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Maruhashi T, Higashi Y. Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction. Antioxidants (Basel) 2021; 10:antiox10081306. [PMID: 34439553 PMCID: PMC8389282 DOI: 10.3390/antiox10081306] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Endothelial dysfunction plays a critical role in atherosclerosis progression, leading to cardiovascular complications. There are significant associations between diabetes mellitus, oxidative stress, and endothelial dysfunction. Oxidative stress is increased by chronic hyperglycemia and acute glucose fluctuations induced by postprandial hyperglycemia in patients with diabetes mellitus. In addition, selective insulin resistance in the phosphoinositide 3-kinase/Akt/endothelial nitric oxide (NO) synthase pathway in endothelial cells is involved in decreased NO production and increased endothelin-1 production from the endothelium, resulting in endothelial dysfunction. In a clinical setting, selecting an appropriate therapeutic intervention that improves or augments endothelial function is important for preventing diabetic vascular complications. Hypoglycemic drugs that reduce glucose fluctuations by decreasing the postprandial rise in blood glucose levels, such as glinides, α-glucosidase inhibitors and dipeptidyl peptidase 4 inhibitors, and hypoglycemic drugs that ameliorate insulin sensitivity, such as thiazolidinediones and metformin, are expected to improve or augment endothelial function in patients with diabetes. Glucagon-like peptide 1 receptor agonists, metformin, and sodium-glucose cotransporter 2 inhibitors may improve endothelial function through multiple mechanisms, some of which are independent of glucose control or insulin signaling. Oral administration of antioxidants is not recommended in patients with diabetes due to the lack of evidence for the efficacy against diabetic complications.
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Affiliation(s)
- Tatsuya Maruhashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
| | - Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima 734-8551, Japan
- Correspondence: ; Tel.: +81-82-257-5831
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Trefz P, Obermeier J, Lehbrink R, Schubert JK, Miekisch W, Fischer DC. Exhaled volatile substances in children suffering from type 1 diabetes mellitus: results from a cross-sectional study. Sci Rep 2019; 9:15707. [PMID: 31673076 PMCID: PMC6823423 DOI: 10.1038/s41598-019-52165-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 10/10/2019] [Indexed: 02/06/2023] Open
Abstract
Monitoring metabolic adaptation to type 1 diabetes mellitus in children is challenging. Analysis of volatile organic compounds (VOCs) in exhaled breath is non-invasive and appears as a promising tool. However, data on breath VOC profiles in pediatric patients are limited. We conducted a cross-sectional study and applied quantitative analysis of exhaled VOCs in children suffering from type 1 diabetes mellitus (T1DM) (n = 53) and healthy controls (n = 60). Both groups were matched for sex and age. For breath gas analysis, a very sensitive direct mass spectrometric technique (PTR-TOF) was applied. The duration of disease, the mode of insulin application (continuous subcutaneous insulin infusion vs. multiple daily insulin injection) and long-term metabolic control were considered as classifiers in patients. The concentration of exhaled VOCs differed between T1DM patients and healthy children. In particular, T1DM patients exhaled significantly higher amounts of ethanol, isopropanol, dimethylsulfid, isoprene and pentanal compared to healthy controls (171, 1223, 19.6, 112 and 13.5 ppbV vs. 82.4, 784, 11.3, 49.6, and 5.30 ppbV). The most remarkable differences in concentrations were found in patients with poor metabolic control, i.e. those with a mean HbA1c above 8%. In conclusion, non-invasive breath testing may support the discovery of basic metabolic mechanisms and adaptation early in the progress of T1DM.
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Affiliation(s)
- Phillip Trefz
- Department of Anesthesiology and Intensive Care Medicine, Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Rostock University Medical Centre, Rostock, Germany.
| | - Juliane Obermeier
- Department of Anesthesiology and Intensive Care Medicine, Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Rostock University Medical Centre, Rostock, Germany
| | - Ruth Lehbrink
- Department of Pediatrics, Rostock University Medical Centre, Rostock, Germany
| | - Jochen K Schubert
- Department of Anesthesiology and Intensive Care Medicine, Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Rostock University Medical Centre, Rostock, Germany
| | - Wolfram Miekisch
- Department of Anesthesiology and Intensive Care Medicine, Rostock Medical Breath Research Analytics and Technologies (ROMBAT), Rostock University Medical Centre, Rostock, Germany
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Teixeira RS, Arriaga MB, Terse-Ramos R, Ferreira TA, Machado VR, Rissatto-Lago MR, Silveira-Mattos PS, Boa-Sorte N, Ladeia AMT, Andrade BB. Higher values of triglycerides:HDL-cholesterol ratio hallmark disease severity in children and adolescents with sickle cell anemia. ACTA ACUST UNITED AC 2019; 52:e8833. [PMID: 31618296 PMCID: PMC6799940 DOI: 10.1590/1414-431x20198833] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 01/01/2023]
Abstract
Dyslipidemia has been described in sickle cell anemia (SCA) but its association with increased disease severity is unknown. Here, we examined 55 children and adolescents with SCA as well as 41 healthy controls to test the association between the lipid profiles in peripheral blood and markers of hemolysis, inflammation, endothelial function, and SCA-related clinical outcomes. SCA patients exhibited lower levels of total cholesterol (P<0.001), low-density lipoprotein cholesterol (LDL-c) (P<0.001), and high-density lipoprotein cholesterol (HDL-c) (P<0.001), while displaying higher triglyceride (TG) levels and TG/HDL-c ratio values (P<0.001). TG/HDL-c values were positively correlated with lactate dehydrogenase (P=0.047), leukocyte count (P=0.006), and blood flow velocity in the right (P=0.02) and left (P=0.05) cerebral artery, while being negatively correlated with hemoglobin levels (P<0.04). Acute chest syndrome (ACS) and vaso-occlusive events (VOE) were more frequent in SCA patients exhibiting higher TG/HDL-c values (odds ratio: 3.77, P=0.027). Multivariate logistic regression analysis confirmed independent associations between elevated TG/HDL-c values and SCA. Thus, children and adolescents with SCA exhibited a lipid profile associated with hemolysis and inflammatory parameters, with increased risk of ACS and VOE. TG/HDL-c is a potential biomarker of severity of disease.
