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We-P11:33 Paraoxonase gene polymorphism (PON1 192) is associated with endothelial function in patients with type 2 diabetes
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Wednesday, June 21, 2006: Poster Session Opti.~fl atherosclerosis management (lstpart)
I
We-P11:32 ] UNCOUPLED ENDOTHELIAL NITRIC OXIDE i
SYNTHASE IN DIABETIC BONE MARROW-IMPACT
ON ENDOTHELIAL PROGENITOR CELLS T. Thum, D. Fraccaxollo, E Galuppo, M. Schultheiss, G. Ertl, J. Bauersachs.
Julius-Maximilians-Universit~it, Mediz#usche Kl#uk I, Kardiologie, Wiirzburg, Germany Endothelial progenitor cells OEPC) mobilized from bone marrow contribute to replacement of diseased endothelial cells, thereby limiting atherosclerotic plaque formation. Translocation of EPC to the circulation involves vascular endothelial growth factor (VEGF)/nitric oxide (NO) and matrix metalloproteinase-9 (MMP-9)-mediated pathways in bone marrow. In rats with streptozotocin-induced diabetes we investigated alterations of bone marrow molecular mobilising pathways, which determine circulating EPC levels. Diabetes was associated with a reduction of circulating EPC to 39-4-5% when compared to controls. Superoxide anion (02-) production was substantially enhanced in diabetic bone marrow, eNOS protein expression was increased in bone marrow extracts of diabetic rats, but eNOS dimer/monomer ratio as well as eNOS and Akt phosphorylation were reduced. NOS inhibition decreased 0 2 - levels in bone marrow of diabetic rats indicating the involvement of eNOS in exaggerated 0 2 - production. MMP-9 activity was significantly depressed in bone marrow of diabetic animals compared to controls. Treatment with the angiotensin receptor blocker telmisaxtan improved phosphorylation of eNOS in diabetic bone marrow and increased EPC levels. Our data show uncoupling of eNOS in diabetic bone marrow, resulting in eNOS-mediated 0 2 - production, and reduced MMP-9 activity. Subsequent reduction of EPC levels is likely to contribute to the pathogenesis of vascular disease in diabetes mellitus. Angiotensin receptor blockade may be a novel therapeutic approach to reverse eNOS uncoupling in bone marrow and normalise impaired EPC levels in diabetes. I
W e - P 1 1 : 3 3 ] P A R A O X O N A S E G E N E P O L Y M O R P H I S M (PON1 192) i IS A S S O C I A T E D W I T H E N D O T H E L I A L F U N C T I O N IN PATIENTS WITH TYPE 2 DIABETES ]
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C. Irace , C. Cortese% F. Dell'Aquila I , L. Llberatoscloh% L. Mannucc1% G. Federici 2 , A. Gnasso 1.1Dept" of Clinical arm E~perimental Medicine,
Universi~ of Catanzaro, Catanzaro, Italy: 2Dept. of bttental Medicine, Universi~ of Tor Vergata, Rome, Italy Objective: Endothelial dysfunction is frequent in diabetic patients and may be related to increased oxidation of circulating LDL. Paraoxonase (PON1) is an HDL-linked anti-oxidant enzyme whose activity is influenced by a genetic polymorphism at codon 192 resulting in a Gln to Arg change. In the present study, we have investigated the possible association between the PON1 polymorphism and the endothelial function in patients with type 2 diabetes mellitus. M e t h o d s : 69 diabetic patients and 41 sex- and age-matched controls were enrolled. The PON1 Gln192Arg polymorphism was determined by PCR amplification and restriction enzyme analysis. Endothelial function was evaluated by flow-mediated vasodilation (FMD) of the brachial artery after forearm ischemia. Data were analyzed according to the presence or absence of the Arg allele of the PON1 gene. Results: In the control group, no difference was observed in FMD between subjects homozygous for the Gln allele and those carrying the Arg allele. In the diabetic group, FMD was lower among those carrying the Arg allele compared with homozygous for the Gln allele (1.90-4-1.65% vs. 3.69-4-2.40%; p=0.02). This difference was even more significant after exclusion of subjects with hypertension (2.01-4-1.27% vs. 5.72-4-3.24%; p=0.01). In a multiple regression analysis, hypertension and PON1 gene polymorphism were independently associated with FMD. Conclusions: The present findings suggest that the Gln/Gln genotype of the PON1 gene is associated with improved FMD in diabetic patients, consistent with a more effective antioxidant and supposedly protective action on circulating LDL of this variant. I
