Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In this study, we evaluated the effects of metformin on the growth and differentiation of osteoblasts in culture. Treatment of two osteoblast-like cells (UMR106 and MC3T3E1) with metformin (25-500 microM) for 24 h led to a dose-dependent increase of cell proliferation. Metformin also promoted osteoblastic differentiation: it increased type-I collagen production in both cell lines and stimulated alkaline phosphatase activity in MC3T3E1 osteoblasts. In addition, metformin markedly increased the formation of nodules of mineralization in 3-week MC3T3E1 cultures. Metformin induced activation and redistribution of phosphorylated extracellular signal-regulated kinase (P-ERK) in a transient manner, and dose-dependently stimulated the expression of endothelial and inducible nitric oxide synthases (e/iNOS). These results show for the first time a direct osteogenic effect of metformin on osteoblasts in culture, which could be mediated by activation/redistribution of ERK-1/2 and induction of e/iNOS.
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PMID:Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture. 1656 24

The aim of this study was to evaluate the comparative effects of rosiglitazone and metformin on metabolic parameters in recently diagnosed type 2 Greek diabetic patients. A total of 41 drug-naive individuals, with recently diagnosed type 2 diabetes, were randomized in 3 groups: DIET, diet alone; ROSI, diet plus rosiglitazone; and MET, diet plus metformin. Anthropometric indexes, blood pressure, hematological and biochemical parameters were estimated at baseline and after 18 weeks of treatment. We observed a significant decrease of fasting glucose (FBG) (p<0.001), glycated haemoglobin (HbA1c) (ROSI: p=0.001, MET: p<0.001), homeostasis model assessment for insulin resistance (HOMA-IR) (ROSI: p=0.006, MET: p =0.009) and glutamic pyruvic transaminase (SGPT) (ROSI: p=0.004, MET: p=0.003) in both ROSI and MET groups. Metformin significantly reduced fasting insulin (p=0.04), body weight (p=0.026), body mass index (BMI) (p=0.022), waist circumference (p=0.022) and gamma glutamyl transpeptidase (gamma-GT) (p=0.039), while rosiglitazone decreased blood pressure (systolic: p = 0.05, mean: p = 0.03) and alkaline phosphatase (ALP) (p =0.001) compared to baseline values. Combined intervention with rosiglitazone and diet led to a slight, not significant, weight loss. Rosiglitazone and metformin are equaly effective in controling diabetes, decreasing insulin resistance and improving liver function. However, considering the more favorable effects of metformin on body composition and its documented cost-effectiveness, it seems to be preferable in newly diagnosed Greek diabetic patients.
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PMID:Metabolic effects of rosiglitazone and metformin in Greek patients with recently diagnosed type 2 diabetes. 1821 Jul 65

Advanced glycation endproducts (AGEs) are implicated in the complications of diabetes and ageing, affecting several tissues, including bone. Metformin, an insulin-sensitizer drug, reduces the risk of life-threatening macrovascular complications. We have evaluated the hypothesis that metformin can abrogate AGE-induced deleterious effects in osteoblastic cells in culture. In two osteoblast-like cell lines (UMR106 and MC3T3E1), AGE-modified albumin induced cell death, caspase-3 activity, altered intracellular oxidative stress and inhibited alkaline phosphatase activity. Metformin-treatment of osteoblastic cells prevented these AGE-induced alterations. We also assessed the expression of AGE receptors as a possible mechanism by which metformin could modulate the action of AGEs. AGEs-treatment of osteoblast-like cells enhanced RAGE protein expression, and this up-regulation was prevented in the presence of metformin. Although the precise mechanisms involved in metformin signaling are still elusive, our data implicate the AGE-RAGE interaction in the modulation of growth and differentiation of osteoblastic cells.
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PMID:Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. 1827 53

It is unclear whether metformin, one of the anti-hyperglycemic agents commonly used for type 2 diabetes, could affect bone formation through activation of AMP-activated protein kinase (AMPK). In order to clarify this issue, we investigated the effects of metformin on the differentiation and mineralization of osteoblastic MC3T3-E1 cells as well as intracellular signal transduction. Metformin (50 microM) significantly increased collagen-I and osteocalcin mRNA expression, stimulated alkaline phosphatase activity, and enhanced cell mineralization. Moreover, metformin significantly activated AMPK in dose- and time-dependent manners, and induced endothelial nitric oxide synthase (eNOS) and bone morphogenetic protein-2 (BMP-2) expressions. Supplementation of Ara-A (0.1mM), a specific AMPK inhibitor, significantly reversed the metformin-induced eNOS and BMP-2 expressions. Our findings suggest that metformin can induce the differentiation and mineralization of osteoblasts via activation of the AMPK signaling pathway, and that this drug might be beneficial for not only diabetes but also osteoporosis by promoting bone formation.
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PMID:Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression. 1872 96