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Affiliation(s)
- R S Teixeira
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - M B Arriaga
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil
| | - R Terse-Ramos
- Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - T A Ferreira
- Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - V R Machado
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil
| | - M R Rissatto-Lago
- Departamento de Ciências da Vida, Universidade Estadual da Bahia, Salvador, BA, Brasil
| | - P S Silveira-Mattos
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil
| | - N Boa-Sorte
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Departamento de Ciências da Vida, Universidade Estadual da Bahia, Salvador, BA, Brasil
| | | | - B B Andrade
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil.,Universidade Salvador, Laureate International Universities, Salvador, BA, Brasil
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4
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Hoffmann M, Neubauer-Geryk J, Wielicka M, Kowaleczko M, Myśliwiec M, Bieniaszewski L. The impact of autoimmune thyroiditis on skin microcirculation in children with non-complicated type 1 diabetes mellitus. Microvasc Res 2019; 123:68-73. [PMID: 30611746 DOI: 10.1016/j.mvr.2019.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/02/2019] [Accepted: 01/02/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND The impairment of endothelial function in type 1 diabetes mellitus (DM1) is considered as the basis of microvascular complications. In DM1 patients autoimmune thyroiditis is a frequent comorbidity which may be responsible for further deterioration of microcirculation function. In studies investigating the relationship between cardiovascular risk factors and microvascular function, skin microcirculation is widely used. The aim of our study was to evaluate the impact of coexisting autoimmune thyroiditis on skin microcirculation in children with type I diabetes mellitus. SUBJECTS The study group consisted of 25 pediatric DM1 patients, 25 pediatric patients with type 1 diabetes and autoimmune thyroiditis (DM1 + AIT) and 29 control subjects matched for age and gender. The DM1 and DM1 + AIT patients were also matched for age at onset of DM and diabetes duration. METHODS Performed capillaroscopy studies employed non-selective stimuli such as post-occlusive reactive hyperemia (PORH) and venous occlusion (VO) tests. The relative area covered by capillaries (coverage) and the distance between capillaries were assessed. These measurements were performed before tests as well as after PORH and VO. RESULTS Coverage at baseline, after PORH and VO and distance after VO differ significantly between control subjects and the group DM1 + AIT. The coverage at baseline, after PORH and VO were significantly smaller in DM1 + AIT compared with the control group. Post-hoc analysis after controlling for lipids levels showed that differences between the DM1 + AIT and control group were remained only for coverage at baseline and after VO. Significant differences between DM1 + AIT and DM1 and control group for coverage after VO were also presented. CONCLUSIONS Coexisting autoimmune thyroiditis significantly deteriorates skin microcirculation function in pediatric non-complicated type 1 diabetic patients. This process is independent of patient age, diabetes duration and age of diabetes onset.
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Affiliation(s)
| | - Jolanta Neubauer-Geryk
- Clinical Physiology Unit, Medical Simulation Centre, Medical University of Gdańsk, Ul. Dębowa 25, 80-204 Gdańsk, Poland.
| | - Melanie Wielicka
- Medical University of Gdańsk, Ul. Dębowa 25, 80-204 Gdańsk, Poland
| | - Magdalena Kowaleczko
- Department of Pediatrics, Diabetology and Endocrinology, Medical University of Gdańsk, Ul. Dębowa 7, 80-211 Gdańsk, Poland
| | - Małgorzata Myśliwiec
- Department of Pediatrics, Diabetology and Endocrinology, Medical University of Gdańsk, Ul. Dębowa 7, 80-211 Gdańsk, Poland
| | - Leszek Bieniaszewski
- Clinical Physiology Unit, Medical Simulation Centre, Medical University of Gdańsk, Ul. Dębowa 25, 80-204 Gdańsk, Poland
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Gourgari E, Dabelea D, Rother K. Modifiable Risk Factors for Cardiovascular Disease in Children with Type 1 Diabetes: Can Early Intervention Prevent Future Cardiovascular Events? Curr Diab Rep 2017; 17:134. [PMID: 29101482 PMCID: PMC5670186 DOI: 10.1007/s11892-017-0968-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW Patients with type 1 diabetes have increased risk for cardiovascular disease. The purpose of this review is to examine the following: i) current evidence for subclinical cardiovascular disease (CVD) in children with type 1 diabetes (T1DM) ii) known modifiable risk factors for CVD and their relationship to subclinical CVD in this population iii) studies that have addressed these risk factors in order to improve CVD outcomes in children with T1DM RECENT FINDINGS: Subclinical CVD presents in children as increased carotid intima-media thickness, increased arterial stiffness, and endothelial and myocardial dysfunction. Modifiable risk factors for CVD include hyperglycemia, hyperlipidemia, obesity, hypertension, depression, and autonomic dysfunction. Very few randomized controlled studies have been done in children with T1DM to examine how modification of these risk factors can affect their CVD. Children with T1DM have subclinical CVD and multiple modifiable risk factors for CVD. More research is needed to define how modification of these factors affects the progression of CVD.
