Glucose Sensing in Pancreatic β-Cells

Abstract

Nutrient homeostasis is known to be regulated by pancreatic islet tissue. The function of islet ␤-cells is controlled by a glucose sensor that operates at physiological glucose concentrations and acts in synergy with signals that integrate messages originating from hypothalamic neurons and endocrine cells in gut and pancreas. Evidence exists that the extrapancreatic cells producing and secreting these (neuro)endocrine signals also exhibit a glucose sensor and an ability to integrate nutrient and (neuro)hormonal messages. Similarities in these cellular and molecular pathways provide a basis for a network of coordinated functions between distant cell groups, which is necessary for an appropriate control of nutrient homeostasis. The glucose sensor seems to be a fundamental component of these control mechanisms. Its molecular characterization is most advanced in pancreatic ␤-cells, with important roles for glucokinase and mitochondrial oxidative fluxes in the regulation of ATPsensitive K + channels. Other glucose-sensitive cells in the endocrine pancreas, hypothalamus, and gut were found to share some of these molecular characteristics. We propose that similar metabolic signaling pathways influence the function of pancreatic ␣-cells, hypothalamic neurons, and gastrointestinal endocrine and neural cells.

Physiological and Molecular Characteristics of Rat Hypothalamic Ventromedial Nucleus Glucosensing Neurons

“…In general, GLUT3 and HK-I were the predominant glucose transporter and hexokinase, and their abundance did not differ statistically among the three types of neurons sampled for these mRNA species (Table 3). Despite studies suggesting an important role for GLUT2 as a regulator of neuronal glucosensing in ␤-cells (13,22,34), GLUT2 mRNA was expressed in Ͻ30% of glucosensing neurons and its expression did not differ statistically among the neuronal types (Table 3). The mRNA for insulin-responsive GLUT4 was expressed in about half of all neurons, but there were no significant intergroup differences in expression (Table 3).…”

“…Although GLUT2 is expressed in the brain (3,13,22,28,33), it appears to be located predominantly in astrocytes (34). Most neurons express primarily GLUT3, a high-capacity, low-K m transporter that is largely saturated at physiological brain glucose levels (35).…”

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

“…One strong candidate in this respect is glucokinase (GK) (hexokinase IV or D), which catalyzes the first step in hepatic glucose metabolism and has a very high control strength on hepatic glucose metabolism (3). This isoform of hexokinase is expressed in pancreatic ␤-cells, where it is a critical component of the glucose sensory mechanism for regulation of insulin secretion (4), and in neuroendocrine cells, where it may act as a glucose sensor (5). GK differs in its kinetic properties from the other hexokinase isoforms in having a low affinity for glucose and sigmoidal kinetics, which accounts for its role as a glucose sensor (4,6).…”

Beneficial effects of intercellular interactions between pancreatic islet cells in blood glucose regulation

“…Furthermore, input from exocrine cells (Bertelli et al, 2001;Bishop & Polak, 1997;Wayland, 1997) and glucose-sensing neurons (Schuit et al, 2001) have been suggested. There may thus be more complex communications in the pancreas for glucose homeostasis, which are left for further study.…”