There is ample evidence for insulin-like growth factor I (IGF I) as an in vitro growth-promoting hormone. Yet, evidence for IGF I as the in vivo growth-promoting hormone is scant. In dogs belonging to breeds differing in body size, the circulating IGF I levels increase with body size. Within one breed, the Poodle, comprising normal-sized dogs (Standard) and the two small-sized variants, the Miniatures and the Toy, there is a highly significant correlation with body size and Standards exhibit a six-fold higher mean circulating IGF I level than Toys, yet the mean GH secretory capacity is similar in all variants. These results suggest the following hypotheses: 1) There is a dose-response relationship between body size and IGF I levels rather than between body size and GH-secretory capacity, 2) the difference in circulating IGF I levels is due to variations in the sensitivity of IGF I producing/secretion sites to the action of GH. The objective of this project is to characterize in depth this naturally occurring model of IGF I deficiency. In 15 Standard and 15 Toy Poodles the following aspects will be studied: 1) Plasma GH and IGF I levels during growth, 2) the 24-hour secretion patterns of GH, the """"""""biological"""""""" activity of GH, and the plasma half-life, metabolic clearance rates, volumes of distribution of GH and IGF I and serum binding properties of IGF I, 3) IGF I receptors in fibroblasts derived from Standard and Toy Poodles, 4) the IGF I production rate, a) in fibroblasts in vitro in response to GH and platelet derived growth factor and b) in the intact animal before and after hypophysectomy by assessing IGF I changes in peripheral plasma, and by assessing the hepatic IGF I production rate in vivo, 5) the insulin sensitivity and the increase in free fatty acids in response to GH administration before and after hypophysectomy. The results gained should provide further indirect evidence for IGF I as an in vivo growth-promoting hormone. Long-term objectives include 1) studies in the toy poodle or tissues derived from these dogs (fibroblasts) which may provide clues as to the mode whereby GH induces IGF I synthesis, 2) breeding studies which should reveal the genetic background of the sensitivity of the IGF I producing sites to GH, and 3) studies pertaining to the in vivo effects of IGF I on growth and on several tissues, and the effects of IGF I on wound/fracture repair in these dogs.
| Gupta, S; Rifici, V; Crowley, S et al. (1992) Interactions of LDL and modified LDL with mesangial cells and matrix. Kidney Int 41:1161-9 |
