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      Non-dipping and arterial hypertension depend on clinical factors rather than on genetic variability of ACE and RGS2 genes in patients with type 1 diabetes

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          Abstract

          The aim of our study was to characterize the association of clinical and genetic risk factors such as: ACE genotype (rs17997552, rs1800764, rs4459609) and RGS2 (rs2746071) with the development of hypertension (HT) and non-dipping phenomenon in patients with type 1 diabetes mellitus (T1DM). A total of 238 adolescents and young adults with T1DM—103 females and 135 males, aged 8–30 years (mean 17.35 ± 5.2) with diabetes duration 1–26 years (mean 7.72 ± 6.2), with mean HbA1c (IFCC) 58 ± 15 mmol/mmol—were subjected to 24-h ambulatory blood pressure measurements (ABPM). The results of the ABPM were analyzed in association with the polymorphisms of ACE and RGS2 genes and clinical data of patients. HT was recognized in 65 (27 %) and non-dipping in 111 (46.63 %) patients. In the multivariate analysis of factors predisposing to HT, the variables that remained significant were the following: male sex (OR 1.62; 95 % CI 1.171–2.250), non-dipping (OR 1.40; 95 % CI 1.03–1.90) and total cholesterol level (OR 1.01; 95 % CI 1.005–1.021). The only factor influencing non-dipping was the duration of diabetes—OR 1.09 (95 % CI 1.04–1.14). The patients displaying non-dipping have a twice increased risk of development of HT (OR 2.17; 95 % CI 1.21–3.89). There was no association between disturbances of blood pressure (BP) and genotypes of ACE: rs17997552, rs1800764, rs4459609 and RGS2: rs2746071. Clinical rather than genetic risk factors seem to be connected with BP disturbances in young patients with T1DM. Although we have identified representative groups of HT versus non-HT and dipping versus non-dipping subjects, the effect of genetic predisposition to the development of higher BP is too weak to be statistically significant.

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          The online version of this article (doi:10.1007/s00592-014-0568-0) contains supplementary material, which is available to authorized users.

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          Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.

          Signaling by hormones and neurotransmitters that activate G protein-coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2+/- and rgs2-/- mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor-mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.
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            The association of hypertension and diabetes: prevalence, cardiovascular risk and protection by blood pressure reduction.

            G Mancia (2005)
            Diabetes and hypertension frequently coexist, and their combination provides additive increases in the risk of life-threatening cardiovascular events. Recent guidelines agree on the need for early, aggressive reduction of blood pressure, with a goal of <130/80 mmHg, in patients with diabetes. The mechanism that underpins the increased sensitivity of diabetic subjects to hypertension is not known, but may involve impaired autoregulation or attenuated nocturnal decrease of blood pressure. All classes of antihypertensive agents are effective in reducing blood pressure in diabetic subjects, and all show evidence of a concomitant reduction in cardiovascular risk. Although there is some evidence that agents that interrupt the renin-angiotensin system (RAS) provide greater protective effects, the data are not conclusive. However, most diabetic subjects will require combination therapy to reach goal blood pressure. Antihypertensive drugs can also significantly influence the probability that otherwise healthy individuals will develop metabolic syndrome or type 2 diabetes. While diuretics and betablockers have a prodiabetic effect, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may prevent diabetes more effectively than the metabolically neutral calcium channel blockers. Given that diabetes is an important cardiovascular risk factor, there is the potential for reductions in risk due to reduced blood pressure to be offset by an increased risk due to the development of diabetes. Such concerns should be considered in the selection of antihypertensive therapy.
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              Implications of Nocturnal Hypertension in Children and Adolescents With Type 1 Diabetes

              OBJECTIVE Diabetes is associated with atherogenic risk factors. Hypertension has a major influence on cardiovascular disease in diabetic patients. Ambulatory blood pressure monitoring (ABPM) is useful for identifying nocturnal hypertension. Carotid intima-media thickness (cIMT) is a good measure for identifying subclinical atherosclerosis. This study aimed to evaluate whether nocturnal hypertension affects atherosclerosis in children and adolescents with type 1 diabetes and to investigate the relationship between atherogenic risk factors and cIMT. RESEARCH DESIGN AND METHODS ABPM and cIMT were measured in 82 diabetic children and adolescents. We reviewed the hemoglobin A1c levels, 24-h urine microalbumin excretion, lipid profiles, and duration of diabetes. Nocturnal hypertension was defined as hypertension observed only at night. RESULTS Forty-three (52%) subjects were hypertensive, and 30 subjects were classified as having nocturnal hypertension. cIMT was higher in the nocturnal hypertensive group than in the normotensive group (0.44 ± 0.03 vs. 0.42 ± 0.04 mm, P = 0.026). Among children and adolescents with nonhypertensive blood pressure levels in clinic blood pressure monitoring, cIMT and daytime blood pressure were higher in the nocturnal hypertensive group. All ABPM parameters were significantly related to cIMT in multiple linear regression analysis. CONCLUSIONS This study showed significantly increased cIMT and daytime blood pressure in diabetic children and adolescents with nocturnal hypertension. ABPM may be a useful method for detecting the macrovascular complications of type 1 diabetes. Longitudinal studies are needed to find the causes of nocturnal hypertension and to evaluate the effect of nocturnal hypertension on atherosclerosis in type 1 diabetes.
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                Author and article information

                Contributors
                +48-322071654 , +48-322071653 , gr.deja@gmail.com
                Journal
                Acta Diabetol
                Acta Diabetol
                Acta Diabetologica
                Springer Milan (Milan )
                0940-5429
                1432-5233
                23 February 2014
                23 February 2014
                2014
                : 51
                : 633-640
                Affiliations
                [ ]Department of Pediatrics, Pediatric Endocrinology and Diabetology, Medical University of Silesia, Medykow 16 Str., 40-752 Katowice, Poland
                [ ]Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland
                [ ]Department of Pediatrics, Pediatric Endocrinology and Diabetology, Upper Silesia Child Health Center, Katowice, Poland
                [ ]Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland
                Author notes

                Communicated by Massimo Porta.

                Article
                568
                10.1007/s00592-014-0568-0
                4127442
                24562335
                49bbb951-b66b-4bc5-b768-976226d0a641
                © The Author(s) 2014

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 19 November 2013
                : 31 January 2014
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag Italia 2014

                Endocrinology & Diabetes
                diabetes mellitus type 1,hypertension,non-dipping,abpm,ace genotype,rgs2 genotype

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