We previously reported that after a bacteria-induced wound in the scalp, type 2 diabetic (db/db) mice had higher levels of apoptosis of fibroblasts and bone-lining cells that are critical for healing compared with normoglycemic controls. To investigate mechanisms by which this might occur, RNA profiling and caspase activity was measured after inoculation of Porphyromonas gingivalis. Diabetes caused a more than twofold induction of 71 genes that directly or indirectly regulate apoptosis and significantly enhanced caspase-8, -9, and -3 activity. The functional significance of diabetes-induced apoptosis was studied by treating diabetic mice with a pancaspase inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone). Inhibiting apoptosis significantly improved several parameters of healing, including fibroblast density, enhanced mRNA levels of collagen I and III, and increased matrix formation. Improvements were also noted in bone, with an increase in the number of bone-lining cells and new bone formation. Thus, diabetes-enhanced apoptosis represents an important mechanism through which healing is impaired, and this can be explained, in part, by diabetes-increased expression of proapoptotic genes and caspase activity. Diabetes 55: 487-495, 2006 D iabetes affects Ͼ18 million Americans and causes significant morbidity and mortality (1). Diabetes complications that are debilitating include poor wound healing (2). The impaired healing affects the resolution of both acute and chronic wounds (3), which represent a significant health care burden in the U.S. As an example, ulcerations of the lower extremities, which heal poorly in diabetic patients, are a significant cause of hospitalization and are usually the first step in limb amputation (4). Of the 18 million people in the U.S. with diabetes, 20% will at some point develop ulcers that heal poorly (5,6).Healing of wounds in diabetes is characterized by delays in the repair process as well as a decrease in the tensile strength of healing wounds (3,7). Deficiencies in fibroblast numbers have been reported to represent an important aspect of delayed wound healing in diabetes (8 -10). It has been suggested that aberrant growth factor expression, altered inflammatory responses, or enhanced glycosylation of proteins may be involved (8,11,12). Alternatively, enhanced apoptosis may decrease fibroblast numbers, which could contribute to impaired diabetic healing (13). Whatever the cause, the generation and maintenance of a sufficient number of fibroblasts to participate in wound repair may be particularly important in diabetes. Humans with type 1 diabetes have impaired osseous healing (14). That this may be caused by reduced bone formation is supported by findings that serum osteocalcin levels are significantly lower in type 1 diabetic patients (15), and there is a reduction in osteoblast numbers and function (16 -18). In type 2 diabetes, there is evidence of diminished bone formation, increased risk of fracture, and impaired healing, but the mechanisms are not we...