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Apo E phenotype is associated with coronary artery calcification in the general population but not in type 1 diabetic patients
Monday June 26, 2000: Poster Abstracts P:W1 Diabetes
14
MoP15:W1 [ Apt E phenotype is associated with coronary artery
calcification in the general population but not in type 1 diabetic patients H.M. Colhoun I , M.R. Taskinen 2, M.B. Rubens 3, J.H. Fuller I . 1University
College London; 3Royal Brompton Hospital London, UK; 2University of Helsinki, Finland Objectives: To examine the association between CAC and Ape E phenotype in 196 type 1 diabetic (DM) men and women and 198 non-diabetic men and women (aged 30-55 yrs). Methods: Electron beam CT scanning was used to quantify CAC. Ape E phenotyping was carried out using a rapid micromethod. Results: The frequency of apt E phenotypes was as follows; E3 (3 3) -60%, E2 (3 2 or 2 2) - 15%, EA (4 3 or 4 4 or 4 2) 25%. Phenotype did not differ by sex or DM. In the non-DM group, compared to those with E3, HDL-cholesterol was slightly lower in those with E4 (-0.13 mmol L - 1 , p = 0.05) and LDL-cholesterol was lower in those with E2 (-0.9 mmol L - 1 , p < 0.001). In the DM group, compared to those with E3, HDL-cholesterul (HDL-C) was non-significantly lower in those with E4 (-0.05 mmol L - 1 , p = 0.5) and LDL-cholesterol (LDL-C) was lower in those with E2 (-0.7 mmol L - 1 , p < 0.001). Triglycerides (TG) did not vary by phenotype in either group. In the non-DM group, compared with E3 phenotype, those with E4 phenotype had an elevated odds of calcification (51% vs. 33%, OR = 2.7, 95% CI 1.3-5.8, p = 0.01). This was independent of LDL-C, HDL-C and TG (OR = 3.0, p = 0.009 on adjustment) and of apt A and ape B. In DM subjects no association was seen (OR = 0.91, p = 0.8, p = 0.05 for the interaction between diabetes and apoE phenotype). The prevalence of CAC was similar in those with E2 and E3 phenotype in both groups. There was no evidence of any modulating effect of ApoE phenotype on the effect of other risk factors on CAC in either group. Concinsion: Ape E 3 phenotype is protective for coronary calcification compared with Apt E 4 phenotype. This is not due to differences lipid levels between phenoptypes. The protective mechanism of E3 or the detrimental effect of E4 is not apparent in type 1 diabetic patients. I
MOP16:Wl ] Glycaemic control and plasma lipoproteins in
menopausal women with type 2 diabetes treated with oral and transderrnal combined hormone replacement therapy D.A. Darko, A. Dornhorst, D.B. O'Shea, M. Seed. Imperial College School of Medicine, Charing Cross Hospital, London W6 8RF, UK
Objective: To compare the effect of a fixed combination of an oestrogen (17-/~ oestradiol) with a cyclical progestagen (norethisterone) on glycaemic control and plasma lipoproteins in women with type 2 diabetes. Methods: Oral and transdermal HRT were compared to no HRT treatment in 33 postmenopausal women with type 2 diabetes, in a 12 week prospective open parallel group study. Results: In the 11 women who received 12 weeks of oral HRT there was a significant fall in total cholesterol {5.9 -4- 1.0 (SD) to 4.9 5= 1.1 mmol.1-1, p = 0.004}, low density lipoprotein (LDL) cholesterol {3.44 4- 0.89 to 2.77 5= 0.92 mmol.l - I , p = 0.004} and triglyceride values {median (range)}, {2.46 (0.96--5.52) to 2.29 (1.00-3.87) mmol.1-1, p < 0.05}. Oral HRT improved HbAlc {7.4 4- 1.4 to 6.8 4- 1.2%, p = <0.005}. No improvement in these metabolic parameters occurred in the 9 women receiving transdermal HRT or the 13 controls randomised on no treatment. Condusion: In women with type 2 diabetes, cyclical oestrogen and progestagen taken orally for 12 weeks significantly improved glycaemic control and lipoprotein concentrations. These metabolic benefits were not apparent when a similar HRT preparation was administered transdermally.
