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β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass

Nature Genetics volume 31, pages 111–115 (2002)Cite this article

Abstract

Regulation of glucose homeostasis by insulin depends on the maintenance of normal β-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function1,2, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on β-cells3,4,5,6. Igf1 has been shown to influence β-cell apoptosis7, and both Igf1 and Igf2 increase islet growth8,9; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r+/− ) are bred with mice lacking insulin receptor substrate 2 (Irs2−/−), the resulting compound knockout mice show a reduction in mass of β-cells11 similar to that observed in pancreas of Igf1r−/− mice (ref. 11), suggesting a role for Igf1r in growth of β-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium12 or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a β-cell–specific knockout of Igf1r (βIgf1r−/−). These mice show normal growth and development of β-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in β-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet β-cell development, but participates in control of differentiated function.

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Figure 1: Conditional Igf1r targeting allows β-cell–specific Igf1r knockout.
Figure 2: βIgf1r−/− islets show normal morphology and insulin content but have blunted glucose-stimulated insulin secretion and loss of Igf1-mediated suppression of insulin secretion.
Figure 3: βIgf1r−/− mice lack glucose-stimulated, acute-phase insulin secretion and have glucose intolerance.
Figure 4: Reduced steady-state mRNA levels of islet-enriched transcription factors and glucose-sensing proteins in βIgf1r−/− islets.

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Acknowledgements

We thank R.L. Quinn and E. Fletcher for assistance with animal care, and J. Marr for secretarial assistance. We thank K.C. Hayes and staff at the Brandeis Animal Facility (Waltham) for housing and maintenance of the mouse colonies. This study was supported by a Clinician Scientist Development Award from the National Institutes of Health (to R.N.K.), grants from the NIH (to C.R.K. and M.S.), the DERC grant (Specialized Assay Core & Advanced Microscopy Core, Joslin Diabetes Center) and a grant from the Juvenile Diabetes Research Foundation.

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Authors and Affiliations

  1. Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, 02215, Massachusetts, USA

    Rohit N. Kulkarni, Umut Ozcan & C. Ronald Kahn

  2. Inserm U515, Croissance, Différenciation et Processus Tumoraux, Hôpital Saint-Antoine, Paris, France

    Martin Holzenberger

  3. Laboratory of Metabolic Diseases, The Rockefeller University, New York, New York, USA

    David Q. Shih & Markus Stoffel

  4. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Mark A. Magnuson

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  1. Rohit N. Kulkarni
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Correspondence to Rohit N. Kulkarni.

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Kulkarni, R., Holzenberger, M., Shih, D. et al. β-cell–specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nat Genet 31, 111–115 (2002). https://doi.org/10.1038/ng872

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