GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus

Background: The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.<p></p> Methods: Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).<p></p> Results: Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.<p></p> Conclusions: Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients

The genetic spectrum of familial hypercholesterolemia in south-eastern Poland

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population. MATERIALS AND METHODS: 161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation. RESULTS: We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol. CONCLUSIONS: These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level

Intima-media thickness and selected parameters of endothelial function in patients with type 2 diabetes

WSTĘP. Cukrzyca typu 2 stanowi poważny problem zdrowotny oraz ekonomiczny, co wiąże się przede wszystkim z rozwojem jej przewlekłych powikłań. Za jeden z mechanizmów prowadzących do ich powstawania uważa się zaburzenia funkcji śródbłonka. Celem niniejszej pracy była ocena wskaźnika grubości kompleksu intima-media (IMT) i wybranych parametrów funkcji śródbłonka u chorych na cukrzycę typu 2. Szczegółowe cele pracy obejmowały: - ocenę grubości IMT w tętnicach szyjnych wspólnych u chorych na cukrzycę typu 2 oraz u osób bez cukrzycy; - ocenę wybranych parametrów funkcji wazomotorycznej i wydzielniczej śródbłonka naczyniowego u chorych na cukrzycę typu 2 oraz u osób bez cukrzycy. MATERIAŁ I METODY. Do badania włączono 182 chorych na cukrzycę typu 2, pozostających pod opieką poradni diabetologicznej przy Katedrze i Klinice Chorób Metabolicznych w Krakowie. Cukrzycę typu 2 rozpoznawano zgodnie z kryteriami WHO. Do badania zakwalifikowano osoby z co najmniej 5-letnim czasem trwania choroby, u których cukrzycę rozpoznano po 35. roku życia i stosowano w nich leki doustne przez co najmniej 2 lata po rozpoznaniu. Grupę kontrolną stanowiło 43 zdrowych, dorosłych ochotników, którzy wyrazili zgodę na udział w badaniu i mieli prawidłowe stężenie glukozy na czczo oraz prawidłowy wynik doustnego testu tolerancji glukozy. U wszystkich pacjentów przeprowadzono podmiotowe i przedmiotowe badanie lekarskie oraz pomiar IMT za pomocą USG. Oceny funkcji śródbłonka dokonano poprzez pomiary: - rozkurczu naczynia związanego z reaktywnym przekrwieniem tętnicy ramiennej metodą FMD; - biochemicznych markerów funkcji śródbłonka: czynnika von Willebranda (vWf) i rozpuszczalnej molekuły adhezyjnej (s-ICAM-1). Analiza statystyczna obejmowała metodę ANOVA, test Manna-Whitneya, nieparametryczny test c2, obliczenie współczynnika korelacji liniowej r-Pearsona. Ponadto zastosowano wielokrotną regresję logistyczną. WYNIKI. Przebadano 182 chorych na cukrzycę typu 2, w tym 91 kobiet (50,0%) i 91 mężczyzn (50,0%) (średni wiek w momencie badania - 56,3 roku) oraz 43 osoby bez cukrzycy (średni wiek w momencie badania - 55,4 roku) stanowiące grupę kontrolną. Średnie wartości IMT były istotnie wyższe, a maksymalne wartości FMD istotnie niższe w grupie chorych na cukrzycę typu 2 niż w grupie kontrolnej (odpowiednio: 0,83 mm vs. 0,66 mm; p < 0,00005 i 9,0% vs. 11,4%; p = 0,0165). Nie stwierdzono istotnych statystycznie różnic pomiędzy stężeniem s-ICAM-1 i czynnika von Willebranda w surowicy u chorych na cukrzycę typu 2 i u osób z grupy kontrolnej. W analizie metodą regresji liniowej cukrzyca typu 2 okazała się niezależnym predyktorem pogrubienia wskaźnika IMT (p < 0,001). Cukrzyca typu 2 nie była w opisanym badaniu niezależnym czynnikiem ryzyka w odniesieniu do pozostałych badanych parametrów: FMD oraz stężeń vWF i s-ICAM-1. WNIOSKI. Chorzy na cukrzycę typu 2 cechują się częstym występowaniem pogrubienia IMT oraz upośledzeniem funkcji rozkurczowej naczyń tętniczych. Cukrzyca typu 2 jest niezależnym predyktorem pogrubienia IMT.INTRODUCTION. Type 2 diabetes (DM 2) is a growing health and economic problem, mainly because of development of its chronic complications. One of possible mechanisms leading to their occurrence is endothelial dysfunction (ED). The aim of the study was to asses intima-media thickness (IMT) and selected parameters of ED in patients with DM 2. Specific aims were: - assessment of IMT in DM 2 and in the controls; - assessment of selected parameters of vasomotor and secretory function of endothelium in DM 2 patients and in the controls. MATERIAL AND METHODS. We examined 182 patients with DM 2 from the outpatient clinic of Department of Metabolic Diseases, Jagiellonian University, Medical College. Diabetes was diagnosed according to WHO criteria. We included in our study DM 2 patients with at least 5 years diabetes duration, who were diagnosed after age 35 and were treated with oral hypoglycemic agents for at least 2 years. The control group included 43 healthy volunteers with normal fasting glucose level and correct result of oral glucose tolerance test according to WHO. All patients were examined and medical history was taken. We also measured IMT by ultrasound. We assessed endothelial function by - flow-mediated dilatation (FMD) method; - assessment of biochemical markers of ED - von Willebrand factor (vWf) and s-ICAM-1 (soluble intercellular adhesion molecule-1) concentrations. Statistical analysis included ANOVA analysis, Mann-Whitney&#8217;s test, &#967;2 test, calculation of Pearson&#8217;s linear correlation coefficient and multiple regression analysis. RESULTS. We examined 182 patients with type 2 DM (mean age at the examination 56.3 yrs) including 91 (50%) women and 91 (50%) men together with 43 non-diabetic volunteers (mean age at the examination 55.4 years). Mean IMT was significantly higher and maximal FMD lower in DM 2 patients than in control group (respectively 0.83 mm vs. 0.66 mm; p < 0.00005 and 9.0% vs. 11.4%; p = 0.0165). No significant differences were found between groups in respect to s-ICAM-1 and vWf concentration. In multiple linear regression DM 2 was an independent predictor of increased IMT (p < 0.001). DM 2 did not appear to be a predictor of the other examined parameters: FMD as well as vWF and s-ICAM-1 levels. CONCLUSIONS. DM 2 patients are characterized by the common occurence of increased IMT and endothelial vasodilation function. DM 2 is an independent predictor of intima-media thickening

