Based on our clinical observations that patients with insulin-dependent diabetes mellitus (IDDM) are subject to periodontal disease, we developed the hypothesis that hyper- or hypoglycemia might contribute to the pathogenesis of diabetic periodontitis. In this article, experimental facts that substantiate this hypothesis are presented on the basis of our studies and then discussed. Hyperglycemia progressively glycates body proteins, forming advanced glycation end products (AGE), which stimulate phagocytes to release inflammatory cytokines such as TNF-alpha and IL-6. In this context, to understand the effects of hyperglycemic episodes on periodontal health, 24 adolescent IDDM patients were examined for their periodontal status, and 3 of them were found to have periodontitis. Laboratory analyses on these 3 patients revealed that 2 had elevated serum TNF-alpha levels. These results may partly support the current hypothesis of a mechanism of diabetic complications in which abnormal cytokine levels induced by AGE could exacerbate inflammatory responses. In IDDM patients, the diabetes is often accompanied not only by hyperglycemic episodes but also by iatrogenic hypoglycemia. Periodontal ligament cells (PDL) cultured under hyperglycemic conditions were impaired in such biological functions as adhesion and motility, while cells cultured under hypoglycemic conditions (10 mg/dL) gradually dissociated from their anchor and underwent cell death. These phenomena correlated well with the expression profile of fibronectin receptor. Interestingly, these changes due to the different glucose levels were observed more intensively in PDL than in other fibroblastic cells, suggesting that the biological functions of PDL are easily led to impairment by variation or rapid fluctuation of glucose levels. These observations suggest that hyperglycemia could indirectly exacerbate inflammatory tissue destruction through the body's scavenger system against AGE, and that both hyper- and hypoglycemia might directly impair the biological functions of periodontal connective tissues through cell-matrix interactions.