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ABSTRACT: Both Type I and Type II diabetes mellitus (DM) have been associated with unusually aggressive periodontitis. Accordingly, rat models of both types of DM were used to study (i) mechanisms mediating this systemic/local interaction and (ii) new pharmacologic approaches involving a series of chemically modified tetracyclines (CMTs) that have lost their antimicrobial but retained their host-modulating (e.g., MMP-inhibitory) properties. In vitro experiments on tissues from Type I DM rats demonstrated that several of these CMTs were better matrix metalloproteinase (MMP) inhibitors than was anti-bacterial doxycycline (doxy), except for CMT-5, which, unlike the other MMP inhibitors, was found not to react with zinc. Data from in vivo studies on the same rat model generally supported the relative efficacy of these compounds: the CMTs and doxy were found to inhibit MMP activity, enzyme expression, and alveolar bone loss. To examine other long-term complications such as nephropathy and retinopathy, a Type II (ZDF) model of DM was studied. Treatment of these DM rats with CMT-8 produced a 37% (p < 0.05), 93% (p < 0.001), and 50% (p < 0.01) reduction in the incidence of cataract development, proteinuria, and tooth loss, respectively; whereas the doxy-treated ZDF rats showed little or no effect on these parameters. CMT treatment decreased mortality of the Type II ZDF diabetic animals, clearly indicating that CMTs, but not commercially available antibiotic tetracyclines (TCs), may have therapeutic applications for the long-term management of diabetes.