W e - P 1 1 : 3 4 I D Y S L I P I D A E M I A S I N N O N - O B E S E T Y P E II i DIABETIC PATIENTS WITH ATHEROSCLEROSIS (HORMONAL PATTERNS) • .~ I. Tsiple 1 , I. Cosciu~al . 1 Centre V. Anestiadi 1 , V. Anestiadi 1 , Z. Anestladi%
for Pathobiology arm Pathology, Academy of Sciences, Chisinau, Moldova: 2Chair of Endocrinology, Medical Universi~, Chisinau, Moldova Objective: The aim was to evaluate the hormonal patterns of dyslipidaemias
353
in non-obese patients (pts) with type II diabetes mellitus (DM) and atherosderosis (ATH). M e t b o d s : Group 1 (grl) was composed of 30 normal subjects (age = 54.50-4-2.03; means-4-SEM). Group 2 (gr2) consisted of 20 non-obese type II DM pts with hypertriglyceridaemia (type IV HLP) and ATH (age = 53.19-4-1.91). Group 3 (gr3) consisted of 23 non-obese type II DM pts with mixed hyperlipidaemia (type IIB HLP) and ATH (age = 56.73-4-1.96). Following have been determined in serum, in fasting state: total cholesterol (CH), HDL-cholesterol (HDL-CH), atherogenicity coefficient (HAC), triglycerides (TG), lipolytic activity (LA), lipoprotein fractions, prostaglandins A1 and E l , prostaglandin F2a (PGF). Following have been determined in plasma, during standard OGTT: glucose, insulin, insulin/glucose index (IGI), glucagon, C-peptide, STH, somatostatin, ACTH, cortisol, aldosterone, beta-endorphin. Results: Both gr2 and gr3 pts, compared to grl, had higher body mass, CH, TG, HAC, and lower HDL-CH, LA, insulin (at OGTT hour 1), IGI, STH (hour 2), basal aldosterone. Gr2 pts, compared to grl, had lower STH (hours 1 and 2). Gr3 pts, compared to grl, had higher glucagon (hour 2), somatostatin (hours 0 and 1), cortisol (hours 1 and 2), PGF, and lower C-peptide (hour 1), STH (hours 0 and 2). Conclusions: Altered hormonal patterns have been observed in non-obese type II DM pts with ATH and dyslipidaemias, including decreased STH and elevated cortisol. q
I We-P11:35 / METFORMIN IMPROVES OXIDATIVE STRESS AND D E C R E A S E S P L A T E L E T A C T I V A T I O N IN N E W L Y DIAGNOSED TYPE 2 DIABETIC SUBJECTS
G. Formoso - , E.A. De Filippis i N. Michetti 1,2 G. Ciabattoni 1,3 E Di • 1"} Fulwo "% A. Pandolfi 1,4 F. Capani 1,2 G. DavI-1,}"%A. Consoh.1,}"-. 1Center of
Excellence On Aging, Universi~ G. d'Atmunzio, Chieti-Pescara, Italy: "-Department of Medicine and Aging Science, Universi~ G. d'Anmmzio, Chieti-Pescara, Italy," - Department of Drug Sciences, Universi~ G. d'Annunzio, Chieti-Pescara, Italy." 4Department of Biomotphology, Universi~ G. d'Annunzio, Chieti-Pescara, Italy Objectives: In type 2 diabetes (T2DM) metformin treatment reduces cardiovascular (CV) risk beyond the effect of glycemic control. Since oxidative stress and the consequent enhanced platelet activation greatly contribute to accelerated atherosclerosis in diabetes, we hypothesized that metformin could concur in reducing oxidative stress in T2DM patients. M e t h o d s : We randomized 26 newly diagnosed T2DM subjects to assume either metformin (M, n=13) or gliclazide (G, n=13) for 12 weeks. Drugs were titrated as needed on the bases of blood glucose profiles and H b A l c levels so to achieve good glycemic control. Before and after treatment, blood and urinary samples were collected to determine blood glucose, insulin, H b A l c , Vit A and Vit E levels and 8-iso-PGF2 and 11-dehydro-tromboxane B2 (TXM) urinary excretion, an in vivo oxidative