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Affiliation(s)
- Evgenia Gourgari
- Department of Pediatrics, Georgetown University, Washington DC, USA
- Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD USA
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO USA
| | - Kristina Rother
- Section on Pediatric Diabetes and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD USA
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Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. PLoS One 2017; 12:e0184076. [PMID: 28863145 PMCID: PMC5580915 DOI: 10.1371/journal.pone.0184076] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 08/17/2017] [Indexed: 01/22/2023] Open
Abstract
Background Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA). An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA. Methods This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6–18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP), glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU) and those who were not. Results Flow-mediated vasodilation (FMD) values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS) episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not. Conclusions Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages.
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Erener S, Marwaha A, Tan R, Panagiotopoulos C, Kieffer TJ. Profiling of circulating microRNAs in children with recent onset of type 1 diabetes. JCI Insight 2017; 2:e89656. [PMID: 28239651 DOI: 10.1172/jci.insight.89656] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that is clinically silent until the majority of β cells are destroyed. There is an unmet need for reliable and cost-effective biomarkers to predict and diagnose diabetes at an early stage. A number of stable microRNAs (miRNAs) have been reported in serum and plasma and are now being investigated as biomarkers of different diseases. We measured the levels of 745 miRNAs in sera of children with recent-onset T1D and age-matched controls using locked nucleic acid-enhanced (LNA-enhanced) quantitative PCR profiling. Thirty-five miRNAs were significantly different between the groups, and 27 miRNAs were elevated in T1D. Good discriminating power was obtained for 6 miRNAs (miR-454-3p, miR-222-3p, miR-144-5p, miR-345-5p, miR-24-3p, and miR-140-5p), which were not elevated at later stages of diabetes. In silico pathway analysis, based on inferred miRNA target genes, associated glycosaminoglycan biosynthesis as well as PI3K/Akt, MAPK, and Wnt signaling pathways with early stages of T1D. Among the 27 upregulated miRNAs in T1D, 2 miRNAs significantly correlated with hemoglobin A1c (HbA1c), as did 5 of 8 downregulated miRNAs. A total of 134 miRNAs significantly correlated with HbA1c when stratifying hyperglycemia-induced miRNAs from T1D-specific miRNAs. In conclusion, we have identified a serum miRNA pattern of recent-onset T1D and signaling pathways that may be involved in its pathogenesis.
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Affiliation(s)
- Suheda Erener
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ashish Marwaha
- Dermatology and Skin Sciences, Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - Rusung Tan
- Department of Pathology, Sidra Medical and Research Center and Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Doha, Qatar
| | | | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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Javanmardi M, Azadi NA, Amini S, Abdi M. Diagnostic value of cystatin C for diagnosis of early renal damages in type 2 diabetic mellitus patients: The first experience in Iran. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2015; 20:571-576. [PMID: 26600832 PMCID: PMC4621651 DOI: 10.4103/1735-1995.165960] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/12/2015] [Accepted: 07/24/2015] [Indexed: 01/13/2023]
Abstract
BACKGROUND Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus. Now-a-days, cystatin C (CysC) is introduced as a new marker for diagnosis of renal damages; however, use of this marker in clinical laboratories is still controversial. The present study was aimed to evaluate the diagnostic value of serum CysC for early detection or monitoring treatment of kidney damages in the Kurdish people with type 2 diabetes mellitus. MATERIALS AND METHODS Glomerular filtration rate (GFR) was estimated by Modification of Diet in Renal Disease formula. Serum CysC and urine microalbumin were also measured in 126 diabetic and healthy subjects. Blood glycated hemoglobin (Hb) also measured in all healthy and diabetic patients. Two independent samples t-test, Mann-Whitney U-test, one-way ANOVA, and Kruskal-Wallis test, as well as Pearson/Spearman correlation coefficient statistical tests were used as appropriate. RESULTS Serum CysC was higher (1312.41 ng/ml) in diabetic patients with GFR <60 ml/min than other subjects (993.25 ng/ml) (patients with normal kidney function and healthy subjects). A borderline significant correlation between CysC and estimating GFR (r s = -0.16, P = 0.05) but highly significant with microalbumin (r s = 0.22, P = 0.014) was observed. Serum CysC sensitivity, negative and positive predictive values were 100 and 4%. CONCLUSION CysC cover variation of GFR and urine microalbumin, but it cannot be used as a surrogating marker of glycated Hb. According to our results, it seems that serum CysC is a useful marker for screening of DN; but it cannot be used for monitoring of treatment in diabetic patients.
