The United Kingdom Prospective Diabetes Study (UKPDS) found that metformin reduces macrovascular complications in type 2 diabetic patients. To investigate the mechanisms involved we examined the effect of metformin on monocyte adhesion to human endothelial cells (ECs) induced by advanced glycation end-products (AGE), and on monocyte differentiation into macrophages and foam cell formation. Treatment of human ECs with AGEs (100 µg/ml) for up to 12 hours significantly increased human monocyte adhesion. Pre-treatment of the cells with metformin (0.1—2.5 µg/ml) inhibited AGE-induced monocyte adhesion and expression of endothelial cell adhesion molecules. In culture, human monocytes spontaneously differentiated into macrophages, as indicated by phenotypic changes, and increased expression of lectin-like oxidised low-density lipoprotein (LDL) receptor and scavenger receptor type A. Incubation of these cells in the presence of metformin decreased expression of all of these parameters. Metformin also inhibited foam cell formation induced by minimally modified LDL. Overall, these results suggest new mechanisms by which metformin may reduce the risk of vascular complications in patients with type 2 diabetes.
Howard BV, Rodriguez BL, Bennett PH et al. Prevention Conference VI: Diabetes and Cardiovascular disease: Writing Group I: epidemiology. Circulation2002;105:e132-7.
2.
UK Prospective Diabetes Study (UKPDS) Group.Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk for complications in patients with type 2 diabetes (UKPDS 33). Lancet1998 ;352:837-53.
3.
UK Prospective Diabetes Study (UKPDS) Group.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet1998;352:854-65.
4.
Cusi K., DeFronzo RAMetformin: a review of its metabolic effects. Diabetes Reviews1998;6:89-131.
5.
Nagi DK, Yudkin JSEffects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care1993;16:653-5.
6.
Uehara MH, Kohlmann NE, Zanella MT, Ferreira SRMetabolic and haemodynamic effects of metformin in patients with type 2 diabetes mellitus and hypertension. Diabetes Obes Metab2001;3:319-25.
7.
Chu NV, Kong APS, Kim DD et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care2002;25:542;9. troglitazone on cardiovascular risk factors in patients with type 2 dia
8.
Grant PJThe effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabetes Metab1991 ;17:168-73.
9.
Pavlovic D., Kocic R., Kocic G. et al. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes Metab2000;2:251-6.
10.
Tessier D., Maheux P., Khalil A., Fulop T.Effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes. Metabolism1999 ;48:897-903.
Mather KJ, Verma S., Anderson TJImproved endothelial function with metformin in type 2 diabetes mellitus . J Am Coll Cardiol2001;37: 1344-50.
13.
Carantoni M. , Abbasi F., Chu L. et al. Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM . Diabetes Care1997;20:1462-6.
14.
Desfaits AC , Serri O., Renier G.Normalization of plasma lipid peroxides, monocyte adhesion, and tumor necrosis factor-α production in NIDDM patients after gliclazide treatment. Diabetes Care1998;21:487-93.
15.
Schmidt AM, Hori O., Chen JX et al. Advanced glycation end products interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: a potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest1995;96:1395-403.
16.
Desfaits AC , Serri O., Renier G.Gliclazide reduces the induction of human monocyte adhesion to endothelial cells by glycated albumin . Diabetes Obes Metab1999;1:113-20.
17.
Kunt T., Forst T., Wilhem A. et al. The influence of advanced glycation endproducts (AGE) on the expression of human endothelial adhesion molecules. Exp Clin Endocrinol Diabetes1998;106:183-8.
18.
Mentzer SJ, Guyre PM, Burakoff SJ, Faller DVSpontaneous aggregation as a mechanism for human monocyte purification . Cell Immunol1986;101:312-19.
19.
Bath PMW , Booth RFG , Hassal DGMonocyte-lymphocyte discrimination in a new microtitre-based adhesion assay . J Immunol Methods1989;118:59-65.
20.
Bradford MMA rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem1976;72:248-54.
21.
Chomczynski P., Sacchi N.Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem1987;162:156-9.
22.
Vosper H., Patel L., Graham TL et al. The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. J Biol Chem2001;276:44258-65.
23.
Gough PJ, Greaves DR, Suzuki H. et al. Analysis of macrophage scavenger receptor (SR-A) expression in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol1999;19:461-71.
24.