stress and a thromboxane dependent platelet activation marker, respectively. Results: Notwithstanding a comparable improvement in metabolic control ( H b A l c < 7 after both M and G), 8-iso-PGF2 (M =942 92 vs 811 75 pg/mg cr, p<.01; G=746 80 vs 765 82, p=n.s) and TXM (M= 2190 196 vs 1865 103 pg/mg cr, p<.01; G=1586 223 vs 1440 270, p=n.s) urinary excretion decreased after metformin but not after gliclazide treatment. After meftormin, antioxidant vitamins A and E levels significantly increased while they remained unchanged or decreased after gliclazide. C o n d u s i o n s : These data suggest that metformin could improve oxidative stress, preserve antioxidant function and restrain platelet activation in T2DM. This could contribute to the observed CV risk reduction following metformin treatment. q
I We-P11:36 /
IMPAIRED GLUCOSE METABOLISM IN PATIENTS WITH NEWLY DIAGNOSED CORONARY ARTERY DISEASE
A. Gotsis, E Bozia, S. Dourtsiou, A. Labrou, L. Papadopoulou, A. Savvopoulou, L. BorghL D. Theodoridis, S. Karras, A. Panagiotidou.
Cardiology Department, General Hospital of Komotini, Komotini, Greece A i m : To assess the prevalence of impaired glucose metabolism comprising
diabetes mellitus (DM) and the prediabetic state in patients with newly established CAD. M e t h o d s : We studied 136 consecutive patients without CAD history, 103 males (M) and 33 females (F) aged 63.14-10.5 years old, admitted with acute coronary syndrome. A detailed medical history was taken and a complete biochemical control was made. Height, weight and waist circumference were
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006
Wednesday, June 21, 2006: Poster Session Opti.~fl atherosclerosis management (lstpart)
I
We-P11:32 ] UNCOUPLED ENDOTHELIAL NITRIC OXIDE i
SYNTHASE IN DIABETIC BONE MARROW-IMPACT
ON ENDOTHELIAL PROGENITOR CELLS T. Thum, D. Fraccaxollo, E Galuppo, M. Schultheiss, G. Ertl, J. Bauersachs.
Julius-Maximilians-Universit~it, Mediz#usche Kl#uk I, Kardiologie, Wiirzburg, Germany Endothelial progenitor cells OEPC) mobilized from bone marrow contribute to replacement of diseased endothelial cells, thereby limiting atherosclerotic plaque formation. Translocation of EPC to the circulation involves vascular endothelial growth factor (VEGF)/nitric oxide (NO) and matrix metalloproteinase-9 (MMP-9)-mediated pathways in bone marrow. In rats with streptozotocin-induced diabetes we investigated alterations of bone marrow molecular mobilising pathways, which determine circulating EPC levels. Diabetes was associated with a reduction of circulating EPC to 39-4-5% when compared to controls. Superoxide anion (02-) production was substantially enhanced in diabetic bone marrow, eNOS protein expression was increased in bone marrow extracts of diabetic rats, but eNOS dimer/monomer ratio as well as eNOS and Akt phosphorylation were reduced. NOS inhibition decreased 0 2 - levels in bone marrow of diabetic rats indicating the involvement of eNOS in exaggerated 0 2 - production. MMP-9 activity was significantly depressed in bone marrow of diabetic animals compared to controls. Treatment with the angiotensin receptor blocker telmisaxtan improved phosphorylation of eNOS in diabetic bone marrow and increased EPC levels. Our data show uncoupling of eNOS in diabetic bone marrow, resulting in eNOS-mediated 0 2 - production, and reduced MMP-9 activity. Subsequent reduction of EPC levels is likely to contribute to the pathogenesis of vascular disease in diabetes mellitus. Angiotensin receptor blockade may be a novel therapeutic approach to reverse eNOS uncoupling in bone marrow and normalise impaired EPC levels in diabetes. I
W e - P 1 1 : 3 3 ] P A R A O X O N A S E G E N E P O L Y M O R P H I S M (PON1 192) i IS A S S O C I A T E D W I T H E N D O T H E L I A L F U N C T I O N IN PATIENTS WITH TYPE 2 DIABETES ]
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.
