Pancreatic islet-specific expression of an insulin-like growth factor-I transgene compensates islet cell growth in growth hormone receptor gene-deficient mice. Endocrinology 146: 26022609, 2005. 10 of 20

apoptosis, and regulate insulin biosynthesis and secretion. GH receptor gene deficiency (GHR/) caused diminished pancreatic islet cellmass and serum insulin level andelevated 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 transgenicmice that express rat IGF-I cDNAunder thedirectionof rat insulinpromoter 1 (RIP-IGF).UsingRNase protection assay and immunohistochemistry, the IGF-I trans-gene expression was revealed specifically in pancreatic islets of the RIP-IGF mice, which exhibited normal growth and de-velopment and possess no abnormalities in glucose homeosta-sis, insulin production, and islet cell mass. GHR/ mice ex-hibited 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 overexpres-sion on a GHR/ background caused no change in the dimin-ished blood glucose and serum insulin levels, pancreatic in-sulin 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. Inter-estingly, double-transgenic male mice demonstrated a tran-sient 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. (Endocrinology 146: 2602–2609