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Lipid lowering therapy is advisable in more than half type 2 diabetic patients in fairly good metabolic control
Monday June 26, 2000: Read by Title Abstracts T:W2 Thrombosisand Fibrinolysis MoT11 :Wl J Postprandial increase in atherogenic remnant-lipoprotein in type 2 diabetes mellitus with fasting normolipidemia N. Takayanagi, T. Onuma, S. Kato, K, Abe, T, Nomiyama, T. Ogiliara, T. Shimizu, Y. Tanaka, Y. Usuki, R. Kawamori. Internal Medicine, Juntendo
University School of Medicine, Tokyo, Japan Objective: An abnormaly postprandial increase in remnant-lipoprotein is recently noticed to be an important risk for atheroselerosis in type 2 diabetes mellitus (DM) with fasting normolipidemia. The ratio of insulin content in peripheral vessel to that in portal one may be higher in being treated with insulin than with sulfonylurea (SU). The purpose of this study is to clarify if the postprandial increase in remnant-lipoprotein is associated with the difference between insulin-action to peripheral adipose tissue and that to liver by the diabetic treatments. Methods: A physiological test-meal was given to 8 insulin-treated inpatients and 9 SU-treated ones of type 2 DM with fasting normolipidemia. Triglyceride and cholesterol of renmant-like lipoprotein (RLP-TG and -C) in serum before and 1, 2, 4 hours after giving the test-meal were measured by using immunoaffinity-gels. Results: Fasting and postprandial (1, 2 h) levels of RLP-TG and the area under the curve of this (AUC-RLP-TG) were significantly higher in SU-treated group than in insulin-treated group. There was no significant difference in fasting and postprandial levels of RLP-C between the two groups. Fasting seruna TG level was significantly higher in SU-treated group than in insulintreated group. Serum total cholesterol, HDL-C and fasting plasma glucose levels were almost the same between the two groups. Conclusions: These results indicate that an abnormaly postprandial increase in chyromicron-remnant shown as the change of RLP-TG might be associated with the difference between insulin-action to the two orgnas by the diabetic treatments in type 2 DM patients with fasting normolipidemia. MoT12:W1 ] 7-ketocholesterol-induced apoptosis of vascular smooth muscle cells enhanced under diabetic condition Y. Miyashita 1, T. Oyama 1, M. Totsuka I , H. Watanabe2, K. Shirai2.
1Department of Internal Medicine; 2Clinical Laboratory Medicine, Sakura Hospital, School of Medicine, Toho University, Chiba, Japan Objective: We reported that oxysterols induce apoptosis in vascular smooth muscle cells (VSMCs). In this time, oxysterol sensitivity of VSMCs under diabetic condition and this mechanism were studied. Method: VSMCs of OLET-F and LETO rat, and 7-ketocholesterul (7-keto) as oxysterols were used. The cell proliferation was evaluated by the outgrowth ratio and the cell number. The amount of fragmented DNA were measured by ELISA. c-Myc expression was analyzed by Western blotting. Results: In OLET-F's VSMCs, the outgrowth ratio and an increase in cell numbers were higher than in LETO's VSMCs. By the addition of 7-keto (100 #M), the fragmented DNA of OLET-F's VSMCs increased significantly compared with LETO's one. The expression of c-myc was enhanced with the addition of 7-keto (100/zM). The expression of c-myc in OLET-F's VSMC was much higher than that of LETO's. Conclusion: These results suggested that in VSMCs under diabetic condition, the ability of proliferation raised and 7-keto-induced apoptosis enhanced. The excess c-myc expression might be involved in 7-ketocholesterol-induced apoptosis. 1
I MoT1 3:Wl J Structural and antioxidant properties of serum albumin altered by glycation and oxidation E. Bourdon, N. Loreau, D. Blache./INSERM U498, Biochimie des
lipoproteines; 2 Universit~ de Bourgogne, 7, bd Jeanne d'Arc, Dijon, France Objectives: Reduced levels of serum albumin, the most abundant protein in the plasma, are consistently associated with an increased mortality risk. Various biological properties evidenced by direct effects of the albumin molecule may explain its antiatherogenic effects. The present work investigated whether in vitro glycation or oxidation would affect the antioxidant properties of bovine serum albumin (BSA) Methods: Glycation was performed by long term incubations (60 days) of BSA with increasing concentrations of glucose at 37°C. Minimally oxidised BSA was obtained after controlled incubations of dialysed BSA samples with an azo-type generator of free radicals. Albumin specifically modified on sulphur containing residues was also studied. Results: Native BSA presented antioxidant activities by significantly inhibiting copper-mediated LDL oxidation and free radical-induced hemolysis.
