Anatomy, Physiology and Regulation of Glucokinase as a Brain Glucosensor

Abstract

The brain has evolved specialized glucosensing neurons which participate in glucose and overall energy homeostasis in the body. Glucosensing neurons utilize glucose as a signaling molecule to alter their firing rate, as opposed to the vast majority of neurons which primarily utilize glucose to fuel their metabolic needs [1]. Oomura [2] and Anand [3] and their co-workers first demonstrated such neurons in both the fore-and hindbrain in 1964. Although these neurons can respond directly or indirectly to either the complete absence of glucose or to levels as high as 20 mM [4][5][6][7][8][9][10][11], it is likely that their primary range is between 0.5-3.5 mM under physiologic conditions [12,13]. Mounting evidence supports a role for glucokinase (GK) as the gatekeeper for neuronal glucosensing within this physiologic range [11,14]. Importantly, glucosensing neurons reside in brain areas known to play critical regulatory roles in energy homeostasis and neuroendocrine and autonomic function [15][16][17][18].Glucose sensing neurons are either excited (glucose excited; GE) or inhibited (glucose inhibited; GI) by rising ambient glucose levels [6,7,9,10]. However, early studies used extracellular recording techniques to monitor neuronal activity at glucose levels virtually never seen by the living brain, i.e. 0 vs. 10-20 mM [6,10]. Neurophysiologic studies have provided direct evidence that GE neurons function much like the pancreatic ␤-cell where elevated glucose levels increase the ATP/ADP ratio and inactivate (close) an inwardly rectifying K ϩ pore-forming unit (Kir6.2) of the ATP-sensitive K ϩ (K ATP ) channel [4,5,9,10,19]. This channel on GE neurons is similar, but not completely identical to

A Glucose Sensor Role for Glucokinase in Anterior Pituitary Cells

“…It will be important, for example, to check what the nature of the glucose transporter(s) might be, whether the SUR-1/Kir-6.2 potassium channel complex is present or not and what the biochemical features of any calcium channels might be. It is possible that a unique glucose sensor cell exists in which glucose acts primarily by altering intracellular calcium storage rather than by modifying ion channels of the cell membrane as true for pancreatic ␤-cells and certain hypothalamic neurons (4,5). Our current general physiological understanding of the anterior pituitary indicates that pituitary cells are controlled entirely by the hypothalamic neuroendocrine system (i.e., by numerous classical stimulatory and inhibitory neurohormones) and by powerful feedback via cortisol, thyroid hormone, sex steroids, etc.…”

“…The secretion of these hormones is governed in turn by glucose sensor cells, most often with glucokinase as the glucose sensor (3,4). Glucose sensing can be either direct as in the case of the insulin-producing ␤-cells or indirect as in the case of the epinephrine-releasing chromaffine cells, which are stimulated by nicotinic cholinergic neurons that are controlled by glucose sensors of the central and autonomic nervous systems (2,4,5). Glucose regulation of glucagon, cortisol, and growth hormone is also believed to be indirect.…”

Glucokinase activators in diabetes management

“…GK is thought to confer glucosensitivity on those CNS neurons in which it is expressed [109,[118][119][120] . Changes in glucose concentration within the physiological range encountered within the brain alter the firing rate of isolated glucosensitive neurons [111,118,120] .…”

Glucokinase, glucose homeostasis, and diabetes mellitus

“…It is now widely accepted that GK serves as a glucose sensor of the pancreatic β cell [30][31][32], and there is some evidence that the enzyme may play a similar role in hypothalamic neurons [33]. GK determines the rate of β-cell glucose metabolism and, thus, the rate by which metabolic coupling factors that connect intermediary metabolism with insulin release are generated.…”