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Affiliation(s)
- Mitra Javanmardi
- Department of Biochemistry, College of Science, Kurdistan Science and Research Branch, Islamic Azad University, Sanandaj, Iran
| | - Namam-Ali Azadi
- Department of Epidemiology and Biostatistics, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sabrieh Amini
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Mohammad Abdi
- Cellular and Molecular Research Center, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Ladeia AM, Sampaio RR, Hita MC, Adan LF. Prognostic value of endothelial dysfunction in type 1 diabetes mellitus. World J Diabetes 2014; 5:601-605. [PMID: 25317238 PMCID: PMC4138584 DOI: 10.4239/wjd.v5.i5.601] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 06/30/2014] [Accepted: 07/18/2014] [Indexed: 02/05/2023] Open
Abstract
Patients with diabetes mellitus are at high risk of developing atherosclerosis, associated with higher rates of micro and macro vascular involvement such as coronary artery disease and renal disease. The role of hyperglycemia to induce synthesis of reactive oxygen species by the oxidation of glucose, leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction (ED). The interaction between C-peptide - the connecting segment of pro-insulin-and nitric oxide in vasodilation is also discussed. Therefore, endothelial dysfunction has been identified as an early marker of vascular disorder in type 1 and type 2 diabetes mellitus. In some other diseases, ED has been considered an independent predictor of vascular disease, regardless of the method used. Studies have demonstrated the importance of endothelial dysfunction as an useful tool for identifying the risk of vascular complications in patients with type 1 diabetes mellitus, particularly as regards to renal impairment. The aim of this review is to clarify the prognostic value of endothelial dysfunction as a marker of vascular disease in these subjects.
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Impaired skin microcirculation in paediatric patients with type 1 diabetes mellitus. Cardiovasc Diabetol 2013; 12:115. [PMID: 23937662 PMCID: PMC3751195 DOI: 10.1186/1475-2840-12-115] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/12/2013] [Indexed: 11/11/2022] Open
Abstract
Aims/hypothesis We used Laser Doppler Fluximetry (LDF) to define "normal" endothelial function in a large cohort of healthy children and adolescents and to evaluate skin microcirculation in paediatric patients with type 1 diabetes mellitus. Methods LDF was performed in 102 healthy children (12.8 ± 3.3 years of age; 48 male) and 68 patients (12.9 ± 3.3 years of age; 33 male). Duration of disease was 5.0 ± 3.97 years. Each participant sequentially underwent three stimulation protocols (localized thermal hyperaemia with localized warming to maximum 40°C, iontophoretic delivery of pilocarpine hydrochloride (PCH) and sodium nitroprusside (SNP)). The maximum relative increase in skin blood flow and the total relative response, i.e. the area under the curve (AUC) to each stimulus (AUCheat, AUCPCH, AUCSNP) was determined. In addition, the area of a right-angled triangle summarizing the time to and the amplitude of the first peak, which represents the axon reflex mediated neurogenic vasodilation (ARR) was calculated. Results In healthy controls, AUCheat, AUCPCH, AUCSNP, and ARR turned out to be independent of sex, age, and anthropometric values. Per parameter the 10th percentile generated from data of healthy controls was used as the lower threshold to define normal endothelial function. Diabetic patients showed significantly reduced vasodilatative response to either physical or pharmacological stimulation with SNP, whereas the response to PCH was comparable in both cohorts. In patients compared to controls i) a significantly higher frequency of impaired vasodilatation in response to heat and SNP was noted and ii) vascular response was classified as pathological in more than one of the parameters with significantly higher frequency. Conclusions/interpretation Skin microvascular endothelial dysfunction is already present in about 25% of paediatric type 1 diabetic patients suffering from type 1 diabetes for at least one year. Future studies are needed to assess the predictive value of endothelial dysfunction in the development of long-term (cardio)vascular comorbidity in these patients.
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Sampaio RR, Ladeia AM, Meneses RB, Lima MDL, Guimaraes AC. C-reactive protein is not correlated with endothelial dysfunction in overweight and obese women. J Clin Med Res 2013; 5:294-9. [PMID: 23864919 PMCID: PMC3712885 DOI: 10.4021/jocmr1418w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2013] [Indexed: 12/27/2022] Open
Abstract
Background Obesity is a complex and multifactorial disease, has an inflammatory pattern and is associated with higher cardiometabolic risk. There are recent reports associating an elevated C-Reactive Protein (CRP) with a microscopic endothelial dysfunction. The objective is to evaluate if there is an association between serum levels of CRP and endothelial function in women with overweight/obesity, as well as the correlation between CRP and anthropometric variables. Methods This is a cross-sectional study that analyzed secondary data from patients treated in an institution of tertiary education, as part of the weight excess and cardiometabolic disease survey. The study included patients with overweight/obesity who had CRP and endothelial function tests already made and inserted into the survey database. The endothelial function was evaluated by: reactive hyperemia test (endothelium-dependent vasodilation). All tests were recorded and later analyzed by the same echocardiographer who performed the examination. Statistical analyses were realized in the Statistical Package for the Social Sciences (SPSS) version 14. It was considered statistically significant a P value < 0.05. Results This study included 47, nonsmoker women. with a BMI of 32.37 ± 5.06 kg/m2, median of CRP of 2.59 mg/L and flow-mediated dilation (FMD) of 8.75% ± 5.22%. There was no correlation between CRP and endothelial dysfunction in this population (rs = 0.08, P = 0.64). No correlation was observed between CRP and BMI. There were no differences of endothelial dysfunction variables and CRP in groups in use or not of medications (Hypolipidemic, antihypertensives and hypoglycemic agents). Conclusion There was no association between CRP and FMD and this can suggest that it is possible that the level of eNOS dysfunction associated with increased CRP is not enough to lead to macroscopic changes and harm vasodilation.
