal structure, revealing a catalytically less active super open conformation and a catalytically active closed conformation with a normal affinity for glucose. The glucose sensor function of GK in liver and β-cells results from the synergy of its regulatory properties with its transcriptionally and posttranslationally controlled levels. These factors have to be taken into account in designing pharmacotherapy for type 2 diabetes.