Methods: Electron beam CT scanning was used to quantify CAC in 199 DM patients and 196 non-DM subjects (age 30-55 yrs; 50% female). CET was measured using a radioisotope method. CETP-a was measured using an exogenous substrate assay, as an estimate of its mass. HDL size was measured by NMR-spectroscopy. Analyses were adjusted for age and sex. Results: CET was positively associated with triglycerides (TG) (p < 0.001) land with CETP-a (p < 0.001). TG were 0.2 mmol/L lower in those with than without DM (p = 0.001). CETP-a was higher in those with DM, independently of HDL-C, LDL-C and TG (4% higher = +3.7 arbitrary units, SD = 18, p = 0.027). CET was lower in those with DM (10% lower = 3.7 nmol/ml/hr, SD = 12, p = 0.003), but not independently of TG (-0.3 nmol/ml/hr, on adjustment p = 0.7). In both groups, a higher CET was associated with lower HDL-C (0.14 mmol/L lower per 10 nmol/mi/hr of CET, p < 0.001) and smaller HDL size (0.17 nm lower per 10 nmol/ml/hr of CET, p < 0.001). CET was associated with CAC (Odds ratio [OR] for CAC per 10 nmol/ml/hr of CET = 1.4, 95% CI: 1.2-1.7, p < 0.001 adjusted for DM). The association was independent of HDL-C and HDL size but not TG (OR = 1.2, p = 0.1). Conclusions: i) DM patients have elevated CETP activity, but their CET is lower than non-DM subjects because of their lower TG. ii) Higher CET is associated with lower HDL size, lower HDL-C and with increased CAC. These data support the concept that the atherogenicity of TG is mediated by increased CET, coinciding with a reduction in HDL size and HDL-C. |
I MOP18:W1 ] Low paraoxonase in small dense HDL may predispose to
coronary heart disease in type 1 diabetes J. Valabhii, A.J. McColl, S. Dhanjil, M. Schachter, W. Richmond, R.S. Elkeles. Unit of Metabolic Medicine, St Mary's Hospital, London, UK
Introduction: High incidence of coronary heart disease (CHD) in type 1 diabetes, despite increased HDL cholesterol, may reflect low activity of paraoxonase, an enzyme closely associated with apt A 1. Objectives: We aimed to assess the ratio of paraoxonase activity to apt A1 concentration (PON/A1) in HDL subfractions of type 1 diabetic and control subjects, and to relate the findings to CHD risk, assessed by measurements of carotid and femoral artery intima-media thickness (IMT). Method: Paraoxonase activity was measured using phenylacetate as substrate. We used single vertical spin density gradient ultracentrifugation to isolate seven HDL subfractions from serum according to density. Mean (SD) retrieval of paraoxonase activity in subfractions was 87 (12)%. Carotid and femoral IMT were measured using t-mode ultrasound. Results: Thirty-five type 1 diabetic (duration of diabetes 22 (13) years, HbAlc 7.67 (1.17)%) and 24 control subjects, matched for age, sex and BMI, were studied. HDL cholesterol was higher (1.53 (0.36) v. 1.32 (0.34) mmol/1; p < 0.05) in diabetic subjects; mean IMT was also higher (0.92 (0.03) v. 0.55 (0.13) mm; p < 0.005). Apt A1 (1.64 (0.35) v. 1.50 (0.26) g/l; NS), serum paraoxonase activity (121 (28) v. 120 (36) #mol/ml/min; NS) and serum PON/A1 (75 (19) v. 80 (20)/zmol/min/mg apoA1; NS) were similar. In both groups, PON/A1 increased progressively as HDL subfraction density increased. PON/A1 was therefore highest in the smallest, densest HDL subfraction, but was significantly lower in this subfraction in diabetic subjects (164 (61) v. 217 (117)/zmol/min/mg apoA1; p < 0.05). Correlation of PON/A1 in this subfraction against mean IMT was of borderline significance (r = -0.24; p = 0.06). Conclusion: Low PON/A1 in small dense HDL may predispose to CHD in type 1 diabetes. I
