Impaired wound healing is a well-documented phenomenon in
diabetes mellitus, yet little is known of the fundamental cause of this pathology. This study examined the effects of
streptozotocin (STZ)-induced diabetes on the healing process using three
wound models: (i) a linear skin incision (tensile strength), (ii) subcutaneously implanted
polyvinyl alcohol sponge
PVAs (
collagen deposition), and (iii)
stainless steel mesh chamber (
TGF-beta,
IGF-I and its
binding proteins, extracellular matrix remodeling
enzymes). RIA specific for
IGF-I revealed that diabetes induced a 42% (
wound fluid) and a 48% (serum) reduction in
IGF-I levels.
IGF-II western
ligand blots found that diabetes produced a marked reduction in the level of a
wound fluid 46 kDa
IGF binding proteins. A proliferation-based bioassay indicates that
TGF-beta level is also reduced in diabetic
wound fluid (55%). Diabetes of graded metabolic severity induced by variable doses of STZ (25 mg-200 mg/kg) showed stepwise reduction in
wound tensile strength and
PVAs collagen deposition. In contrast, zymographic analysis of extracellular matrix
proteases revealed that the diabetic
wound fluid contains increased levels of 21, 69, and 72 kDa
gelatinases. A single dose of
TGF-beta (2 micrograms) in a
collagen vehicle partially reversed the diabetes-related decrease in the tensile strength of standardized incisions. These data support the premise that wound-healing impairment in diabetes is due, at least in part, to a deficiency in
growth factor activity within the
wound environment.