Glucokinase and glucose homeostasis: proven concepts and new ideas

Abstract

The enzyme GK (glucokinase), which phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor of insulin-producing beta-cells. GK has thermodynamic, kinetic, regulatory and molecular genetic characteristics that are ideal for its glucose sensor function and allow it to control glycolytic flux of the beta-cells as indicated by control-, elasticity- and response-coefficients close to or larger than 1.0. GK operates in tandem with the K(+) and Ca(2+) channels of the beta-cell membrane, resulting in a threshold for glucose-stimulated insulin release of approx. 5 mM, which is the set point of glucose homoeostasis for most laboratory animals and humans. Point mutations of GK cause 'glucokinase disease' in humans, which includes hypo- and hyper-glycaemia syndromes resulting from activating or inactivating mutations respectively. GK is allosterically activated by pharmacological agents (called GK activators), which lower blood glucose in normal animals and animal models of T2DM. On the basis of crystallographic studies that identified a ligand-free 'super-open' and a liganded closed structure of GK, on thermostability studies using glucose or mannoheptulose as ligands and studies showing that mannoheptulose alone or combined with GK activators induces expression of GK in pancreatic islets and partially preserves insulin secretory competency, a new hypothesis was developed that GK may function as a metabolic switch per se without involvement of enhanced glucose metabolism. Current research has the goal to find molecular targets of this putative 'GK-switch'. The case of GK research illustrates how basic science may culminate in therapeutic advances of human medicine.

Alx3-deficient mice exhibit decreased insulin in beta cells, altered glucose homeostasis and increased apoptosis in pancreatic islets

“…In addition, the observation that Alx3-deficient mice exhibit relatively high blood glucose levels in fasting conditions despite normal levels of serum insulin is consistent with the existence of a defect in the glucose-sensing mechanisms in beta cells, resulting in a displacement of the threshold at which glucose concentration elicits the release of appropriate amounts of insulin to the circulation. As GCK acts as a glucose sensor in beta cells, this notion is in line with our finding of reduced GCK levels in Alx3-null mice [25,26].…”

From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

“…*"A" denotes the maximal fold drug effect on k cat , "B" on the glucose affinity, and "C" on the activity index. †EC 50 values are the half-maximal drug concentrations for the effect on the k cat , the glucose affinity, and the activity index. NR, not responsive to the GKA.…”

“…G264S is not mapped to any site known to interact with either GKA or GKRP, but it could be involved in the regulation of glucokinase by other cellular components. Recently, a provocative hypothesis was proposed based on studies of glucokinase induction in isolated pancreatic islets using glucose in the presence of the competitive inhibitor mannoheptulose (50). From these studies, the idea of glucokinase functioning as a metabolic messenger in pancreatic islet cells and hepatocytes (the "glucokinase switch") independent of glucose metabolism was advanced, implying the existence of intracellular targets for this metabolism-independent glucokinase switch.…”

Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity

“…GCK plays a role as a beta cell glucose sensor by integrating blood glucose levels and glucose metabolism with insulin secretion [4][5][6]. This specific function of GCK is based on the particular kinetic characteristics of this enzyme, which include a low affinity for glucose, cooperativity with this substrate, and a lack of end-product inhibition at physiological concentrations.…”