METABOLIC RESPONSE OF SHEEP SKIN TO A CHRONIC INFUSION OF A VARIANT OF INSULIN-LIKE GROWTH-FACTOR-I

The effects of a chronic (21-day) skin infusion of a variant of insuli n-like growth factor I (IGF-I) (long-Arg(3)-IGF-I; LR3IGF-I) on short- term (48 h) responses of skin metabolism and 21-day plasma hormone con centration, wool-follicle characteristics and wool production were inv estigated in well-fed castrated Romney sheep. A bilateral arteriovenou s preparation was used to infuse LR3IGF-I continuously into the skin o n one abdominal flank and saline into the other abdominal flank of six sheep; a further six sheep had one flank infused with saline (control s). LR3IGF-I caused an initial (4-24 h) reduction in the plasma concen trations of amino acids, especially tyrosine, valine and lysine, and, after 24 h, significant (P < 0.05) reductions in blood oxygen and plas ma glucose concentrations. After 4 h of LR3IGF-I infusion, there was a significant increase in blood flow (P < 0.05) and oxygen uptake (P < 0.05), and net uptake of amino acids [which was significant (P < 0.05) for valine and phenylalanine] by the LR3IGF-I-infused skin was increa sed. Total uptake of phenylalanine for skin protein synthesis, measure d using [H-3]phenylalanine uptake, was also significantly increased af ter 4 and 24 h of infusion. After 48 h of infusion all LR3IGF-I-depend ent measurements of metabolic parameters had fallen to preinfusion val ues. By day 7 of the 21-day infusion there was a significant (P < 0.05 ) decrease in circulating endogenous IGF-I in plasma of treated sheep compared with that of control sheep, followed by a significant (P < 0. 05) increase between day 7 and 21. Plasma insulin levels followed a si milar pattern. There was no change at any stage of infusion in IGF-bin ding proteins in the plasma of the two LR3IGF-I-infused sheep tested, and it is concluded that LR3IGF-I caused a down-regulation of the type -I IGF-I receptors followed by a rise in endogenous IGF-I concentratio n consequent on lack of feedback regulation. After 21 days of infusion there was no effect of LR3IGF-I on wool-follicle-bulb-cell mitotic ra te, bulb diameter or wool production. In well-fed sheep, LR3IGF-I has an acute effect (4-24 h) on skin metabolism; in part this can be accou nted for by increased blood flow to the skin which enhances nutrient f lux, which in turn increases protein synthesis. However, there are als o effects of LR3IGF-I on skin protein degradation which are not tempor ally related to changes in blood flow and it is concluded that these a re a direct response to the LR3IGF-I. All metabolic responses rapidly return the body to homoeostasis, suggesting a down-regulation of type- I IGF-I receptors in the follicle, and resulting in no long-term chang es in the protein pools of the skin.