MOP19:Wl ] HDL oxidability in type 2 diabetic patients L. Schreier, S. Sanguinetti, J. Verona, A. Elbert, R. Wikinski. Laboratory of
Lipids and Lipoproteins, Department of Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina
t
MoP17:W1 [ Cholesteryl ester transfer is associated with HDL size and
coronary artery calcification in type 1 diabetic and non-diabetic subjects H.M. Cothoun I , L.M. Scheek 2, J. Otvos3, J.H. Fuller I , A. Van Tol 2. 1University College London, UK; 2Erasmus University Rotterdam, The
Netherlands; 3 LipoMed lnc, Raleigh, NC, US Objectives: We compared plasma cholesteryl ester transfer (CET) and protein activity (CETP-a) in type 1 diabetic (DM) and non-diabetic (non-DM) subjects, and ii) examined the association of CET with HDL-cholesterol (HDL-C), HDL particle size and coronary artery calcification (CAC), a measure of atherosclerosis.
Objective: To evaluate HDL oxidability (Ox) in type 2 diabetic patients (D) and its relation with HDL chemical composition (CC), ot-tocophenol (~-t) and paraoxonase (PON) activity. Methods: We studied 17 D and 17 healthy controls (C). Isolated HDL was oxidized by incubation with CuCI2. Conjugated dienes (CD) production was monitored by increase in absorbance at 234 nm. We calculated lag time (/agt), maximum rate of CD production (Vmax) and maximum amount of CD (Dmax). TBARS were measured after 2 h oxidation. We determined HDL cholesterol (Cho), triglycerides (Tg), phospholipids (Ph), proteins (P), ot-t and HDL glycation as fructosamine (FR). PON activity was evaluated with paraoxon and phenylacetate as substrates (PON and ARE) and with IM NaCI (PON 1M).
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
14
MoP15:W1 [ Apt E phenotype is associated with coronary artery
calcification in the general population but not in type 1 diabetic patients H.M. Colhoun I , M.R. Taskinen 2, M.B. Rubens 3, J.H. Fuller I . 1University
College London; 3Royal Brompton Hospital London, UK; 2University of Helsinki, Finland Objectives: To examine the association between CAC and Ape E phenotype in 196 type 1 diabetic (DM) men and women and 198 non-diabetic men and women (aged 30-55 yrs). Methods: Electron beam CT scanning was used to quantify CAC. Ape E phenotyping was carried out using a rapid micromethod. Results: The frequency of apt E phenotypes was as follows; E3 (3 3) -60%, E2 (3 2 or 2 2) - 15%, EA (4 3 or 4 4 or 4 2) 25%. Phenotype did not differ by sex or DM. In the non-DM group, compared to those with E3, HDL-cholesterol was slightly lower in those with E4 (-0.13 mmol L - 1 , p = 0.05) and LDL-cholesterol was lower in those with E2 (-0.9 mmol L - 1 , p < 0.001). In the DM group, compared to those with E3, HDL-cholesterul (HDL-C) was non-significantly lower in those with E4 (-0.05 mmol L - 1 , p = 0.5) and LDL-cholesterol (LDL-C) was lower in those with E2 (-0.7 mmol L - 1 , p < 0.001). Triglycerides (TG) did not vary by phenotype in either group. In the non-DM group, compared with E3 phenotype, those with E4 phenotype had an elevated odds of calcification (51% vs. 33%, OR = 2.7, 95% CI 1.3-5.8, p = 0.01). This was independent of LDL-C, HDL-C and TG (OR = 3.0, p = 0.009 on adjustment) and of apt A and ape B. In DM subjects no association was seen (OR = 0.91, p = 0.8, p = 0.05 for the interaction between diabetes and apoE phenotype). The prevalence of CAC was similar in those with E2 and E3 phenotype in both groups. There was no evidence of any modulating effect of ApoE phenotype on the effect of other risk factors on CAC in either group. Concinsion: Ape E 3 phenotype is protective for coronary calcification compared with Apt E 4 phenotype. This is not due to differences lipid levels between phenoptypes. The protective mechanism of E3 or the detrimental effect of E4 is not apparent in type 1 diabetic patients. I
