tetracycline and Hyperglycemia

Diabetes is a chronic hyperglycemic disorder and results in a tendency to develop osteoporosis. Furthermore, the delayed healing of tooth-extraction wounds, the activation of alveolar resorption and the suppressed formation of bone around implants are difficult for dentists to resolve. In diabetes, insulin-like growth factor I (IGF-I) appears to enhance the differentiation of osteoblasts and to activate the mineralization of bone. Hence, the aim of this study was to investigate the effects of insulin-like growth factor I on the remodeling of alveolar bone in diabetic rats.. Diabetes was induced in 40 male Sprague-Dawley rats by intravenous administration of alloxan. The teeth of the rats were extracted to investigate remodeling of alveolar bone. Insulin-like growth factor I was administered, via intraperitoneal injection, to diabetic rats following tooth extraction. The remodeling of alveolar bone was determined using radiographic data, histological analyses and tetracycline fluorescence labeling.. Compared with the control group, diabetes decreased alveolar bone formation. The height of alveolar bone and the bone-formation rate was significantly lower in the untreated diabetic group than in the control group or in the treated rats. Treatment with insulin-like growth factor I not only regulated abnormal blood glucose levels but also increased the height of the alveolar bone and increased the bone-formation rate relative to the results in diabetic animals. Furthermore, the expression of glucose transporter-1, the main transporter of glucose, was changed by hyperglycemia.. The results suggest that insulin-like growth factor I treatment increases the volume of newly formed bone following tooth extraction and normalizes the expression of glucose transporter-1 in diabetic rats, which may play an important role in bone formation and mineralization.

Topics: Alloxan; Alveolar Process; Animals; Blood Glucose; Bone Density; Bone Remodeling; Calcification, Physiologic; Diabetes Mellitus, Experimental; Fluorescent Dyes; Glucose Transporter Type 1; Hyperglycemia; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Insulin-Like Growth Factor I; Male; Osteoblasts; Osteogenesis; Rats; Rats, Sprague-Dawley; Tetracycline; Tooth Extraction; Tooth Socket

Hyperglycemia is a crucial factor in the development of diabetic nephropathy. We previously showed that high glucose upregulates thrombospondin 1 (TSP1)-dependent transforming growth factor (TGF)-beta activation by altering cGMP-dependent protein kinase (PKG) activity as a result of decreased nitric oxide signaling. In the present study, we showed that high glucose concentrations significantly reduced endogenous PKG activity. To further examine the mechanisms by which PKG regulates TSP1 expression and TSP1-dependent TGF-beta activation, we generated stably transfected rat mesangial cells (RMCs) with inducible expression tetracycline-induced gene expression of the catalytic domain of PKG. After tetracycline induction, the catalytic domain of PKG is expressed as a cGMP-independent active kinase. Expression of the catalytic domain prevented high glucose-mediated increases in transcription of the TSP1 gene with no alteration in TSP1 mRNA stability. Glucose stimulation of TSP1 protein expression and TGF-beta bioactivity were also downregulated. TGF-beta-dependent fibronectin and type IV collagen expression under high glucose conditions were significantly reduced upon catalytic domain expression in transfected RMCs. These results show that constitutively active PKG inhibits the fibrogenic potential of high glucose through repression of TSP1-dependent TGF-beta bioactivity, suggesting that gene transfer of the catalytic domain of PKG might provide a new strategy for treatment of diabetic renal fibrosis.

Topics: Animals; Anti-Bacterial Agents; Catalytic Domain; Cell Line; Collagen; Cyclic GMP-Dependent Protein Kinases; Diabetic Nephropathies; Enzyme Activation; Extracellular Matrix; Fibronectins; Gene Expression Regulation, Enzymologic; Glomerular Mesangium; Glucose; Humans; Hyperglycemia; Rats; Tetracycline; Thrombospondin 1; Transfection; Transforming Growth Factor beta

Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Doxycycline; Female; Genotype; Hippocampus; Huntingtin Protein; Huntington Disease; Hyperglycemia; Immunohistochemistry; Male; Mice; Minocycline; Nerve Tissue Proteins; Nuclear Proteins; Organ Culture Techniques; Peptides; Phenotype; Postural Balance; Tetracycline

A tetracycline (doxycycline) was administered daily by oral intubation to adult diabetic rats to assess the effect on skeletal tissue; the rationale--osteopenia is a complication of diabetes and tetracyclines (TCs) were recently found to inhibit pathologic collagen loss (e.g. in diabetic rat skin) by a mechanism independent of their antimicrobial efficacy. Osteopenia was induced by streptozotocin-diabetes as indicated by physical (e.g. specific gravity), chemical (e.g. calcium (Ca) content) and ultrastructural characteristics of the femurs, and TC administration (including treatment with a chemically-modified non-antimicrobial analog) appeared to prevent the development of the bone deficiency disease without affecting the severity of hyperglycemia.

Topics: Administration, Oral; Animals; Bone Diseases, Metabolic; Diabetes Mellitus, Experimental; Doxycycline; Femur; Hyperglycemia; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Streptozocin; Tetracycline

Topics: Administration, Topical; Adult; Diabetes Complications; Diabetes Mellitus; Diabetic Coma; Foot Dermatoses; Gangrene; Humans; Hyperglycemia; Insulin; Ischemia; Skin Ulcer; Tetracycline; Tetracyclines