Insights into the role of neuronal glucokinase

Abstract

Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counterregulatory responses to hypoglycemia and in regulating appetite. We describe clinical implications from these advances in our knowledge, especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics is suggested.

Keywords: appetite; counterregulatory response; glucokinase; glucose homeostasis; glucose sensing; neuronal.

Fig. 1.

Location of main brain centers containing glucokinase-expressing neurons in the rat brain. A: sagittal section diagram illustrating the position of the brain regions in the rat brain-expressing glucokinase believed to be involved in glucose sensing, which are located mostly in the hypothalamus and in the brainstem. B: coronal section diagram of glucokinase-expressing nuclei of the brainstem. C: coronal section diagram of glucokinase-expressing hypothalamic nuclei. D: coronal section diagram of glucokinase-expressing nuclei closer to the forebrain. MAN, medial amygdalar nucleus; PVN, paraventricular nucleus; pPVN, parvocellular PVN; LH, lateral hypothalamus; VMN, ventromedial nucleus; DMN, dorsomedial nucleus; ARC, arcuate nucleus; AP, area postrema; NTS, nucleus tractus solitarius; DMV, dorsal motor nucleus of the vagus; ROb, raphe obscurus; RPa, raphe pallidus; LV, lateral ventricle; chp, choroid plexus; 3V, third ventricle; d3V, dorsal 3rd ventricle. cNTS, central nucleus tractus solitarius.

Fig. 2.

Role of glucokinase in the peptide release mechanism of pancreatic β-cells and glucose-excited neurons. Glucokinase activity leads to cellular depolarization, followed by insulin secretion in pancreatic β-cells or neurotransmitter release in glucose-excited neurons. As extracellular glucose concentrations increase, glucose is taken up into the islet cell predominantly by glucose transporter 2 (GLUT2) (158) and into the neuron predominantly via GLUT3 glucose transporters (160). Once in the cytosolic space, glucose is phosphorylated by glucokinase to form glucose 6-phosphate (95). Although this reaction consumes adenosine triphosphate (ATP), the levels of ATP ultimately rise due to further glycolysis of glucose. The coupling of glucose entry with glycolysis and ATP production allows the increase in ATP concentration to inhibit ATP-sensitive potassium (K_ATP) channels. This prevents the efflux of K⁺ ions. As a result K⁺ ions accumulate within the neuron, and the membrane potential of the cell rises. The difference in membrane voltage triggers the influx of Ca²⁺ ions through voltage-gated Ca²⁺ channels. Ca²⁺ entry causes cellular depolarization, which in turn leads to an action potential (130). This proposed mechanism allows glucokinase to function as a glucose sensor by coupling glucose availability with β-cell and neuronal activity and insulin and neurotransmitter release (108).

Fig. 3.

Proposed mechanism by which glucokinase activity leads to neuronal hyperpolarization and inhibits neurotransmitter release in glucose-inhibited neurons. As extracellular glucose concentrations increase, glucose is taken up into the islet cell predominantly by GLUT2 (158) and into the neuron predominantly via GLUT3 glucose transporters (160). Once in the cytosolic space, glucose is phosphorylated by glucokinase to form glucose 6-phosphate (95). Although this reaction consumes adenosine triphosphate (ATP), the levels of ATP ultimately rise due to further glycolysis of glucose. The coupling of glucose entry with glycolysis and ATP production allows the increase in ATP concentration to stimulate sodium potassium ATPase (Na⁺/K⁺ ATPase) pumps. For one ATP molecule, each pump pumps three Na⁺ ions out of the cell and enables the entry of two K⁺ ions. This causes a decrease in membrane voltage and results in hyperpolarization of the cell (80), ultimately leading to a decrease in neuronal firing.

Fig. 4.

Postulated roles of glucokinase in the hypothalamus. Summary illustration describing the role of glucokinase in each of the major hypothalamic nuclei expressing the glucose sensor. PVN, paraventricular nucleus; LH, lateral hypothalamus; VMN, ventromedial nucleus; DMN, dorsomedial nucleus; ARC, arcuate nucleus; CRR, counterregulatory response.