Background. Growth-promoting polypeptides, including insulin-like growth factor-I (IGF-I), orchestrate different biochemical events that culminate in the restoration of functional integrity of wounded skin. The nonhealing cutaneous wound is a well-documented phenomenon in experimental and clinical diabetes. Accordingly, we undertook this study to ascertain whether diabetes impairs the healing process by suppressing the wound microenvironmental IGF-I system (eg, IGF-I; IGF-I receptor [IGF-I R]; and IGF-I binding protein [IGF- BP3]). Methods. The induction of diabetes was achieved by the intravenous injection of streptozotocin at a dose of 55 mg/kg. Subcutaneously implanted polyvinyl alcohol sponge and stainless steel mesh chamber models were used to study wound healing. Nondiabetic and diabetic animals received, respectively, subcutaneous 30-day time-release pellets of glucocorticoid (200 mg) and mifepristone (RU-486, 25 mg). Corresponding control animals received placebo pellets. Polyvinyl alcohol sponge and wound fluid expression of the IGF-I system were evaluated by using ligand blotting, radioimmunoassay, and reverse transcriptase polymerase chain reaction-based techniques. Results. Polyvinyl alcohol sponge contents of messenger RNA (mRNA) transcripts encoding for IGF- I, IGF-I R, and IGF-BP3 were reduced in diabetic and glucocorticoid-treated control animals. A similar pattern of changes in protein levels of IGF-I and IGF-BP3 occurred in wound fluid collected from these animals. Partial normalization of the associated hyperglycemic and hypercortisolemic states of diabetes with insulin (hyperglycemia) and the glucocorticoid receptor blocker RU-486 (hyporcortisolemia) ameliorated the diabetes-related decrease in the IGF-I system during wound healing. Conclusions. The current data, together with data garnered from the literature, support the concept that the state of hyporcortisolemia in diabetes mellitus impairs the healing process, at least in part, by suppressing the wound microenvironmental IGF-I system. Confirmation regarding this premise awaits further investigation.