MOP16:Wl ] Glycaemic control and plasma lipoproteins in
menopausal women with type 2 diabetes treated with oral and transderrnal combined hormone replacement therapy D.A. Darko, A. Dornhorst, D.B. O'Shea, M. Seed. Imperial College School of Medicine, Charing Cross Hospital, London W6 8RF, UK
Objective: To compare the effect of a fixed combination of an oestrogen (17-/~ oestradiol) with a cyclical progestagen (norethisterone) on glycaemic control and plasma lipoproteins in women with type 2 diabetes. Methods: Oral and transdermal HRT were compared to no HRT treatment in 33 postmenopausal women with type 2 diabetes, in a 12 week prospective open parallel group study. Results: In the 11 women who received 12 weeks of oral HRT there was a significant fall in total cholesterol {5.9 -4- 1.0 (SD) to 4.9 5= 1.1 mmol.1-1, p = 0.004}, low density lipoprotein (LDL) cholesterol {3.44 4- 0.89 to 2.77 5= 0.92 mmol.l - I , p = 0.004} and triglyceride values {median (range)}, {2.46 (0.96--5.52) to 2.29 (1.00-3.87) mmol.1-1, p < 0.05}. Oral HRT improved HbAlc {7.4 4- 1.4 to 6.8 4- 1.2%, p = <0.005}. No improvement in these metabolic parameters occurred in the 9 women receiving transdermal HRT or the 13 controls randomised on no treatment. Condusion: In women with type 2 diabetes, cyclical oestrogen and progestagen taken orally for 12 weeks significantly improved glycaemic control and lipoprotein concentrations. These metabolic benefits were not apparent when a similar HRT preparation was administered transdermally.
Methods: Electron beam CT scanning was used to quantify CAC in 199 DM patients and 196 non-DM subjects (age 30-55 yrs; 50% female). CET was measured using a radioisotope method. CETP-a was measured using an exogenous substrate assay, as an estimate of its mass. HDL size was measured by NMR-spectroscopy. Analyses were adjusted for age and sex. Results: CET was positively associated with triglycerides (TG) (p < 0.001) land with CETP-a (p < 0.001). TG were 0.2 mmol/L lower in those with than without DM (p = 0.001). CETP-a was higher in those with DM, independently of HDL-C, LDL-C and TG (4% higher = +3.7 arbitrary units, SD = 18, p = 0.027). CET was lower in those with DM (10% lower = 3.7 nmol/ml/hr, SD = 12, p = 0.003), but not independently of TG (-0.3 nmol/ml/hr, on adjustment p = 0.7). In both groups, a higher CET was associated with lower HDL-C (0.14 mmol/L lower per 10 nmol/mi/hr of CET, p < 0.001) and smaller HDL size (0.17 nm lower per 10 nmol/ml/hr of CET, p < 0.001). CET was associated with CAC (Odds ratio [OR] for CAC per 10 nmol/ml/hr of CET = 1.4, 95% CI: 1.2-1.7, p < 0.001 adjusted for DM). The association was independent of HDL-C and HDL size but not TG (OR = 1.2, p = 0.1). Conclusions: i) DM patients have elevated CETP activity, but their CET is lower than non-DM subjects because of their lower TG. ii) Higher CET is associated with lower HDL size, lower HDL-C and with increased CAC. These data support the concept that the atherogenicity of TG is mediated by increased CET, coinciding with a reduction in HDL size and HDL-C. |
I MOP18:W1 ] Low paraoxonase in small dense HDL may predispose to
coronary heart disease in type 1 diabetes J. Valabhii, A.J. McColl, S. Dhanjil, M. Schachter, W. Richmond, R.S. Elkeles. Unit of Metabolic Medicine, St Mary's Hospital, London, UK
