Pancreatic islet-specific expression of an insulin-like growth factor-I transgene compensates islet cell growth in growth hormone receptor gene-deficient mice.
Both GH and IGF-I stimulate islet cell growth, inhibit cell apoptosis, and regulate insulin biosynthesis and secretion. GH receptor gene deficiency (GHR(-/-)) caused diminished pancreatic islet cell mass and serum insulin level and elevated insulin sensitivity. Because IGF-I gene expression was nearly abolished in these mice, we sought to determine whether that had caused the islet defects. To restore IGF-I level, we have generated transgenic mice that express rat IGF-I cDNA under the direction of rat insulin promoter 1 (RIP-IGF). Using RNase protection assay and immunohistochemistry, the IGF-I transgene expression was revealed specifically in pancreatic islets of the RIP-IGF mice, which exhibited normal growth and development and possess no abnormalities in glucose homeostasis, insulin production, and islet cell mass. GHR(-/-) mice exhibited 50% reduction in the ratio of islet cell mass to body weight and increased insulin sensitivity but impaired glucose tolerance. Compared with GHR(-/-) alone, IGF-I overexpression on a GHR(-/-) background caused no change in the diminished blood glucose and serum insulin levels, pancreatic insulin contents, and insulin tolerance but improved glucose tolerance and insulin secretion. Remarkably, islet-specific overexpression of IGF-I gene in GHR(-/-) mice restored islet cell mass, at least partially through cell hypertrophy. Interestingly, double-transgenic male mice demonstrated a transient rescue in growth rates vs. GHR(-/-) alone, at 2-3 months of age. Our results suggest that IGF-I deficiency is part of the underlying mechanism of diminished islet growth in GHR(-/-) mice and are consistent with the notion that IGF-I mediates GH-induced islet cell growth.
Guo
Yubin
Y
Fraser Laboratories, Room M3-15, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
Lu
Yarong
Y
Houle
Daniel
D
Robertson
Katie
K
Tang
Zhengyi
Z
Kopchick
John J
JJ
Liu
Ye Lauren
YL
Liu
Jun-Li
JL
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D018149:Glucose Intolerance / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000502:physiology; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011986:Receptors, Somatotropin / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D019076:Transgenes / Q000502:physiology
D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D011986:Receptors, Somatotropin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D007334:Insulin-Like Growth Factor I; D005934:Glucagon