A gene knockout approach in mice to identify glucose sensors controlling glucose homeostasis.
A key aspect of glucose homeostasis is the constant monitoring of blood glucose concentrations by specific glucose sensing units. These sensors, via stimulation of hormone secretion and activation of the autonomic nervous system (ANS), regulate tissue glucose uptake, utilization or production. The best described glucose detection system is that of the pancreatic beta-cells which controls insulin secretion. Secretion of other hormones, in particular glucagon, and activation of the ANS, are regulated by glucose through sensing mechanisms which are much less well characterized. Here I review some of the studies we have performed over the recent years on a mouse model of impaired glucose sensing generated by inactivation of the gene for the glucose transporter GLUT2. This transporter catalyzes glucose uptake by pancreatic beta-cells, the first step in the signaling cascade leading to glucose-stimulated insulin secretion. Inactivation of its gene leads to a loss of glucose sensing and impaired insulin secretion. Transgenic reexpression of the transporter in GLUT2/beta-cells restores their normal secretory function and rescues the mice from early death. As GLUT2 is also expressed in other tissues, these mice were then studied for the presence of other physiological defects due to absence of this transporter. These studies led to the identification of extra-pancreatic, GLUT2-dependent, glucose sensors controlling glucagon secretion and glucose utilization by peripheral tissues, in part through a control of the autonomic nervous system.
Thorens
Bernard
B
Institute of Pharmacology and Toxicology, 27, rue du Bugnon, 1005 Lausanne, Switzerland.
D000818:Animals; D004195:Disease Models, Animal; D005947:Glucose / Q000235:genetics*; D051273:Glucose Transporter Type 2; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000235:genetics*
D051273:Glucose Transporter Type 2; D009004:Monosaccharide Transport Proteins; D005947:Glucose