Diabetes mellitus is associated with bone loss. Patients with type 2 diabetes are frequently treated with oral antidiabetic drugs such as sulfonylureas, biguanides, and thiazolidinediones. Rosiglitazone treatment has been shown to increase adipogenesis in bone marrow and to induce bone loss. In this study we evaluated the effect of in vivo and in vitro treatment with metformin on bone marrow progenitor cells (BMPCs), as well as the involvement of AMPK pathway in its effects. The in vitro effect of coincubation with metformin and rosiglitazone on the adipogenic differentiation of BMPCs also was studied. In addition, we evaluated the effect of in vivo metformin treatment on bone regeneration in a model of parietal lesions in nondiabetic and streptozotocin-induced diabetic rats. We found that metformin administration both in vivo and in vitro caused an increase in alkaline phosphatase activity, type I collagen synthesis, osteocalcin expression, and extracellular calcium deposition of BMPCs. Moreover, metformin significantly activated AMPK in undifferentiated BMPCs. In vivo, metformin administration enhanced the expression of osteoblast-specific transcription factor Runx2/Cbfa1 and activation of AMPK in a time-dependent manner. Metformin treatment also stimulated bone lesion regeneration in control and diabetic rats. In vitro, metformin partially inhibited the adipogenic actions of rosiglitazone on BMPCs. In conclusion, our results indicate that metformin causes an osteogenic effect both in vivo and in vitro, possibly mediated by Runx2/Cbfa1 and AMPK activation, suggesting a possible action of metformin in a shift toward the osteoblastic differentiation of BMPCs.
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PMID:Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. 1959 6

An association has been previously established between uncompensated diabetes mellitus and the loss of bone mineral density and/or quality. In the present study, we examined the effects of different concentrations of glucose (5.5, 11, 22, and 44 mmol/L) with or without metformin (10-640 micromol/L) on rat primary osteoblasts cultured in an osteogenic medium. With 11 mmol/L glucose, cellular proliferation, alkaline phosphatase (ALP) activity, the number of nodules formed, and calcium deposition in mineralized nodules were increased significantly; intracellular reactive oxygen species (ROS) and apoptosis were slightly reduced, although these reductions were not statistically significant. At higher concentrations of glucose (22 and 44 mmol/L), cellular proliferation, ALP activity, the number of nodules formed, and calcium deposition were greatly reduced; ROS and apoptosis were significantly increased in a dose-dependent manner. Metformin markedly increased cellular proliferation, ALP activity, calcium deposition, and the number of nodules formed and inhibited ROS and apoptosis in all glucose groups. Moreover, we assessed the gene expression levels of Runx2, IGF-1, and IGF-1R. Eleven micromole per liter glucose stimulated Runx2 and IGF-1 expression; 44 mmol/L glucose inhibited Runx2, IGF-1, and IGF-1R expression. Metformin stimulated the expression of Runx2 and IGF-1 in three glucose groups, but it did not affect IGF-1R. In conclusion, our findings suggest that the dual effects of glucose on cell proliferation and development are dose dependent. Metformin not only significantly decreased intracellular ROS and apoptosis, but also had a direct osteogenic effect on osteoblasts at all glucose concentrations, which could be partially mediated via promotion of Runx2 and IGF-1 expression.
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PMID:Metformin reverses the deleterious effects of high glucose on osteoblast function. 1962 13