.o
.o
C. Irace , C. Cortese% F. Dell'Aquila I , L. Llberatoscloh% L. Mannucc1% G. Federici 2 , A. Gnasso 1.1Dept" of Clinical arm E~perimental Medicine,
Universi~ of Catanzaro, Catanzaro, Italy: 2Dept. of bttental Medicine, Universi~ of Tor Vergata, Rome, Italy Objective: Endothelial dysfunction is frequent in diabetic patients and may be related to increased oxidation of circulating LDL. Paraoxonase (PON1) is an HDL-linked anti-oxidant enzyme whose activity is influenced by a genetic polymorphism at codon 192 resulting in a Gln to Arg change. In the present study, we have investigated the possible association between the PON1 polymorphism and the endothelial function in patients with type 2 diabetes mellitus. M e t h o d s : 69 diabetic patients and 41 sex- and age-matched controls were enrolled. The PON1 Gln192Arg polymorphism was determined by PCR amplification and restriction enzyme analysis. Endothelial function was evaluated by flow-mediated vasodilation (FMD) of the brachial artery after forearm ischemia. Data were analyzed according to the presence or absence of the Arg allele of the PON1 gene. Results: In the control group, no difference was observed in FMD between subjects homozygous for the Gln allele and those carrying the Arg allele. In the diabetic group, FMD was lower among those carrying the Arg allele compared with homozygous for the Gln allele (1.90-4-1.65% vs. 3.69-4-2.40%; p=0.02). This difference was even more significant after exclusion of subjects with hypertension (2.01-4-1.27% vs. 5.72-4-3.24%; p=0.01). In a multiple regression analysis, hypertension and PON1 gene polymorphism were independently associated with FMD. Conclusions: The present findings suggest that the Gln/Gln genotype of the PON1 gene is associated with improved FMD in diabetic patients, consistent with a more effective antioxidant and supposedly protective action on circulating LDL of this variant. I
W e - P 1 1 : 3 4 I D Y S L I P I D A E M I A S I N N O N - O B E S E T Y P E II i DIABETIC PATIENTS WITH ATHEROSCLEROSIS (HORMONAL PATTERNS) • .~ I. Tsiple 1 , I. Cosciu~al . 1 Centre V. Anestiadi 1 , V. Anestiadi 1 , Z. Anestladi%
for Pathobiology arm Pathology, Academy of Sciences, Chisinau, Moldova: 2Chair of Endocrinology, Medical Universi~, Chisinau, Moldova Objective: The aim was to evaluate the hormonal patterns of dyslipidaemias
353
in non-obese patients (pts) with type II diabetes mellitus (DM) and atherosderosis (ATH). M e t b o d s : Group 1 (grl) was composed of 30 normal subjects (age = 54.50-4-2.03; means-4-SEM). Group 2 (gr2) consisted of 20 non-obese type II DM pts with hypertriglyceridaemia (type IV HLP) and ATH (age = 53.19-4-1.91). Group 3 (gr3) consisted of 23 non-obese type II DM pts with mixed hyperlipidaemia (type IIB HLP) and ATH (age = 56.73-4-1.96). Following have been determined in serum, in fasting state: total cholesterol (CH), HDL-cholesterol (HDL-CH), atherogenicity coefficient (HAC), triglycerides (TG), lipolytic activity (LA), lipoprotein fractions, prostaglandins A1 and E l , prostaglandin F2a (PGF). Following have been determined in plasma, during standard OGTT: glucose, insulin, insulin/glucose index (IGI), glucagon, C-peptide, STH, somatostatin, ACTH, cortisol, aldosterone, beta-endorphin. Results: Both gr2 and gr3 pts, compared to grl, had higher body mass, CH, TG, HAC, and lower HDL-CH, LA, insulin (at OGTT hour 1), IGI, STH (hour 2), basal aldosterone. Gr2 pts, compared to grl, had lower STH (hours 1 and 2). Gr3 pts, compared to grl, had higher glucagon (hour 2), somatostatin (hours 0 and 1), cortisol (hours 1 and 2), PGF, and lower C-peptide (hour 1), STH (hours 0 and 2). Conclusions: Altered hormonal patterns have been observed in non-obese type II DM pts with ATH and dyslipidaemias, including decreased STH and elevated cortisol. q