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Affiliation(s)
- Raphael Ribeiro Sampaio
- Bahiana School of Medicine and Public Health, Bahia Foundation for the Development of Sciences, FBDC, Salvador, Bahia, Brazil
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12
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Ott IM, Alter ML, von Websky K, Kretschmer A, Tsuprykov O, Sharkovska Y, Krause-Relle K, Raila J, Henze A, Stasch JP, Hocher B. Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade. PLoS One 2012; 7:e42623. [PMID: 22900035 PMCID: PMC3416804 DOI: 10.1371/journal.pone.0042623] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 07/10/2012] [Indexed: 01/13/2023] Open
Abstract
The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2±2.3 mmHg vs. 117.1±2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2±2.5 mmHg and 105.0±3.2 mmHg, respectively, vs. 117.1±2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3±9.6 µg/24 h vs. 170.8±34.2 µg/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4±10.6 µg/24 h), whereas the reduction by single treatment with either telmisartan (97.8±26.4 µg/24 h) or riociguat (97.1±15.7 µg/24 h) was not statistically significant. The combination treatment led to a significant (p<0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.
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Affiliation(s)
- Ina M. Ott
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Markus L. Alter
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
- Department of Nephrology, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Karoline von Websky
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | | | - Oleg Tsuprykov
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Yuliya Sharkovska
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Katharina Krause-Relle
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
| | - Jens Raila
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Andrea Henze
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Johannes-Peter Stasch
- Bayer HealthCare AG, Wuppertal, Germany
- Institute of Pharmacy, University of Halle-Wittenberg, Halle (Saale), Germany
| | - Berthold Hocher
- Institute for Nutritional Science, University of Potsdam, Potsdam, Germany
- Center for Cardiovascular Research, Charité Campus Mitte, Berlin, Germany
- * E-mail:
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Tavares AC, Bocchi EA, Guimarães GV. Endothelial function in pre-pubertal children at risk of developing cardiomyopathy: a new frontier. Clinics (Sao Paulo) 2012; 67:273-8. [PMID: 22473410 PMCID: PMC3297038 DOI: 10.6061/clinics/2012(03)12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Revised: 11/03/2011] [Accepted: 11/22/2011] [Indexed: 01/22/2023] Open
Abstract
Although it is known that obesity, diabetes, and Kawasaki's disease play important roles in systemic inflammation and in the development of both endothelial dysfunction and cardiomyopathy, there is a lack of data regarding the endothelial function of pre-pubertal children suffering from cardiomyopathy. In this study, we performed a systematic review of the literature on pre-pubertal children at risk of developing cardiomyopathy to assess the endothelial function of pre-pubertal children at risk of developing cardiomyopathy. We searched the published literature indexed in PubMed, Bireme and SciELO using the keywords 'endothelial', 'children', 'pediatric' and 'infant' and then compiled a systematic review. The end points were age, the pubertal stage, sex differences, the method used for the endothelial evaluation and the endothelial values themselves. No studies on children with cardiomyopathy were found. Only 11 papers were selected for our complete analysis, where these included reports on the flow-mediated percentage dilatation, the values of which were 9.80±1.80, 5.90±1.29, 4.50±0.70, and 7.10±1.27 for healthy, obese, diabetic and pre-pubertal children with Kawasaki's disease, respectively. There was no significant difference in the dilatation, independent of the endothelium, either among the groups or between the genders for both of the measurements in children; similar results have been found in adolescents and adults. The endothelial function in cardiomyopathic children remains unclear because of the lack of data; nevertheless, the known dysfunctions in children with obesity, type 1 diabetes and Kawasaki's disease may influence the severity of the cardiovascular symptoms, the prognosis, and the mortality rate. The results of this study encourage future research into the consequences of endothelial dysfunction in pre-pubertal children.
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Affiliation(s)
- Aline Cristina Tavares
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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14
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Abstract
Management strategies are increasingly focused on tackling the increasing burden of cardiovascular disease worldwide. Microalbuminuria is a powerful predictor of cardiovascular disease and mortality in adults. This holds true in the general adult population but is particularly recognized in those with diabetes, where it identifies those likely to develop progressive atherosclerotic vascular disease and renal impairment. The atherosclerotic process begins in childhood with likely consequences in later life. In-depth understanding of the mechanisms through which microalbuminuria occurs holds promise for designing therapies to arrest its development in the future. Microalbuminuria arises from increased leakage of albumin through the complex glomerular sieve known as the glomerular filtration barrier. This requires changes in the physio-chemical properties of components of this barrier. However, the increased glomerular permeability confirmed in disease does not necessarily correlate with recognized histological changes in the glomerulus, suggesting that perhaps more subtle ultrastructural changes may be relevant. The epidemiology of microalbuminuria reveals a close association between systemic endothelial dysfunction and vascular disease, also implicating glomerular endothelial dysfunction in microalbuminuria. This review discusses the mechanisms of microalbuminuria in disease, particularly the emerging role of the glomerular endothelium and its glycocalyx, and examines its implications for cardiovascular disease in the pediatric population.
