osteoprotegerin and Hyperglycemia

The etiologic role of inflammatory pathways in the development of diabetic complications, especially cardiovascular events, has been established. The anti-inflammatory role of metformin and pioglitazone has been described; however, no study to date has compared the efficacy of these common oral agents in this regard. In this study, the authors aimed to compare the anti-inflammatory properties of pioglitazone and metformin, with respect to their effect on serum concentrations of highly sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG), intercellular adhesion molecule-1 (ICAM-1) and adiponectin.. In an open-label randomized clinical trial, 117 patients with newly diagnosed type 2 diabetes mellitus were visited; 84 fulfilled the inclusion criteria, and were randomly allocated to 2 arms receiving either 1,000 mg/d metformin or 30 mg/d pioglitazone, respectively. Biochemical assessments were made at baseline and the end of the 3 months trial.. Significant reduction in FPG, insulin and HbA1c in women and men of both arms were observed. Log-hsCRP values significantly decreased in both arms. A decreasing, but non-significant trend in log-OPG levels was observed in women of the metformin arm (p=0.063). A greater reduction in log-ICAM levels was identifiable in men receiving pioglitazone compared to the other arm (p=0.008); in addition, the same trend was observed in log-OPG values (p=0.029). Nonetheless, reduction in log-ICAM and log-OPG levels was comparable between the 2 arms. A significant increase in adiponectin was observed in both men and women in the pioglitazone arm (p<0.001), whereas changes were non-significant in the metformin arm.. Remarkably, patients receiving pioglitazone revealed more significant reduction in inflammatory markers.

Topics: Adiponectin; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation Mediators; Intercellular Adhesion Molecule-1; Male; Metformin; Middle Aged; Osteoprotegerin; Pioglitazone; Sex Characteristics; Thiazolidinediones

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Topics: Chronic Disease; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

To investigate early alterations on bone mineral density (BMD) and RANK, RANKL and OPG mRNA expression in peripheral blood leukocytes (PBL) in children and adolescents with type 1 diabetes (T1D) and the relationship with glycemic control and bone biomarkers.. This cross-sectional study included 75 children and adolescents with T1D and 100 individuals without diabetes (normoglycemic-NG) aged 6-20 years old. T1D individuals were considered to have good (T1DG) or poor (T1DP) glycemic control according to the values of HbA1c. Phosphorus, magnesium, total and ionized calcium, osteocalcin, alkaline phosphatase and tartaric-resistant acid phosphatase (TRAP) values were determined in blood samples. BMD was measured by DEXA. RANK, RANKL and OPG mRNA expression was measured in PBL by real-time PCR.. Osteocalcin values were decreased in diabetic groups in comparison to NG group (p<0.05), and a negative correlation with both serum glucose (r=-0.265, p<0.01) and Hb1Ac (r=-0.252, p<0.01) in T1D group was found. BMD was lower in diabetic groups in comparison with NG group (p<0.05) and a negative correlation was observed between BMD and both serum glucose (r=-0.357, p<0.01) and HbA1c (r=-0.351, p<0.01) in T1D group. OPG mRNA expression was significantly increased in T1D and T1DP groups in comparison with NG group (p<0.05). In conclusion, children and adolescents with early onset T1D presented low bone mineral density associated to unsatisfactory glycemic control, increased OPG mRNA expression and low osteocalcin concentration.

Topics: Adolescent; Adult; Alkaline Phosphatase; Biomarkers; Bone Density; Calcium; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Leukocytes, Mononuclear; Male; Osteocalcin; Osteoprotegerin; Phosphorus; RANK Ligand; Real-Time Polymerase Chain Reaction; Receptor Activator of Nuclear Factor-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Young Adult

AIMS. To study the proliferation of osteoblasts and genes expression under normal glucose, high glucose, and metformin (Met). METHODS. MG63 osteoblast-like cells were cultured in osteogenic medium supplemented with normal glucose (glucose 5.5 mmol/L) or high glucose (glucose 16.7 mmol/L) and metformin + high glucose (Met 300  μmol/L + glucose 16.7 mmol/L). Proliferation was detected with CCK-8 assay at days 1, 3, and 7. Real-time PCR and Western blot were performed to compare the expression of collagen I (Col I), osteocalcin (OCN), osteoprotegerin (OPG), receptor activator for NF- κB ligand (RANKL), and metal matrix proteinases 1 and 2 (MMP1, MMP2). Alkaline phosphatase (ALP) activity was also detected at days 6, 12, and 18. RESULTS. Exposure to high glucose inhibited the proliferation of osteoblasts (P < 0.05), with suppressed OCN and OPG. Meanwhile, Col I, RANKL, MMP1, and MMP2 were unaffected. Metformin attenuated the suppression on proliferation with increased expression of Col I, OCN, and OPG, meanwhile suppressing MMP1 and MMP2. High glucose lowered the intracellular ALP, while metformin raised it. Metformin attenuated the downregulation of ALP completely at day 6, partly at day 12, but not at day 18. CONCLUSIONS. Metformin attenuated the suppression effect of high glucose to the osteoblast proliferation and gene expression, more prominently in earlier stage.