69
These data are in favour of a metal chelating effect and of a free radical trapping activity of BSA. These inhibitory properties were markedly reduced by glycation and/or oxidation. Moreover, our data indicate that highly glycated BSA had pro-oxidant properties likely due to free radical production. We also found that glycation of BSA resulted in large modifications which were enhanced by oxidation. Part of the free radical trapping properties were also ascribable to methionine and thiol Conclusion: As diabetes is recognised as being exposed to oxidant stress, the transformation of the antioxidant properties of BSA toward pro-oxidant ones favoured by high circulating concentrations of glucose might be one of the key elements leading in vivo to the development of cardiovascular complications in diabetes. I MoT14:W1 I Lipid lowering therapy is advisable in more than half type 2 diabetic patients in fairly good metabolic control I
A. Toni I , A. Branchi2, C. Ben'a I , E. Dalla Valle I , D. Sommariva I .
7-Department of lnternal Medicine, G. Salvini Hospital, Garbagnate Milanese; 2Department of lnterr~l Medicine, University of Milan, Maggiore Hospital IRCCS, Milan, Italy Objective: According to the recent guidelines of the American Diabetes Association (ADA), lipid lowering drug therapy should be initiated when LDL cholesterol (LDL-C) level remains >100 mg/dl in type 2 diabetics with cardiovascular disease (CVD) after optimization of diabetic therapy and behavioral intervention aimed to control dyslipidemia and obesity. LDL-C > = 130 mg/dl is the initiation level of drug therapy in subjects without CVD. Methods: The CVD risk profile was evaluated in 624 type 2 diabetic patients (296 females, 328 males). Their ages ranged from 30 to 75 years (mean 59 =l=0.4 years). Serum triglycerides (TG) were higher than 400 mg/dl in 24 patients and in them LDL-C (Friedewald equation) was not calculated. Results: 542 of 624 patients were in fairly good metabolic conditions. Of them, 74 (14%) had CVD. Of CVD patients, 55 (74%) had LDL-C > 100 mg/dl and of non CVD patients, 240 (51%) had LDL-C > = 130 mg/dl. Of the remaining 228 patients, 17 had serum TG > 400 mg/dl and 92 had other risk factors such as low HDL-C, hypertension and smoking. Of the 82 patients in bad glycemic control, 8 (10%) had CVD (5 with LDL-C > 100 mg/dl) and 74 did not have CVD (55% with LDL-C > = 130 and 3% with TG > 400 mg/dl). Conclusions: 54% of diabetic patients in fairly good diabetic control need cholesterol lowering therapy. Since ADA recommendations include high TG levels as a target for intervention, further 22 (4%) patients must be treated with lipid lowering agent. According to some authorities, the initiation level of drug therapy is LDL-C > 100 mg/di when other coronary risk factors are present. This should lead to 409 (75%) the number of diabetic patients in fairly good diabetic control requiring a lipid lowering therapy.
