In order to investigate the pathophysiology of the diabetic osteopenia observed in non-insulin-dependent diabetes mellitus, the circulating levels and the bone contents of bone γ-carboxyglutamic acid-containing protein (osteocalcin) were determined in rat models of non-insulin-dependent diabetes mellitus, neonatally streptozotocin-induced rats and in genetic Wistar fatty rats. In Wistar fatty rats the plasma level of osteocalcin was 8.1±0.8 nmol/l, significantly lower than the value of 1 7.3±0.9 nmol/l in their lean littermates (p<0.001). Bone length, bone strength, and weight of powdered bone in Wistar fatty rats were significantly decreased compared to control rats (p<0.001, p<0.02 and p<0.001, respectively). Bone content of osteocalcin per femur in Wistar fatty rats was also significantly decreased compared to controls (p<0.001). In addition, plasma osteocalcin in neonatally streptozotocin-induced diabetic rats was 2.9±0.3 nmol/l, which was also significantly decreased compared to the value of 5.6±0.5 nmol/l in their controls (p<0.001). Since it has been established that the plasma level of osteocalcin is well related to bone formation and turnover, the low plasma values in these animal models suggest that bone formation and turnover are decreased in non-insulin-dependent diabetes mellitus. Low bone formation and turnover are, therefore, postulated to be one of the pathophysiological characteristics of the skeletal tissue in non-insulin-dependent diabetes mellitus, and to be at least in part responsible for the occurrence of this complication.