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

Nature Genetics volume 17, pages 327330 (1997) | Download Citation

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Abstract

Glut-2 is a low-affinity transporter present in the plasma membrane of pancreatic (β-cells, hepatocytes and intestine and kidney absorptive epithelial cells of mice1. In β-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 diabetes24. 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 low7 or almost undetectable8 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 β-hydroxybutyrate. In vivo, their glucose tolerance is abnormal. In vitro, (β-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 α- to (β-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.

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Affiliations

  1. Institute of Pharmacology and Toxicology, 27, rue du Bugnon, 1005 Lausanne, Switzerland.

    • Marie-Thérèse Guillam
    • , Edith Hümmler
    • , Elisabeth Schaerer
    • , Nathalie Dériaz
    •  & Bernard Thorens
  2. Department of Family Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan.

    • J.-Y Wu
  3. Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148, USA

    • Morris J. Birnbaum
  4. Swiss Institute for Experimental Research on Cancer, Ch. des Boveresses, 1066 Epalinges, Switzerland

    • Friedrich Beermann
    •  & Andrea Schmidt

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Correspondence to Bernard Thorens.

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DOI

https://doi.org/10.1038/ng1197-327