T:W2
THROMBOSIS AND FIBRINOLYSIS
MOT1 :W2 [ Plasmin generation reduced in hypertriglyceridemia, but enhanced in low HDL cholesterolemia Akito Kawaguchi, Hisao Kato, Akira Yamamoto. National Cardiovascular
Center, Osaka, Japan Impaired fibrinolysis frequandy associated with hypertrigiyceridemia (HTG) accompanied by low HDL cholestemlemia (HDL.c) plays a central role in onset of coronary events. We assessed the independent contribution of HTG and low HDL.c to plasmin generation as the final response of fibrinolytic system. Methods: 161 patients with coronary artery disease (CAD) were studied on serum lipids, plasmin/alpha-2 plasmin inhibitor complex (PIC) as a marker of plasmin generation, PAL 1 and tPA antigens as regulators of fibrinolytic system. In addition, post-heparin plasma was obtained to estimate endothelial free-TFPI as an anti-thrombotic property of vessel wall. To evaluate the independent significance of TG and HDL.c, the patients were divided into four categories (2 × 2 factorial groups) according to the presence or not of HTG (> 130 mg/dl) and/or low HDL.c (<35 mg/dl) and compared the fibrinolytic profile by 2-way ANOVA and a partial correlation coefficient analysis. Results: PAI-1 is proportional to tPA levels, and both PAI-1 and tPA are negatively correlated to PIC. The patients with HTG showed increased tPA and PAI-I, but reduced PIC. On the other hand, the patients with low HDL.c showed increased PIC independent tPA level and increased heparin-releasable free TFPI.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
University School of Medicine, Tokyo, Japan Objective: An abnormaly postprandial increase in remnant-lipoprotein is recently noticed to be an important risk for atheroselerosis in type 2 diabetes mellitus (DM) with fasting normolipidemia. The ratio of insulin content in peripheral vessel to that in portal one may be higher in being treated with insulin than with sulfonylurea (SU). The purpose of this study is to clarify if the postprandial increase in remnant-lipoprotein is associated with the difference between insulin-action to peripheral adipose tissue and that to liver by the diabetic treatments. Methods: A physiological test-meal was given to 8 insulin-treated inpatients and 9 SU-treated ones of type 2 DM with fasting normolipidemia. Triglyceride and cholesterol of renmant-like lipoprotein (RLP-TG and -C) in serum before and 1, 2, 4 hours after giving the test-meal were measured by using immunoaffinity-gels. Results: Fasting and postprandial (1, 2 h) levels of RLP-TG and the area under the curve of this (AUC-RLP-TG) were significantly higher in SU-treated group than in insulin-treated group. There was no significant difference in fasting and postprandial levels of RLP-C between the two groups. Fasting seruna TG level was significantly higher in SU-treated group than in insulintreated group. Serum total cholesterol, HDL-C and fasting plasma glucose levels were almost the same between the two groups. Conclusions: These results indicate that an abnormaly postprandial increase in chyromicron-remnant shown as the change of RLP-TG might be associated with the difference between insulin-action to the two orgnas by the diabetic treatments in type 2 DM patients with fasting normolipidemia. MoT12:W1 ] 7-ketocholesterol-induced apoptosis of vascular smooth muscle cells enhanced under diabetic condition Y. Miyashita 1, T. Oyama 1, M. Totsuka I , H. Watanabe2, K. Shirai2.
1Department of Internal Medicine; 2Clinical Laboratory Medicine, Sakura Hospital, School of Medicine, Toho University, Chiba, Japan Objective: We reported that oxysterols induce apoptosis in vascular smooth muscle cells (VSMCs). In this time, oxysterol sensitivity of VSMCs under diabetic condition and this mechanism were studied. Method: VSMCs of OLET-F and LETO rat, and 7-ketocholesterul (7-keto) as oxysterols were used. The cell proliferation was evaluated by the outgrowth ratio and the cell number. The amount of fragmented DNA were measured by ELISA. c-Myc expression was analyzed by Western blotting. Results: In OLET-F's VSMCs, the outgrowth ratio and an increase in cell numbers were higher than in LETO's VSMCs. By the addition of 7-keto (100 #M), the fragmented DNA of OLET-F's VSMCs increased significantly compared with LETO's one. The expression of c-myc was enhanced with the addition of 7-keto (100/zM). The expression of c-myc in OLET-F's VSMC was much higher than that of LETO's. Conclusion: These results suggested that in VSMCs under diabetic condition, the ability of proliferation raised and 7-keto-induced apoptosis enhanced. The excess c-myc expression might be involved in 7-ketocholesterol-induced apoptosis. 1
I MoT1 3:Wl J Structural and antioxidant properties of serum albumin altered by glycation and oxidation E. Bourdon, N. Loreau, D. Blache./INSERM U498, Biochimie des
lipoproteines; 2 Universit~ de Bourgogne, 7, bd Jeanne d'Arc, Dijon, France Objectives: Reduced levels of serum albumin, the most abundant protein in the plasma, are consistently associated with an increased mortality risk. Various biological properties evidenced by direct effects of the albumin molecule may explain its antiatherogenic effects. The present work investigated whether in vitro glycation or oxidation would affect the antioxidant properties of bovine serum albumin (BSA) Methods: Glycation was performed by long term incubations (60 days) of BSA with increasing concentrations of glucose at 37°C. Minimally oxidised BSA was obtained after controlled incubations of dialysed BSA samples with an azo-type generator of free radicals. Albumin specifically modified on sulphur containing residues was also studied. Results: Native BSA presented antioxidant activities by significantly inhibiting copper-mediated LDL oxidation and free radical-induced hemolysis.
