Because of its role in cellular energetics and brain function the concentration of glucose in the blood is constantly monitored to adapt cellular and whole body physiology to maintain glycaemia at ∼5 mmol/l.

Glucose is a major source of metabolic energy for most cells of the body and is of critical importance for the brain. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. In humans, inactivating mutations in GLUT2 cause Fanconi–Bickel syndrome, which is characterised by hepatomegaly and kidney disease defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms.

The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes.

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