Metformin is an oral anti-diabetic drug of the biguanide class that is commonly used to treat type 2 diabetes mellitus. This study examined the molecular mechanism for the action of metformin on osteoblast differentiation. Metformin-induced mRNA expression of the osteogenic genes and small heterodimer partner (SHP) in MC3T3E1 cells were determined by RT-PCR and real-time PCR. Metformin increased significantly the expression of the key osteogenic genes, such as alkaline phosphatase (ALP), osteocalcin (OC) and bone sialoprotein (BSP) as well as SHP. Transient transfection assays were performed in MC3T3E1 cells to confirm the effects of metformin on SHP, OC and Runx2 promoter activities. Metformin increased the transcription of the SHP and OC genes, and the metformin effect was inhibited by dominant negative form of AMPK (DN-AMPK) or compound C (an inhibitor of AMPK). The adenoviral overexpression of SHP increased significantly the level of ALP staining and OC production. However, metformin did not have any significant effect on osteogenic gene expression, ALP staining and activity, and OC production in SHP null (SHP-/-) primary calvarial cells. Moreover, upstream stimulatory factor-1 (USF-1) specifically mediated metformin-induced SHP gene expression. In addition, metformin-induced AMPK activation increased the level of Runx2 mRNA and protein. However, USF-1 and SHP were not involved in metformin-induced Runx2 expression. Transient transfection and chromatin immunoprecipitation assays confirmed that metformin-induced SHP interacts physically and forms a complex with Runx2 on the osteocalcin gene promoter in MC3T3E1 cells. These results suggest that metformin may stimulate osteoblast differentiation through the transactivation of Runx2 via AMPK/USF-1/SHP regulatory cascade in mouse calvaria-derived cells.
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PMID:Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2. 2114 83

A report that effects of butyrate on some cells may be mediated by activation of AMP-activated protein kinase (AMPK) prompted this study which examines if other AMPK activators can induce differentiation and inhibit proliferation of colon cancer cells in a manner similar to butyrate. Using induction of alkaline phosphatase as a marker, it was observed that compound C, an AMPK inhibitor, is able to reduce the differentiating effect of butyrate on SW1116 and Caco-2 colon cancer cells. Metformin was observed to be less effective than butyrate in the induction of alkaline phosphatase but was more effective as a growth inhibitor. Phenformin was found to be a more potent growth inhibitor than metformin and both compounds cause acidification of the medium when incubated with colon cancer cells. Combined incubation of 2-deoxyglucose with either of the biguanides prevented the acidification of the medium but enhanced the growth inhibitory effects.
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PMID:Addition of 2-deoxyglucose enhances growth inhibition but reverses acidification in colon cancer cells treated with phenformin. 2137 20

Insulin resistance has an important role in the development of nonalcoholic fatty liver disease (NAFLD) and is involved in both pathological processes: hepatic steatosis and atherosclerosis. Therefore, treatment of NAFLD with insulin sensitizers is likely to have a favorable effect toward hepatic steatosis and cardiovascular outcomes. The present study investigated the effect of metformin on arterial properties, metabolic parameters, and liver function in patients with NAFLD. In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to 1 of 2 groups: Group 1 received daily metformin; group 2 received placebo. Pulse wave velocity (PWV) and augmentation index (AI) were measured using SphygmoCor (version 7.1; AtCor Medical, Sydney, Australia) at baseline and at the end of the 4-month treatment period. Metabolic measures and serum adiponectin levels were determined. Among metformin-treated patients, PWV and AI decreased significantly during the study. Significant declines in fasting glucose, triglyceride, and alkaline phosphatase and a significant increase in high-density lipoprotein cholesterol were observed. Alanine aminotransferase decreased and serum adiponectin increased marginally. In the placebo group, neither PWV nor AI improved significantly during the treatment period. Alanine aminotransferase, aspartate aminotransferase, and adiponectin did not change in the placebo group. Metformin treatment was associated with significant decrease in PWV and AI in NAFLD patients. This beneficial vascular effect was accompanied by an improvement in glucose and lipid metabolism as well as liver enzymes.
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PMID:Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial. 2191 77

Metformin and asymmetric dimethylarginine (ADMA) are structural analogs. They have opposite effects at multiple points on complex signaling pathways that coordinate energy, molecular synthesis, growth, and metabolism with nutrient intake. Excess saturated fats and glucose may initiate the methylation of arginine residues in proteins involved in the transcription of genes mediating inflammation, cell proliferation, apoptosis, and oncogenesis. Free ADMA may appear in the circulation after proteolysis of these proteins when the work of transcription is complete and ADMA subsequently functions as a signaling molecule. In children, ADMA levels are not significantly related to the usual metabolic syndrome risk factors but instead there is a significant association between ADMA and alkaline phosphatase - a marker of normal growth. There is only one direct study that shows that ADMA negates the metabolic effects of metformin. There are no investigations that demonstrate that metformin blocks the effect of ADMA and so this review must be considered hypothesis generating. The potential implications of the metformin-ADMA relationship merit further investigation.
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PMID:The ADMA-Metformin Hypothesis: Linking the Cardiovascular Consequences of the Metabolic Syndrome and Type 2 Diabetes. 2213 30


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