[Val12] HRAS downregulates GLUT2 in beta cells of transgenic mice without affecting glucose homeostasis.
Glucose-induced insulin release from pancreatic beta cells depends on the beta-cell metabolism of glucose, which generates intracellular signals for secretion. The beta-cell glucose transporter isotype GLUT2 and the glucose phosphorylating enzyme glucokinase have both been implicated in coupling insulin secretion to extracellular glucose levels. Here we present evidence that a pronounced decrease in beta-cell GLUT2 has no immediate effect on glucose homeostasis. Analysis of transgenic mice overexpressing human [Val12]HRAS oncoprotein under control of the insulin promoter reveals a great reduction in plasma-membrane GLUT2 levels. These mice are nonetheless able to maintain normal fed and fasting plasma glucose and insulin levels for a period of several months. Insulin secretion studied in isolated islets and the perfused pancreas is characterized by a normal incremental response to increasing glucose concentrations. Glucose metabolism, as measured by glucose phosphorylation and oxidation in isolated islets, shows a normal dose dependence on extracellular glucose concentrations. These findings suggest that normal GLUT2 expression in beta cells is not essential for glucose sensing. The transgenic mice provide an experimental system for studying the role of glucose phosphorylation in regulation of insulin release in the absence of GLUT2.
Tal
M
M
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Wu
Y J
YJ
Leiser
M
M
Surana
M
M
Lodish
H
H
Fleischer
N
N
Weir
G
G
Efrat
S
S
D000818:Animals; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D011905:Genes, ras; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*
D007328:Insulin; D009004:Monosaccharide Transport Proteins; D006593:Hexokinase; D005941:Glucokinase; D005947:Glucose