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15
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Babar GS, Zidan H, Widlansky ME, Das E, Hoffmann RG, Daoud M, Alemzadeh R. Impaired endothelial function in preadolescent children with type 1 diabetes. Diabetes Care 2011; 34:681-5. [PMID: 21289230 PMCID: PMC3041207 DOI: 10.2337/dc10-2134] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We evaluated the prevalence of endothelial dysfunction as measured by flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thickness (c-IMT) in relationship to vascular inflammatory biomarkers in preadolescent children with type 1 diabetes. RESEARCH DESIGN AND METHODS We studied 21 type 1 diabetic children (aged 8.3 ± 0.3 years with diabetes duration of 4.3 ± 0.4 years) and 15 group-matched healthy siblings (aged 7.6 ± 0.3 years). Fasting plasma glucose (FPG), lipid profile, HbA(1c), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, homocysteine, and erythrocyte (red blood cell [RBC]) folate were evaluated in all subjects. Each subject underwent c-IMT and brachial artery FMD percentage (FMD%) measurements using high-resolution vascular ultrasound. RESULTS Type 1 diabetic children had higher FPG (173.4 ± 7.9 mg/dL vs. 81.40 ± 1.7 mg/dL; P < 0.0001), HbA(1c) (8.0 ± 0.2% vs. 5.0 ± 0.1%; P < 0.0001), and hs-CRP (1.8 ± 0.3 vs. 0.70 ± 0.2; P = 0.017) than control children without significant differences in BMI, homocysteine, and fibrinogen levels; RBC folate content; and c-IMT between the groups. Children with type 1 diabetes had lower FMD% than control children (7.1 ± 0.8% vs. 9.8 ± 1.1%; P = 0.04), whereas c-IMT did not differ between groups. CONCLUSIONS Preadolescent children with type 1 diabetes and mean diabetes duration of 4 years displayed evidence of low-intensity vascular inflammation and attenuated FMD measurements. These data suggest that endothelial dysfunction and systemic inflammation, known harbingers of future cardiovascular risk, are present even in preadolescent children.
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Affiliation(s)
- Ghufran S Babar
- Department of Pediatric Endocrinology, Children’s Mercy Hospital, Kansas City, Missouri, USA
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16
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Silva AMV, Schaan BD, Signori LU, Plentz RDM, Moreno H, Bertoluci MC, Irigoyen MC. Microalbuminuria is associated with impaired arterial and venous endothelium-dependent vasodilation in patients with Type 2 diabetes. J Endocrinol Invest 2010; 33:696-700. [PMID: 20354354 DOI: 10.1007/bf03346672] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Microalbuminuria in Type 2 diabetes is associated with arterial endothelial dysfunction, but the venous bed was never evaluated. AIM To study the endothelial function in the venous and arterial bed in patients with Type 2 diabetes with normoalbuminuria or microalbuminuria. MATERIAL AND METHODS We evaluated 28 patients with Type 2 diabetes, glycated hemoglobin (HbA(₁c)) <7.5%, who were classified as normo- (albuminuria <30 mg/24 h; no.=16) or microalbuminuric (albuminuria 30-300 mg/24 h; no.=12). Venous and arterial endothelial function were assessed by the dorsal hand vein technique (venodilation by acetylcholine) and brachial artery flow-mediated vasodilation, respectively. RESULTS Patients were normotensive (systolic arterial pressure: 131.1±10.6 mmHg) and on good metabolic control (HbA(₁c): 6.6±0.6%). Microalbuminuric patients presented impaired venous (32.9±17.4 vs 59.3±26.5%; p=0.004) and arterial vasodilation (1.8±0.9 vs 5.1±2.4; p<0.001), as compared to normoalbuminuric patients. There was a negative correlation between acetylcholine-induced venodilation and albuminuria (r=-0.62; p<0.001) and HbA(₁c) (r=-0.41; p=0.032). The same was observed between flow mediated arterial vasodilation and albuminuria (r=-0.49; p=0.007) and HbA(₁c) (r=-0.44; p=0.019). Venous and arterial vasodilation was positively correlated (r=0.50; p=0.007). CONCLUSIONS Both venous and arterial endothelial function are impaired in Type 2 microalbuminuric diabetics, in spite of good metabolic control, suggesting that other factors are involved in its pathogenesis.
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Affiliation(s)
- A M V Silva
- Department of Physiology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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17
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Ritz E, Schmieder RE, Pollock CA. Renal protection in diabetes: lessons from ONTARGET. Cardiovasc Diabetol 2010; 9:60. [PMID: 20920303 PMCID: PMC2959007 DOI: 10.1186/1475-2840-9-60] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Accepted: 10/01/2010] [Indexed: 01/13/2023] Open
Abstract
Hypertension is an important independent risk factor for renal disease. If hypertension and chronic renal disease co-exist, as is common in patients with diabetes mellitus, the risk of cardiovascular disease is heightened. The importance of rigorous blood pressure control is recognized in current guidelines, with a recommended target of office blood pressure of < 130/80 mmHg; although ambulatory blood pressure may be more appropriate in order to identify the 24-hour hypertensive burden. Even lower blood pressure may further reduce the progression of chronic kidney disease, but the incidence of cardiovascular events may increase. Albuminuria not only indicates renal damage, but is also a powerful predictor of cardiovascular morbidity and mortality at least in patients with high cardiovascular risk and potentially pre-existing vascular damage. Management of the multiple factors for renal and cardiovascular disease is mandatory in the diabetic patient. The renin-angiotensin system (RAS) plays a pivotal role in the progression of renal disease, as well as in hypertension and target-organ damage. The use of agents that target the RAS confer renoprotection in addition to antihypertensive activity. There is extensive evidence of the renoprotective effect of angiotensin II receptor blockers (ARBs), and specifically telmisartan. In addition to providing 24-hour blood pressure control, clinical studies in patients with diabetes show that telmisartan improves renal endothelial function, prevents progression from microalbuminuria to macroalbuminuria, slows the decline in glomerular filtration rate and reduces proteinuria in overt nephropathy. These effects cannot be solely attributed to blood pressure control. In contrast to other members of the ARB class, the renoprotective effect of telmisartan is not confined to the management of diabetic nephropathy; slowing the progression of albuminuria has been demonstrated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which included diabetic and non-diabetic patients at high risk of cardiovascular events.