Plasma asymmetric dimethylarginine (ADMA) is associated with retinopathy in type 2 diabetes

No abstract available

Retinopathy in type 2 diabetes mellitus is associated with increased intima-media thickness and endothelial dysfunction

Background  Microangioathy and macroangiopathy in type 2 diabetes mellitus (T2DM) frequently coexist. Both types of vascular complications share traditional risk factors. It is not clear whether the presence of microangiopathy, such as diabetic retinopathy (DR), constitutes a predictor of atherosclerosis in T2DM. Here we described the search for the association between DR and intima-media thickness (IMT) in T2DM. We also compared endothelial function in subjects with and without DR. Material and methods  We examined 182 consecutive patients with T2DM for at least 5 years (mean age at examination 56·3 ± 6·52 years). We assessed (i) IMT of carotid artery by ultrasound and (ii) endothelial function by flow-mediated dilatation (FMD) method as well as by measurement of concentrations of von Willebrand factor (vWF) and s-ICAM-1. All patients underwent ophthalmological examination. Statistical analysis included Student's, Mann–Whitney, chi-square, Fisher tests and multiple regression. Results  DR was found in 71 (39·0%) subjects. IMT was higher in patients with DR than those without DR (0·87 mm vs. 0·79 mm, respectively, P = 0·0001). FMD was lower in the complication group than in subjects without DR (8·38% vs. 10·45%, respectively, P = 0·0023). Concentrations of s-ICAM-1 and vWF were not different between the groups. In multiple regression analysis, DR was among the predictors of increased IMT (P = 0·016) and decreased FMD (P = 0·002). We did not find a significant association of DR with vWF and s-ICAM-1 (P = 0·09 and P = 0·11, respectively). Conclusions  DR is associated with increased IMT and endothelial dysfunction in T2DM. Impaired endothelial function may be a common denominator of pathogenesis of microvascular complications and atherosclerosis in T2DM