69
These data are in favour of a metal chelating effect and of a free radical trapping activity of BSA. These inhibitory properties were markedly reduced by glycation and/or oxidation. Moreover, our data indicate that highly glycated BSA had pro-oxidant properties likely due to free radical production. We also found that glycation of BSA resulted in large modifications which were enhanced by oxidation. Part of the free radical trapping properties were also ascribable to methionine and thiol Conclusion: As diabetes is recognised as being exposed to oxidant stress, the transformation of the antioxidant properties of BSA toward pro-oxidant ones favoured by high circulating concentrations of glucose might be one of the key elements leading in vivo to the development of cardiovascular complications in diabetes. I MoT14:W1 I Lipid lowering therapy is advisable in more than half type 2 diabetic patients in fairly good metabolic control I
A. Toni I , A. Branchi2, C. Ben'a I , E. Dalla Valle I , D. Sommariva I .
7-Department of lnternal Medicine, G. Salvini Hospital, Garbagnate Milanese; 2Department of lnterr~l Medicine, University of Milan, Maggiore Hospital IRCCS, Milan, Italy Objective: According to the recent guidelines of the American Diabetes Association (ADA), lipid lowering drug therapy should be initiated when LDL cholesterol (LDL-C) level remains >100 mg/dl in type 2 diabetics with cardiovascular disease (CVD) after optimization of diabetic therapy and behavioral intervention aimed to control dyslipidemia and obesity. LDL-C > = 130 mg/dl is the initiation level of drug therapy in subjects without CVD. Methods: The CVD risk profile was evaluated in 624 type 2 diabetic patients (296 females, 328 males). Their ages ranged from 30 to 75 years (mean 59 =l=0.4 years). Serum triglycerides (TG) were higher than 400 mg/dl in 24 patients and in them LDL-C (Friedewald equation) was not calculated. Results: 542 of 624 patients were in fairly good metabolic conditions. Of them, 74 (14%) had CVD. Of CVD patients, 55 (74%) had LDL-C > 100 mg/dl and of non CVD patients, 240 (51%) had LDL-C > = 130 mg/dl. Of the remaining 228 patients, 17 had serum TG > 400 mg/dl and 92 had other risk factors such as low HDL-C, hypertension and smoking. Of the 82 patients in bad glycemic control, 8 (10%) had CVD (5 with LDL-C > 100 mg/dl) and 74 did not have CVD (55% with LDL-C > = 130 and 3% with TG > 400 mg/dl). Conclusions: 54% of diabetic patients in fairly good diabetic control need cholesterol lowering therapy. Since ADA recommendations include high TG levels as a target for intervention, further 22 (4%) patients must be treated with lipid lowering agent. According to some authorities, the initiation level of drug therapy is LDL-C > 100 mg/di when other coronary risk factors are present. This should lead to 409 (75%) the number of diabetic patients in fairly good diabetic control requiring a lipid lowering therapy.
T:W2
THROMBOSIS AND FIBRINOLYSIS
MOT1 :W2 [ Plasmin generation reduced in hypertriglyceridemia, but enhanced in low HDL cholesterolemia Akito Kawaguchi, Hisao Kato, Akira Yamamoto. National Cardiovascular
Center, Osaka, Japan Impaired fibrinolysis frequandy associated with hypertrigiyceridemia (HTG) accompanied by low HDL cholestemlemia (HDL.c) plays a central role in onset of coronary events. We assessed the independent contribution of HTG and low HDL.c to plasmin generation as the final response of fibrinolytic system. Methods: 161 patients with coronary artery disease (CAD) were studied on serum lipids, plasmin/alpha-2 plasmin inhibitor complex (PIC) as a marker of plasmin generation, PAL 1 and tPA antigens as regulators of fibrinolytic system. In addition, post-heparin plasma was obtained to estimate endothelial free-TFPI as an anti-thrombotic property of vessel wall. To evaluate the independent significance of TG and HDL.c, the patients were divided into four categories (2 × 2 factorial groups) according to the presence or not of HTG (> 130 mg/dl) and/or low HDL.c (<35 mg/dl) and compared the fibrinolytic profile by 2-way ANOVA and a partial correlation coefficient analysis. Results: PAI-1 is proportional to tPA levels, and both PAI-1 and tPA are negatively correlated to PIC. The patients with HTG showed increased tPA and PAI-I, but reduced PIC. On the other hand, the patients with low HDL.c showed increased PIC independent tPA level and increased heparin-releasable free TFPI.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000