Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion.
GLUT2-null mice are hyperglycemic, hypoinsulinemic, hyperglucagonemic, and glycosuric and die within the first 3 weeks of life. Their endocrine pancreas shows a loss of first phase glucose-stimulated insulin secretion (GSIS) and inverse alpha to beta cell ratio. Here we show that reexpression by transgenesis of either GLUT1 or GLUT2 in the pancreatic beta cells of these mice allowed mouse survival and breeding. The rescued mice had normal-fed glycemia but fasted hypoglycemia, glycosuria, and an elevated glucagon to insulin ratio. Glucose tolerance was, however, normal. In vivo, insulin secretion assessed following hyperglycemic clamps was normal. In vitro, islet perifusion studies revealed that first phase of insulin secretion was restored as well by GLUT1 or GLUT2, and this was accompanied by normalization of the glucose utilization rate. The ratio of pancreatic insulin to glucagon and volume densities of alpha to beta cells were, however, not corrected. These data demonstrate that 1) reexpression of GLUT1 or GLUT2 in beta cells is sufficient to rescue GLUT2-null mice from lethality, 2) GLUT1 as well as GLUT2 can restore normal GSIS, 3) restoration of GSIS does not correct the abnormal composition of the endocrine pancreas. Thus, normal GSIS does not depend on transporter affinity but on the rate of uptake at stimulatory glucose concentrations.
Thorens
B
B
Institute of Pharmacology and Toxicology, 27, rue du Bugnon, CH-1005 Lausanne and Swiss Institute for Experimental Research on Cancer, Ch. des Boveresses, 1066 Epalinges, Switzerland. Bernard.Thorens@ipharm.unil.ch
Guillam
M T
MT
Beermann
F
F
Burcelin
R
R
Jaquet
M
M
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D005934:Glucagon / Q000097:blood / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D012333:RNA, Messenger / Q000032:analysis; D014018:Tissue Distribution
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D005934:Glucagon; D005947:Glucose