DIFFERENTIAL EXPRESSION AND LOCALIZATION OF INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II IN CUTANEOUS WOUNDS OF DIABETIC AND NONDIABETIC MICE

Insulin-like growth factor (IGF)-I has profound effects on tissue repa ir, IGF-II is felt to exert its influence predominately during fetal d evelopment. The purpose of this study was to localize and quantify the expression of IGF-I and IGF-IL mRNA and protein during early wound he aling in. diabetic and nondiabetic mice. The hypothesis is that IGF-I and IGF-II are upregulated in the healing wound, but their expression is inhibited in diabetics. Full-thickness cutaneous wounds were made o n genetically diabetic (C57BL/ KsJ-db/db) mice and their nondiabetic l ittermates. At various times after wounding, one-half of each wound wa s fixed and paraffin embedded for immunohistochemistry and in situ hyb ridization. The other half was flash-frozen for quantification of IGF mRNA by competitive reverse transcriptase polymerase chain reaction an d protein by radioimmunoassay, IGF-I mRNA rose sharply in nondiabetics at day 3, Expression In diabetic wounds was significantly delayed unt il 14 days after wounding. Even then, diabetic IGF-I mRNA levels were 50% less than those in the nondiabetics at their peak, Although not us ually considered active in adult life, IGF-II mRNA expression was augm ented after wounding, peaking at 3 days in nondiabetics. As with IGF-I , diabetic wounds exhibited a delay in IGF-II mRNA expression, with ma ximal levels at 10 days after wounding. Interestingly, peak concentrat ions of IGF-II mRNA were four times greater in diabetics versus nondia betics. Trends in IGF-I protein expression followed the patterns of mR NA expression. IGF-I levels in nondiabetics were initially double thos e in diabetics and peaked at 5 days. Diabetic wound concentrations of IGF-I did not peak until 21 days after wounding, at which time they ro se to nondiabetic levels. IGF-I and IGF-II proteins mere localized to the advancing epithelial edge, to the epithelial cells of adjacent hai r follicles, and to the granulation tissue of the wounds, IGF-I and IG F-II mRNA expression was noted in the epithelial edge and, in the hair follicles adjacent to the wound, paralleling protein expression. Both IGF-I and IGE-II are up-regulated in the healing wound. A delay in IG F-I and -II presence is noted in the diabetic wound The impairment in tissue repair in diabetic animals is at least partially due to a defic iency in the production of the IGFs.