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Affiliation(s)
- Eberhard Ritz
- Universitat Erlangen, Medizinische Klinik IV, Erlangen, Germany
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18
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van den Heuvel M, Batenburg WW, Danser AHJ. Diabetic complications: a role for the prorenin-(pro)renin receptor-TGF-beta1 axis? Mol Cell Endocrinol 2009; 302:213-8. [PMID: 18840499 DOI: 10.1016/j.mce.2008.09.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2008] [Revised: 08/28/2008] [Accepted: 09/05/2008] [Indexed: 11/23/2022]
Abstract
Morbidity and mortality of diabetes mellitus are strongly associated with cardiovascular disease including nephropathy. A discordant tissue renin-angiotensin system (RAS) might be a mediator of the endothelial dysfunction leading to both micro- and macrovascular complications of diabetes. The elevated plasma levels of prorenin in diabetic subjects with microvascular complications might be part of this discordant RAS, especially since the plasma renin levels in diabetes are low. Prorenin, previously thought of as an inactive precursor of renin, is now known to bind to a (pro)renin receptor, thus activating locally angiotensin-dependent and -independent pathways. In particular, the stimulation of the transforming growth factor-beta (TGF-beta) system by prorenin could be an important contributor to diabetic disease complications. This review discusses the concept of the prorenin-(pro)renin receptor-TGF-beta(1) axis, concluding that interference with this pathway might be a next logical step in the search for new therapeutic regimens to reduce diabetes-related morbidity and mortality.
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Affiliation(s)
- Mieke van den Heuvel
- Division of Pharmacology, Vascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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19
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Hurks R, Eisinger MJ, Goovaerts I, van Gaal L, Vrints C, Weyler J, Hendriks J, van Schil P, Lauwers P. Early endothelial dysfunction in young type 1 diabetics. Eur J Vasc Endovasc Surg 2009; 37:611-5. [PMID: 19297215 DOI: 10.1016/j.ejvs.2009.01.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2008] [Accepted: 01/24/2009] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Endothelial dysfunction is a known precursor of atherosclerosis and can be assessed by measuring the brachial artery flow-mediated dilatation (FMD) via ultrasonography. This study investigated endothelial function in young type 1 diabetics without cardiovascular morbidity or diabetes-related pathology. METHODS Young diabetics and healthy controls were recruited, both meeting strict inclusion and exclusion criteria. To prove absence of subclinical atherosclerosis, intima-media thickness (IMT) measurements at the carotid bifurcation were done in all of them. FMD was measured at the brachial artery. The results were compared using the t-test and the influences of different variables on FMD were assessed using multiple linear regression. RESULTS Twenty-six diabetics (23.4+/-5.8 years) and 36 healthy volunteers (23.1+/-2.8 years) were recruited. The duration of diabetes was 9.2+/-5.3 years; metabolic control was moderate (HbA1c 7.6+/-1.0%) and IMT was normal in both groups. FMD was significantly impaired in type 1 diabetics (7.13+/-0.43 vs. 8.77+/-0.43%; p=0.002). The FMD grade was associated with diabetes and age. Patients with a good metabolic control (HbA1c</=7.0%) had a better FMD. CONCLUSIONS In type 1 diabetics, even without preclinical or clinical atherosclerosis, endothelial function is already disturbed and can be detected using ultrasonography.
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Affiliation(s)
- R Hurks
- Department of Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, B 2650 Edegem, Belgium
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20
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Bertoluci MC, Cé GV, da Silva AMV, Puñales MKC. [Endothelial dysfunction in type 1 diabetes]. ACTA ACUST UNITED AC 2009; 52:416-26. [PMID: 18438553 DOI: 10.1590/s0004-27302008000200030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Accepted: 12/16/2007] [Indexed: 11/21/2022]
Abstract
Vascular complications are the main cause of mortality and morbidity in diabetes. Mechanisms involved in the development of micro and macrovascular disease are complex and partially understood, but invariably begin as a dysfunctional endothelium. Nitric oxide is an important regulator of endothelial function and the impairment of its activity is determinant of the endothelial dysfunction. In type 1 diabetes, many factors like acute, chronic and post-prandial hyperglycemia, as well as the duration of diabetes or autonomic neuropathy and microalbuminuria are associated to endothelial dysfunction. Oxidative stress, polyol pathway activation, protein kinase C activation and the presence of advanced glycation end-products are potential mechanisms involved in the development of endothelial dysfunction. Early detection of endothelial dysfunction has prognostic value for the development of vascular complications and may be important in strategies for primary prevention of cardiovascular endpoints in type 1 diabetes.
