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Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes

Lu, Yarong
Guo, Yubin
Sun, David
Tang, Zhengyi
LeRoith, Derek
Liu, J. L.
Published in Diabetes. 2004, vol. 53, no. 12, p. 3131-3141
Abstract 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 beta-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 beta-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 beta-cells and potential in combating diabetes.
Keywords AnimalsApoptosisBlood Glucose/metabolismFemaleGene Silencing/ physiologyGlucagon/bloodGlucose Tolerance TestImmunity, Innate/geneticsInsulin/bloodInsulin-Like Growth Factor I/ deficiency/ geneticsIslets of Langerhans/ cytologyMaleMiceMice, Inbred DBAMice, KnockoutPancreas/ physiology
PMID: 15561943
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Research group Types cellulaires pancréatiques pendant l'ontogénèse (522)
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LU, Yarong et al. Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. In: Diabetes, 2004, vol. 53, n° 12, p. 3131-3141. doi: 10.2337/diabetes.53.12.3131 https://archive-ouverte.unige.ch/unige:8867

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Deposited on : 2010-07-12

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