Impaired bone formation resulting from a decline of osteoblast activity has been implicated in the pathogenesis of diabetic osteopenia. We examined the effects of high glucose concentration alone, independent of insulin deficiency, on the growth of a human osteoblast-like cell line (MG-63). Sustained exposure to high glucose for 7 days inhibited cell growth in a concentration-dependent manner up to 49.5 mmol/L, as compared with cells cultured with a normal glucose concentration (5.5 mmol/L) or a high mannitol concentration (an iso-osmolar control). Glucose (49.5 mmol/L) attenuated the increment either in DNA content or in [3H]thymidine incorporation induced by insulin-like growth factor I (IGF-I). The IGF-I-induced increase of ornithine decarboxylase (ODC) activity, which plays an important role in cell growth, was also attenuated. The half-life of ODC protein was not shortened by the high glucose culture, but the intracellular content of putrescine (an end product of ODC) was significantly decreased. These changes did not occur in the high mannitol culture, strongly suggesting a specific effect of glucose. In summary, our observations suggest that a high glucose concentration significantly impairs the proliferative response of osteoblastic cells to IGF-I and that the defective cell function caused by sustained exposure to high glucose levels might contribute to impaired bone formation in patients with diabetic osteopenia.