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Diabetes 53:3131-3141, 2004
© 2004 by the American Diabetes Association, Inc.
Pancreatic-Specific Inactivation of IGF-I Gene Causes Enlarged Pancreatic Islets and Significant Resistance to Diabetes
1 Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
2 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
3 Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland
4 Division of Endocrine and Metabolic, E-Institutes of Shanghai Universities, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai, China
The dogma that IGF-I stimulates pancreatic islet growth has been challenged by combinational targeting of IGF or IGF-IR (IGF receptor) genes as well as ß-cell–specific IGF-IR gene deficiency, which caused no defect in islet cell growth. To assess the physiological role of locally produced IGF-I, we have developed pancreatic-specific IGF-I gene deficiency (PID) by crossing Pdx1-Cre and IGF-I/loxP mice. PID mice are normal except for decreased blood glucose level and a 2.3-fold enlarged islet cell mass. When challenged with low doses of streptozotocin, control mice developed hyperglycemia after 6 days that was maintained at high levels for at least 2 months. In contrast, PID mice only exhibited marginal hyperglycemia after 12 days, maintained throughout the experiment. Fifteen days after streptozotocin, PID mice demonstrated significantly higher levels of insulin production. Furthermore, streptozotocin-induced ß-cell apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL] assay) was significantly prevented in PID mice. Finally, PID mice exhibited a delayed onset of type 2 diabetes induced by a high-fat diet, accompanied by super enlarged pancreatic islets, increased insulin mRNA levels, and preserved sensitivity to insulin. Our results suggest that locally produced IGF-I within the pancreas inhibits islet cell growth; its deficiency provides a protective environment to the ß-cells and potential in combating diabetes.
Address correspondence and reprint requests to Dr. Jun-Li Liu, Fraser Laboratories, Room M3-15, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, QC H3A 1A1, Canada. E-mail: jun-li.liu{at}mcgill.ca
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