Pancreatic Islet-Specific Expression of an Insulin-Like Growth Factor-I Transgene Compensates Islet Cell Growth in Growth Hormone Receptor Gene-Deficient Mice

Abstract

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.

Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

“…Serum glucagon levels were also reduced, although not as severely as insulin levels (Liu et al 2004). Maintenance of near normal glucose levels appeared to result from an increase in tissue sensitivity to insulin Liu et al 2004;Guo et al 2005). However, GHR/BP j/j mice displayed significant impairment of glucose tolerance in intraperitoneal glucose tolerance tests, suggesting reduced synthesis or release of insulin Guo et al 2005).…”

“…One theory relates decreased insulin exposure and increased longevity (Parr 1997). Evaluations of glucose homeostasis in the GHR/BP j/j mice revealed severely depressed levels of circulating insulin but insignificant to moderate decreases in glucose levels in comparison to +/+ mice Dominici et al 2000;Liu et al 2004;Guo et al 2005). Serum glucagon levels were also reduced, although not as severely as insulin levels (Liu et al 2004).…”

“…Maintenance of near normal glucose levels appeared to result from an increase in tissue sensitivity to insulin Liu et al 2004;Guo et al 2005). However, GHR/BP j/j mice displayed significant impairment of glucose tolerance in intraperitoneal glucose tolerance tests, suggesting reduced synthesis or release of insulin Guo et al 2005). Pancreatic islet size and b-cell mass were reduced, apparently due to decreases in proliferation and cell growth (Liu et al 2004;Guo et al 2005).…”

“…However, GHR/BP j/j mice displayed significant impairment of glucose tolerance in intraperitoneal glucose tolerance tests, suggesting reduced synthesis or release of insulin Guo et al 2005). Pancreatic islet size and b-cell mass were reduced, apparently due to decreases in proliferation and cell growth (Liu et al 2004;Guo et al 2005). Significant changes in glucose and insulin levels as well as reduced pancreatic islet size were seen in 10-day-old GHR/BP j/j pups, when growth retardation was relatively mild (Liu et al 2004).…”

Metabolicheskie effekty gormona rosta

“…Изолированное восстановление экспрессии ИФР-1 в поджелудочной железе у таких мышей не сопровож далось увеличением инсулинового ре-зерва, хотя была отмечена нормализация количества островковых клеток [11].…”