Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes.
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.
Lu
Yarong
Y
Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
Herrera
Pedro L
PL
Guo
Yubin
Y
Sun
David
D
Tang
Zhengyi
Z
LeRoith
Derek
D
Liu
Jun-Li
JL
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D007113:Immunity, Innate / Q000235:genetics; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000172:deficiency* / Q000235:genetics*; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010179:Pancreas / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D005934:Glucagon