Topics: Alkaline Phosphatase; Biomarkers; Cell Line; Cell Proliferation; Collagen Type I; Collagen Type I, alpha 1 Chain; Enzyme Repression; Gene Expression Regulation; Humans; Hyperglycemia; Hypoglycemic Agents; Kinetics; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Metformin; Osteoblasts; Osteocalcin; Osteogenesis; Osteoprotegerin; Protective Agents; Up-Regulation

Periodontal disease (PD) has recently been recognized as the 'sixth' major complication of diabetes but the mechanisms involved in diabetic PD remain unclear. This study was to elucidate the potential bone-sparing effect of insulin in diabetic PD conditions.. The human periodontal ligament (hPDL) cells were obtained from the healthy hPDL tissue and were treated with high concentrations (25 or 45mM) of glucose with or without different concentrations (10(-6), 10(-7) or 10(-8)mM) of insulin.. High concentrations of glucose increased the production of pro-inflammatory cytokines interleukin-1 beta (IL-1β), tumour necrosis factor alpha (TNF-α), Interleukin-6 (IL-6) at both mRNA and protein levels, and receptor activator of NF-кB ligand (RANKL) at mRNA levels in hPDL cells. Insulin treatment alleviated the stimulatory effects of high glucose on pro-inflammatory cytokines and RANKL expression by hPDL cells. Moreover, insulin up-regulated OPG expression and therefore attenuated the reduction of OPG vs. RANKL ratio.. Insulin plays significant roles in modulating the periodontal tissue responses to hyperglycemia, and thus exerts its bone-sparing effects on periodontal tissues via altering the inflammatory cytokines expression in hPDL cells.

Topics: Adolescent; Bone Resorption; Cells, Cultured; China; Cytokines; Enzyme-Linked Immunosorbent Assay; Glucose; Humans; Hyperglycemia; Insulin; Osteoprotegerin; Periodontal Ligament; Real-Time Polymerase Chain Reaction

Hyperglycemia occurs in patients with poorly controlled diabetes mellitus and contributes to bone resorption and increased susceptibility to bacterial infections. Hyperglycemia can incite low-grade inflammation that can contribute to the resorption of bone, especially the periodontal bone. The increased susceptibility to periodontal infections can contribute to bone resorption through the activation of osteoclasts. In this study, the osteoblastic, clonal cell line, MC3T3-E1, was used in an in vitro model of hyperglycemia and lipopolysaccharide-induced reactive oxygen species generation to determine the potential anti-inflammatory effect of 635 nm light-emitting diode (LED) irradiation or whether 635 nm LED irradiation can be a potential anti-inflammatory treatment. LED irradiation of MC3T3-E1 cells stimulated with lipopolysaccharide in a high glucose-containing medium decreased the level of cyclooxygenase gene and protein expression and reduced the level of prostaglandin E2 expression by decreasing the amount of reactive oxygen species generation. LED irradiation also inhibited the osteoclastogenesis in MC3T3-E1 cells by regulating the receptor activator of nuclear factor kappa-B ligand and osteoprotegerin. These findings reveal the mechanisms which are important in the pathogenesis of diabetic periodontitis and highlight the beneficial effects of 635 nm LED irradiation in reducing the adverse effects of diabetic periodontitis.

Topics: 3T3 Cells; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Gene Expression; Glucose; Hyperglycemia; Inflammation; Inflammation Mediators; Light; Lipopolysaccharides; Membrane Proteins; Mice; Osteoblasts; Osteoprotegerin; Phototherapy; RANK Ligand; Reactive Oxygen Species

Human bone marrow mesenchymal stem cells (MSCs) are pleiotrophic cells that differentiate to either adipocytes or osteoblasts as a result of crosstalk by specific signaling pathways including heme oxygenase (HO)-1/-2 expression. We examined the effect of inducers of HO-1 expression and inhibitors of HO activity on MSC differentiation to the osteoblast and following high glucose exposure. MSC cultured in osteogenic medium increased expression of osteonectin, Runt-related transcription factor 2 (RUNX-2), osteocalcin, and alkaline phosphatase. HO-1 expression during differentiation was initially decreased and then followed by a rebound increase after 15 days of culture. Additionally, the effect of HO-1 on osteoblasts appears different to that seen in adipocyte stem cells. On addition of a cobalt compound, the resultant induction of HO-1 decreases adipogenesis. Moreover, glucose (30 mM) inhibited osteoblast differentiation, as evidenced by decreased bone morphogenetic protein (BMP)-2, osteonectin, osteocalcin, and osteoprotegerin (OPG). In contrast, MSC-derived adipocytes were increased by glucose. Increased HO-1 expression increased the levels of osteonectin, OPG, and BMP-2. Inhibition of HO activity prevented the increase in osteonectin and potentiated the decrease of osteocalcin and OPG in cells exposed to high glucose levels. Furthermore, targeting HO-1 expression increased pAMPK and endothelial nitric oxide synthase (eNOS) and restored osteoblastic markers. Our findings suggest that targeting HO-1 gene expression attenuates the hyperglycemia-mediated decrease in MSC-derived osteoblast differentiation. Finally, the mechanism underlying the HO-1-specific cell effect on osteoblasts and adipocytes is yet to be explored. Thus, the targeting of HO-1 gene expression presents a portal to increase osteoblast function and differentiation and attenuate osteoporosis by promoting bone formation.

Topics: Adipogenesis; AMP-Activated Protein Kinases; Biomarkers; Bone Diseases, Metabolic; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Hyperglycemia; Mesenchymal Stem Cells; Nitric Oxide Synthase Type III; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Osteoprotegerin; RNA, Messenger; Time Factors

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor-deficient mice synthetizing only apolipoprotein B100 (LDLR(-/-) ApoB(100/100)). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR(-/-)ApoB(100/100) mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR(-/-)ApoB(100/100) controls. In addition, old IGF-II/LDLR(-/-)ApoB(100/100) mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR(-/-)ApoB(100/100) mice did not differ from LDLR(-/-)ApoB(100/100) controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.

Topics: Animals; Apolipoproteins B; Atherosclerosis; Blood Glucose; Calcinosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Hypercholesterolemia; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor II; Lipids; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoprotegerin; Receptors, LDL