Yoshida H., Kondratenko N., Green S., Steinberg D., Quehenberger O.Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor . Biochem J1998;334:9-13.
25.
Jungi TW, Miserez R., Brcic M., Pfister H.Change in sensitivity to lipopolysaccharide during the differentiation of human monocytes to macrophages in vitro. Experientia1994;50:110-14.
26.
Friedman EAAdvanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications. Diabetes Care1999; 22:B65-B71.
27.
Singh R., Barden A., Mori T. et al. Advanced glycation end-products: a review. Diabetologia2001;44:129-46.
28.
Vlassara H. , Palace MRDiabetes and advanced glycation endproducts . J Intern Med2002;251:87-101.
29.
Krieglstein CF, Granger DNAdhesion molecules and their role in vascular disease. Am J Hypertens2001;14:44-54.
30.
Faruqi RM, Poptic EJ, Faruqi TR, de la Motte C., DiCorleto P.Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced Eselectin and VCAM-1 expression. Am J Physiol1997;273:817-26.
31.
Detaille D. , Guigas B., Leverve X., Wiernsperger N., Devos P.Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function. Biochem Pharmacol2002;63:1259-72.
32.
Chen XL, Panek K., Rembold CMMetformin relaxes rat tail artery by repolarization and resultant decreases in Ca2+ influx and intracellular [Ca2+]. J Hypertens1997;15:269-74.
33.
Altieri DCOccupancy of CD11b/CD18 (Mac-1) divalent ion binding site (s) induces leukocyte adhesion. J Immunol1991;147:1891-8.
34.
Pawlowski NA , Abraham EL, Pontier S., Scott WA, Cohn ZAHuman monocyte-endothelial cell interaction in vitro. Proc Natl Acad Sci1985;82:8208-12.
35.
Omi H., Okayama N., Shimuzu M. et al. Participation of high glucose concentrations in neutrophil adhesion and surface expression of adhesion molecules on cultured human endothelial cells. Effect of antidiabetic medicines. J Diabetes Complications2002;16:201-08.
36.
Gerrity RGThe role of monocyte in atherogenesis, I: transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol1981;103:181-90.
37.
Shelley CS, Teodoridis JM, Park H., Farokhzad OC, Bottinger EP, Arnaout MADuring differentiation of the monocytic cell line U937, Pur alpha mediates induction of the CD11c beta 2 integrin gene promoter. J Immunol2002;168:3887-93.
38.
Noti JD, Reinemann BCThe leukocyte integrin gene CD11c is transcriptionally regulated during monocyte differentiation. Mol Immunol1995 ;32:361-9.
39.
Mollinedo F. , Gajate C., Tugores A. et al. Differences in expression of transcription factor AP-1 in human promyelocytic HL-60 cells during differentiation towards macrophages versus granulocytes. Biochem J1993;294:137-44.
40.
Coccia EM, Del Russo N., Stellacci E. et al. STAT1 activation during monocyte to macrophage maturation: role of adhesion molecules. Int Immunol1999;11:1075-83.
41.
Pennington KN , Taylor JA, Bren GD, Paya CVIκB kinase-dependent chronic activation of NF-κB is necessary for p21WAF1/Cip1 inhibition of differentiation-induced apoptosis of monocytes. Mol Cell Biol2001 ;21: 1930-41.
42.
Nagase M., Ando K., Nagase T., Kamane S., Sawamura T., Fujita T.Redox-sensitive regulation of LOX-1 gene expression in vascular endothelium . Biochem Biophys Res Commun2001;281:720-5.
43.
Mietus-Snyder M., Gowri MS, Pitas REClass A scavenger up-regulation in smooth muscle cells by oxidized low density lipoprotein. Enhancement by calcium flux and concurrent cyclooxygenase-2 up-regulation. J Biol Chem2000;275:17661-70.
44.
Svensson L. , Noren K., Wiklund O., Lindmark H., Ohlsson B., Hulten LMInhibitory effects of N-acetylcysteine on scavenger receptor class A expression in human macrophages . J Intern Med2002;251:437-46.
45.
Ricciarelli R., Zingg JM, Azzi A.Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation2000;102:82-7.
46.
Teupser D., Thiery J., Seidel D.Alpha-tocopherol down-regulates scavenger receptor activity in macrophages . Atherosclerosis1999;144:109-15.
