Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.
Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic beta-cells, hepatocytes and intestine and kidney absorptive epithelial cells of mice. In beta-cells, Glut-2 has been proposed to be active in the control of glucose-stimulated insulin secretion (GSIS; ref. 2), and its expression is strongly reduced in glucose-unresponsive islets from different animal models of diabetes. However, recent investigations have yielded conflicting data on the possible role of Glut-2 in GSIS. Whereas some reports have supported a specific role for Glut-2 (refs 5,6), others have suggested that GSIS could proceed normally even in the presence of low or almost undetectable levels of this transporter. Here we show that homozygous, but not heterozygous, mice deficient in Glut-2 are hyperglycaemic and relatively hypo-insulinaemic and have elevated plasma levels of glucagon, free fatty acids and beta-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, beta-cells display loss of control of insulin gene expression by glucose and impaired GSIS with a loss of first phase but preserved second phase of secretion, while the secretory response to non-glucidic nutrients or to D-glyceraldehyde is normal. This is accompanied by alterations in the postnatal development of pancreatic islets, evidenced by an inversion of the alpha- to beta-cell ratio. Glut-2 is thus required to maintain normal glucose homeostasis and normal function and development of the endocrine pancreas. Its absence leads to symptoms characteristic of non-insulin-dependent diabetes mellitus.
Guillam
M T
MT
Institute of Pharmacology and Toxicology, Lausanne, Switzerland.
Hümmler
E
E
Schaerer
E
E
Yeh
J I
JI
Birnbaum
M J
MJ
Beermann
F
F
Schmidt
A
A
Dériaz
N
N
Thorens
B
B
Wu
J Y
JY
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051274:Glucose Transporter Type 3; D006720:Homozygote; D006943:Hyperglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051274:Glucose Transporter Type 3; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009419:Nerve Tissue Proteins; C495689:Slc2a3 protein, mouse; D005934:Glucagon; D005947:Glucose