Introduction: High incidence of coronary heart disease (CHD) in type 1 diabetes, despite increased HDL cholesterol, may reflect low activity of paraoxonase, an enzyme closely associated with apt A 1. Objectives: We aimed to assess the ratio of paraoxonase activity to apt A1 concentration (PON/A1) in HDL subfractions of type 1 diabetic and control subjects, and to relate the findings to CHD risk, assessed by measurements of carotid and femoral artery intima-media thickness (IMT). Method: Paraoxonase activity was measured using phenylacetate as substrate. We used single vertical spin density gradient ultracentrifugation to isolate seven HDL subfractions from serum according to density. Mean (SD) retrieval of paraoxonase activity in subfractions was 87 (12)%. Carotid and femoral IMT were measured using t-mode ultrasound. Results: Thirty-five type 1 diabetic (duration of diabetes 22 (13) years, HbAlc 7.67 (1.17)%) and 24 control subjects, matched for age, sex and BMI, were studied. HDL cholesterol was higher (1.53 (0.36) v. 1.32 (0.34) mmol/1; p < 0.05) in diabetic subjects; mean IMT was also higher (0.92 (0.03) v. 0.55 (0.13) mm; p < 0.005). Apt A1 (1.64 (0.35) v. 1.50 (0.26) g/l; NS), serum paraoxonase activity (121 (28) v. 120 (36) #mol/ml/min; NS) and serum PON/A1 (75 (19) v. 80 (20)/zmol/min/mg apoA1; NS) were similar. In both groups, PON/A1 increased progressively as HDL subfraction density increased. PON/A1 was therefore highest in the smallest, densest HDL subfraction, but was significantly lower in this subfraction in diabetic subjects (164 (61) v. 217 (117)/zmol/min/mg apoA1; p < 0.05). Correlation of PON/A1 in this subfraction against mean IMT was of borderline significance (r = -0.24; p = 0.06). Conclusion: Low PON/A1 in small dense HDL may predispose to CHD in type 1 diabetes. I
MOP19:Wl ] HDL oxidability in type 2 diabetic patients L. Schreier, S. Sanguinetti, J. Verona, A. Elbert, R. Wikinski. Laboratory of
Lipids and Lipoproteins, Department of Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina
t
MoP17:W1 [ Cholesteryl ester transfer is associated with HDL size and
coronary artery calcification in type 1 diabetic and non-diabetic subjects H.M. Cothoun I , L.M. Scheek 2, J. Otvos3, J.H. Fuller I , A. Van Tol 2. 1University College London, UK; 2Erasmus University Rotterdam, The
Netherlands; 3 LipoMed lnc, Raleigh, NC, US Objectives: We compared plasma cholesteryl ester transfer (CET) and protein activity (CETP-a) in type 1 diabetic (DM) and non-diabetic (non-DM) subjects, and ii) examined the association of CET with HDL-cholesterol (HDL-C), HDL particle size and coronary artery calcification (CAC), a measure of atherosclerosis.
Objective: To evaluate HDL oxidability (Ox) in type 2 diabetic patients (D) and its relation with HDL chemical composition (CC), ot-tocophenol (~-t) and paraoxonase (PON) activity. Methods: We studied 17 D and 17 healthy controls (C). Isolated HDL was oxidized by incubation with CuCI2. Conjugated dienes (CD) production was monitored by increase in absorbance at 234 nm. We calculated lag time (/agt), maximum rate of CD production (Vmax) and maximum amount of CD (Dmax). TBARS were measured after 2 h oxidation. We determined HDL cholesterol (Cho), triglycerides (Tg), phospholipids (Ph), proteins (P), ot-t and HDL glycation as fructosamine (FR). PON activity was evaluated with paraoxon and phenylacetate as substrates (PON and ARE) and with IM NaCI (PON 1M).
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000