EARLY DIABETES AND ABNORMAL POSTNATAL PANCREATIC-ISLET DEVELOPMENT INMICE LACKING GLUT-2

Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic beta-cells, hepatocytes and intestine and kidney absorptiv e epithelial cells of mice(1). 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-unres ponsive islets from different animal models of diabetes(2-4). However, recent investigations have yielded conflicting data on the possible r ole 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 proc eed normally even in the presence of low(7) or almost undetectable(8) levels of this transporter. Here we show that homozygous, but not hete rozygous, mice deficient in Glut-2 are hyperglycaemic and relatively h ypo-insulinaemic and have elevated plasma levels of glucagon, free fat ty acids and beta-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, beta-cells display loss of control of insulin gen e expression by glucose and impaired GSIS with a loss of first phase b ut preserved second phase of secretion, while the secretory response t o non-glucidic nutrients or to D-glyceraldehyde is normal. This is acc ompanied by alterations in the postnatal development of pancreatic isl ets, evidenced by an inversion of the alpha- to beta-cell ratio. Glut- 2 is thus required to maintain normal glucose homeostasis and normal f unction and development of the endocrine pancreas. Its absence leads t o symptoms characteristic of non-insulin-dependent diabetes mellitus.