Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2

Abstract

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.

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

“…GLUT2 is required for glucose sensing, normal glucose homeostasis and insulin secretion [44]. Glut2 was one of the most highly regulated candidate genes in activin A-or follistatin-treated islets and MIN6 cells.…”

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

“…Before we began this study, we considered that, because Glut2 −/− pups are viable until weaning [26], GLUT2 is not necessary for embryonic or fetal development. Therefore, as explained above, its presence or absence would appear to have little consequence during non-diabetic pregnancy, and so the expression of Glut2 may be vestigial.…”

“…Mice carrying a Glut2 knockout allele [26] on a 129/SvJ background were used to generate embryos that were GLUT2-deficient. The Glut2 knockout strain was originally generated on a mixed C57Bl/6J×129/Sv background.…”

“…Postnatally, GLUT2 is produced by pancreatic beta cells, hepatocytes, intestine and kidney-tissues that must transport glucose with high efficiency when its concentration is high, for example after intestinal absorption of nutrients following feeding [11,25]. GLUT2 is essential for glucose-stimulated insulin release, and also regulates glucose sensing by extrapancreatic tissues [26,27]. However, the early embryo is not normally exposed to glucose concentrations approaching the K m of the GLUT2 transporter.…”

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

“…GLUT2 is also the major glucose transporter in pancreatic ß‐cells, where its genetic inactivation impairs glucose uptake and suppresses glucose‐stimulated insulin secretion. GLUT2 −/− mice die at around the weaning period, and transgenic expression of another glucose transporter, GLUT1, in β‐cells (RIPGlut1;GLUT2 −/− ) restores normal glucose‐stimulated insulin biosynthesis (Bady et al, 2006; Guillam et al, 1997; Thorens et al, 2000). …”