The Central Role of Glucokinase in Glucose Homeostasis: A Perspective 50 Years After Demonstrating the Presence of the Enzyme in Islets of Langerhans

Abstract

It is hypothesized that glucokinase (GCK) is the glucose sensor not only for regulation of insulin release by pancreatic β-cells, but also for the rest of the cells that contribute to glucose homeostasis in mammals. This includes other cells in endocrine pancreas (α- and δ-cells), adrenal gland, glucose sensitive neurons, entero-endocrine cells, and cells in the anterior pituitary. Glucose transport is by facilitated diffusion and is not rate limiting. Once inside, glucose is phosphorylated to glucose-6-phosphate by GCK in a reaction that is dependent on glucose throughout the physiological range of concentrations, is irreversible, and not product inhibited. High glycerol phosphate shuttle, pyruvate dehydrogenase, and pyruvate carboxylase activities, combined with low pentose-P shunt, lactate dehydrogenase, plasma membrane monocarboxylate transport, and glycogen synthase activities constrain glucose-6-phosphate to being metabolized through glycolysis. Under these conditions, glycolysis produces mostly pyruvate and little lactate. Pyruvate either enters the citric acid cycle through pyruvate dehydrogenase or is carboxylated by pyruvate carboxylase. Reducing equivalents from glycolysis enter oxidative phosphorylation through both the glycerol phosphate shuttle and citric acid cycle. Raising glucose concentration increases intramitochondrial [NADH]/[NAD⁺] and thereby the energy state ([ATP]/[ADP][Pi]), decreasing [Mg²⁺ADP] and [AMP]. [Mg²⁺ADP] acts through control of K_ATP channel conductance, whereas [AMP] acts through regulation of AMP-dependent protein kinase. Specific roles of different cell types are determined by the diverse molecular mechanisms used to couple energy state to cell specific responses. Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network.

Keywords: counter regulatory hormones; diabetes; glucokinase; glucose homeostasis; metabolic regulation.

Figure 1

A schematic representation of GCK containing cells in sensing systemic glucose and regulating glucose homeostasis. Systemic glucose concentration is sensed by cells through its metabolism by GCK and the rate of production of G-6-P on cellular energy state. Cell-specific mechanisms then translate alterations in energy state into responses (hormone release, neural activity) that either augment or inhibit glucose consumption and/or production of glucose as appropriate to maintenance of homeostasis. The central role of the liver in metabolizing dietary sugars (glucose, galactose, and fructose), nearly quantitative removal of the galactose and fructose, is noted. ANS, autonomic nervous system; GCK, glucokinase; GALK-1, galactokinase-1; KHK-C, ketohexokinase-C (i.e., fructokinase); GLP-1-producing enteroendocrine L-cells; GnRH, gonadotropin-releasing hormone; α, β, δ, the alpha, beta, and delta cells of pancreatic islets.

Figure 2

(A,B) Response of pancreatic α, β, and δ-cells to systemic glucose concentration and the relationship of hormone release by each cell type as a function of blood glucose levels. Schematically represents the role of each cell type in controlling blood glucose concentration. Increasing glucose suppresses glucagon release by α-cells while increasing insulin release by β-cells. It also increases release of somatostatin from δ-cells, a paracrine signal that suppresses hormone release by both α- and β-cells. (B) schematically shows the relative amount of hormone released at each glucose concentration. A dotted vertical bar is shown at 5 ± 0.5 mM, the set point for glucose homeostasis. (B) is based on graphic depictions (Matschinsky et al., 1976; Gylfe, 2016; Rorsman and Huising, 2018).

Figure 3

Regulation of glucokinse activity in liver by liver specific GCK regulatory protein (GCKRP). In hepatocytes, in contrast to glucose sensing cells in regulation of glucose homeostasis, there is a specific inhibitory protein that regulates GCK activity. The figure schematically represents the association of GCK and GCKRP and the metabolic factors that affect that interaction. This can be considered a “switch” that turns enzyme activity on when blood glucose in elevated and off when it is low relative to normal (for background and details, see Zelent et al. (2014). SL, small lobe; LL, large lobe; ARR, allosteric regulatory region; SIS-1, sugar isomerase; SIS-2, sugar isomerase-2; LID, lid.

Figure 4

A schematic overview of how glucose regulates blood glucose by affecting α- and β-cells. The blood glucose level, through the activity of GCK which produces G6P as a “second messenger”, regulates release of glucagon from α-cells and of insulin from β-cells. Insulin is responsible for controlling consumption of glucose (removal from the blood), largely for storage as glycogen in muscle and liver. This is opposed by glucagon which is responsible for controlling production of glucose, mostly from liver glycogen and/or gluconeogenesis, and for activating fatty acid oxidation, primarily through production of fatty acids by adipose tissue. This “opposing forces” counter regulatory process is designed to achieve a balance (production equals consumption) at a blood glucose concentration near 5 mM.