The Influence of Hypoglycaemic Agents on the Growth and Metabolism of Human Endothelial Cells

Petty, R.; Pearson, Jeremy D.

doi:10.1111/j.1464-5491.1992.tb01710.x

Cited by 10 publications

(3 citation statements)

References 42 publications

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“…Different authors have investigated the effects of metformin on the proliferation of other cell types. This biguanide did not influence cell proliferation in cultured arterial smooth muscle cells, human dermal fibroblasts, umbilical artery-derived smooth muscle cells or 3T3 fibroblastic cells (Peuler et al, 1996;Petty and Pearson, 1992). In the present in vitro study, we present data that clearly shows a proliferative effect of metformin on osteoblast-like cells, in a concentration range similar to that used by other authors (Peuler et al, 1996;Petty and Pearson, 1992).…”

Section: Discussionsupporting

confidence: 76%

Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture

Cortizo¹,

Sedlinsky²,

McCarthy³

et al. 2006

European Journal of Pharmacology

217

158

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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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Section: Discussionsupporting

confidence: 76%

Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture

Cortizo¹,

Sedlinsky²,

McCarthy³

et al. 2006

European Journal of Pharmacology

217

158

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“…In agreement with these previous results, Zhen et al [61] demonstrated that metformin, at a similar concentration range, markedly increases proliferation of rat primary osteoblasts using the MTT assay. However, similarly to our results, metformin had no effect on cell proliferation in many other cell types including smooth muscle cells and endothelial cells [62,63]. This inconsistency regarding the proliferative effect of metformin and AICAR in different cell types as well as among various osteoblastic cell lines is still unclear and requires further investigation.…”

Section: Discussionsupporting

confidence: 63%

AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass

Shah

Kola²,

Bataveljic

et al. 2010

Bone

177

155

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Adenosine 5'-monophosphate-activated protein kinase (AMPK), a regulator of energy homeostasis, has a central role in mediating the appetite-modulating and metabolic effects of many hormones and antidiabetic drugs metformin and glitazones. The objective of this study was to determine if AMPK can be activated in osteoblasts by known AMPK modulators and if AMPK activity is involved in osteoblast function in vitro and regulation of bone mass in vivo. ROS 17/2.8 rat osteoblast-like cells were cultured in the presence of AMPK activators (AICAR and metformin), AMPK inhibitor (compound C), the gastric peptide hormone ghrelin and the beta-adrenergic blocker propranolol. AMPK activity was measured in cell lysates by a functional kinase assay and AMPK protein phosphorylation was studied by Western Blotting using an antibody recognizing AMPK Thr-172 residue. We demonstrated that treatment of ROS 17/2.8 cells with AICAR and metformin stimulates Thr-172 phosphorylation of AMPK and dose-dependently increases its activity. In contrast, treatment of ROS 17/2.8 cells with compound C inhibited AMPK phosphorylation. Ghrelin and propranolol dose-dependently increased AMPK phosphorylation and activity. Cell proliferation and alkaline phosphatase activity were not affected by metformin treatment while AICAR significantly inhibited ROS 17/2.8 cell proliferation and alkaline phosphatase activity at high concentrations. To study the effect of AMPK activation on bone formation in vitro, primary osteoblasts obtained from rat calvaria were cultured for 14-17days in the presence of AICAR, metformin and compound C. Formation of 'trabecular-shaped' bone nodules was evaluated following alizarin red staining. We demonstrated that both AICAR and metformin dose-dependently increase trabecular bone nodule formation, while compound C inhibits bone formation. When primary osteoblasts were co-treated with AICAR and compound C, compound C suppressed the stimulatory effect of AICAR on bone nodule formation. AMPK is a alphabetagamma heterotrimer, where alpha is the catalytic subunit. RT-PCR analysis of AMPK subunits in ROS17/2.8 osteoblastic cells and in mouse tibia showed that the AMPKalpha1 subunit is the dominant isoform expressed in bone. We analysed the bone phenotype of 4month-old male wild type (WT) and AMPKalpha1-/- KO mice using micro-CT. Both cortical and trabecular bone compartments were smaller in the AMPK alpha1-deficient mice compared to the WT mice. Altogether, our data support a role for AMPK signalling in skeletal physiology.

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“…Many of the studies on metformin action centred on tissues directly involved in glucose homeostasis, such as skeletal muscle, adipose tissue and liver (Meyer et al, 1967;Wollen & Baily, 1988;Pedersen et al, 1989;Matthaei et al, 1991;Klip et al, 1992;Hundal et al, 1992;Sarabia et al, 1992;Fischer et al, 1995). In recent studies metformin was shown to inhibit the proliferation of human arterial smooth muscle cells and fibroblasts (Koschinsky et al, 1988); in endothelial cells from human umbilical vein, the effect of the drug was variable depending on its concentration (Petty & Pearson, 1992). However, the effect of metformin on the hexose transport system in vascular cells has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Regulation by metformin of the hexose transport system in vascular endothelial and smooth muscle cells

Sasson¹,

Gorowits²,

Joost³

et al. 1996

British J Pharmacology

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1 The effect of the biguanide metformin on hexose transport activity was studied in bovine cultured aortic endothelial (BEC) and smooth muscle cells (BSMC). 2 Metformin elevated the rate of hexose transport determined with 2-deoxyglucose (2DG) in a doseand time-dependent manner in both cell types. Similar ED50 values (0.8-1.0 mM) were determined for the effect of metformin on 2DG uptake in both BEC and BSMC following 24 h exposure to increasing concentrations of metformin, with maximal stimulation at 2 mM. 3 In BEC, metformin increased the hexose transport rate 2-3 fold at all glucose concentrations tested (3.3-22.2 mM). In BSMC incubated with 22.2 mM glucose, metformin elevated the hexose transport -2 fold. The drug was also effective at lower glucose levels, but did not exceed the maximal transport rate observed in glucose-deprived cells. 4 Similar results were obtained when the effect of metformin on hexose transport activity was assessed with the non-metabolizable hexose analogue, 3-O-methylglucose, suggesting that the drug affects primarily the rate of hexose transport rather than its subsequent phosphorylation.5 The metformin-induced increase in hexose transport in BSMC tpeated for 24 h with the drug correlated with increased abundance of GLUTI protein in the plasma membrane, as determined by Western blot analysis. 6 These data indicate that in addition to its known effects on hexose metabolism in insulin responsive tissues, metformin also affects the hexose transport system in vascular cells. This may contribute to its blood glucose lowering capacity in patients with Type 2, non-insulin-dependent diabetes mellitus.

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The Influence of Hypoglycaemic Agents on the Growth and Metabolism of Human Endothelial Cells

Cited by 10 publications

References 42 publications

Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture

Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture

AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass

Regulation by metformin of the hexose transport system in vascular endothelial and smooth muscle cells

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