I We-P11:35 / METFORMIN IMPROVES OXIDATIVE STRESS AND D E C R E A S E S P L A T E L E T A C T I V A T I O N IN N E W L Y DIAGNOSED TYPE 2 DIABETIC SUBJECTS
G. Formoso - , E.A. De Filippis i N. Michetti 1,2 G. Ciabattoni 1,3 E Di • 1"} Fulwo "% A. Pandolfi 1,4 F. Capani 1,2 G. DavI-1,}"%A. Consoh.1,}"-. 1Center of
Excellence On Aging, Universi~ G. d'Atmunzio, Chieti-Pescara, Italy: "-Department of Medicine and Aging Science, Universi~ G. d'Anmmzio, Chieti-Pescara, Italy," - Department of Drug Sciences, Universi~ G. d'Annunzio, Chieti-Pescara, Italy." 4Department of Biomotphology, Universi~ G. d'Annunzio, Chieti-Pescara, Italy Objectives: In type 2 diabetes (T2DM) metformin treatment reduces cardiovascular (CV) risk beyond the effect of glycemic control. Since oxidative stress and the consequent enhanced platelet activation greatly contribute to accelerated atherosclerosis in diabetes, we hypothesized that metformin could concur in reducing oxidative stress in T2DM patients. M e t h o d s : We randomized 26 newly diagnosed T2DM subjects to assume either metformin (M, n=13) or gliclazide (G, n=13) for 12 weeks. Drugs were titrated as needed on the bases of blood glucose profiles and H b A l c levels so to achieve good glycemic control. Before and after treatment, blood and urinary samples were collected to determine blood glucose, insulin, H b A l c , Vit A and Vit E levels and 8-iso-PGF2 and 11-dehydro-tromboxane B2 (TXM) urinary excretion, an in vivo oxidative stress and a thromboxane dependent platelet activation marker, respectively. Results: Notwithstanding a comparable improvement in metabolic control ( H b A l c < 7 after both M and G), 8-iso-PGF2 (M =942 92 vs 811 75 pg/mg cr, p<.01; G=746 80 vs 765 82, p=n.s) and TXM (M= 2190 196 vs 1865 103 pg/mg cr, p<.01; G=1586 223 vs 1440 270, p=n.s) urinary excretion decreased after metformin but not after gliclazide treatment. After meftormin, antioxidant vitamins A and E levels significantly increased while they remained unchanged or decreased after gliclazide. C o n d u s i o n s : These data suggest that metformin could improve oxidative stress, preserve antioxidant function and restrain platelet activation in T2DM. This could contribute to the observed CV risk reduction following metformin treatment. q
I We-P11:36 /
IMPAIRED GLUCOSE METABOLISM IN PATIENTS WITH NEWLY DIAGNOSED CORONARY ARTERY DISEASE
A. Gotsis, E Bozia, S. Dourtsiou, A. Labrou, L. Papadopoulou, A. Savvopoulou, L. BorghL D. Theodoridis, S. Karras, A. Panagiotidou.
Cardiology Department, General Hospital of Komotini, Komotini, Greece A i m : To assess the prevalence of impaired glucose metabolism comprising
diabetes mellitus (DM) and the prediabetic state in patients with newly established CAD. M e t h o d s : We studied 136 consecutive patients without CAD history, 103 males (M) and 33 females (F) aged 63.14-10.5 years old, admitted with acute coronary syndrome. A detailed medical history was taken and a complete biochemical control was made. Height, weight and waist circumference were
XIV bztentational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006