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21
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Serum platelet-activating factor acetylhydrolase activity: A novel potential inflammatory marker in type 1 diabetes. Prostaglandins Other Lipid Mediat 2008; 87:42-6. [DOI: 10.1016/j.prostaglandins.2008.07.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2008] [Revised: 07/04/2008] [Accepted: 07/21/2008] [Indexed: 11/20/2022]
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22
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Tibirica E, Rodrigues E, Cobas R, Gomes MB. Impairment of skin capillary recruitment precedes chronic complications in patients with type 1 diabetes. Rev Diabet Stud 2007; 4:85-8. [PMID: 17823692 PMCID: PMC2036263 DOI: 10.1900/rds.2007.4.85] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Microvascular function in patients with type 1 diabetes without chronic complications was assessed using skin capillary recruitment during post-occlusive reactive hyperemia (PORH). Structural (maximal) capillary density was evaluated during venous occlusion. The study included 48 consecutive outpatients aged 26.3 +/- 10.8 years with type 1 diabetes (duration of 9.5 years) without chronic complications and 34 control subjects. Intravital capillary video-microscopy was used in the dynamic study of skin capillaries in the dorsum of the fingers and toes. Capillary recruitment during PORH (% increase in mean capillary density, MCD) was significantly higher in the controls than the patients in both the fingers (p < 0.001) and toes (p < 0.001). During venous occlusion, MCD increase was also higher in the controls than the patients in both the fingers (p < 0.05) and toes (p < 0.0001). In patients, no difference was found between MCD at baseline and after venous occlusion in the fingers but a decrease was observed in the toes (p < 0.001). It is concluded that skin capillary function is significantly impaired in both fingers and toes of patients with type 1 diabetes without chronic complications. Moreover, capillary density during venous occlusion did not increase in either extremity in the patients, suggesting that their capillaries at rest are already maximally recruited.
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Affiliation(s)
- Eduardo Tibirica
- Department of Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
- Laboratory of Neuro-Cardiovascular Pharmacology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil
- Address correspondence to: Eduardo Tibirica, e-mail:
| | - Elba Rodrigues
- Laboratory of Neuro-Cardiovascular Pharmacology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil
| | - Roberta Cobas
- Department of Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
| | - Marilia B. Gomes
- Department of Medicine, Diabetes Unit, State University of Rio de Janeiro, Brazil
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23
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Schmieder RE, Delles C, Mimran A, Fauvel JP, Ruilope LM. Impact of telmisartan versus ramipril on renal endothelial function in patients with hypertension and type 2 diabetes. Diabetes Care 2007; 30:1351-6. [PMID: 17337492 DOI: 10.2337/dc06-1551] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE One of the earliest signs of vascular change is endothelial dysfunction, which is also known to provoke albuminuria and to predict cardiovascular prognosis. The aim of this study was to analyze the effects of renin-angiotensin system (RAS) blockade on renal endothelial function. RESEARCH DESIGN AND METHODS In a multicenter, prospective, double-blind, forced-titration, randomized study, 96 patients with type 2 diabetes, hypertension, glomerular filtration rate >80 ml/min, and normo- or microalbuminuria were treated once daily with 40/80 mg telmisartan or 5/10 mg ramipril for 9 weeks. RESULTS The mean +/- SE fall in renal plasma flow (RPF) in response to intravenous N(G)-monomethyl-L-arginine (L-NMMA), reflecting the magnitude of nitric oxide (NO) activity, increased with telmisartan from 71.9 +/- 9.0 ml/min before therapy to 105.2 +/- 9.7 ml/min at the end of treatment (P < 0.001). With ramipril, RPF response to L-NMMA increased from 60.1 +/- 12.2 to 87.8 +/- 9.2 ml/min (P = 0.018). The adjusted difference between treatments was -17.1 +/- 13.7 ml/min (P = 0.214). In accordance, telmisartan increased RPF at rest (i.e., without L-NMMA) from 652.0 +/- 27.0 to 696.1 +/- 31.0 ml/min (P = 0.047), whereas ramipril produced no significant changes in RPF. The more the basal NO activity improved, the greater was the vasodilatory effect on renal vasculature (r = 0.47, P < 0.001). CONCLUSIONS In patients with type 2 diabetes, telmisartan and ramipril both increased NO activity of the renal endothelium significantly, which in turn may support the preservation of cardiovascular and renal function.
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Affiliation(s)
- Roland E Schmieder
- Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.
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24
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Pambianco G, Costacou T, Orchard TJ. The prediction of major outcomes of type 1 diabetes: a 12-year prospective evaluation of three separate definitions of the metabolic syndrome and their components and estimated glucose disposal rate: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes Care 2007; 30:1248-54. [PMID: 17303788 DOI: 10.2337/dc06-2053] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The metabolic syndrome has been shown to confer an increased risk of cardiovascular disease in both the general and type 2 diabetic populations, but few studies have assessed the metabolic syndrome in type 1 diabetic patients. In a type 1 diabetic cohort, we assessed the prevalence and value of the metabolic syndrome in improving the prediction of major complication outcomes compared with its components and a surrogate measure of insulin resistance, estimated glucose disposal rate (eGDR). RESEARCH DESIGN AND METHODS A total of 514 (78%) subjects participating in the Pittsburgh Epidemiology of Diabetes Complications Study with complete 12-year follow-up clinical data were classified by baseline metabolic syndrome status according to three definitions: those of the National Cholesterol Education Program Adult Treatment Panel III (modified by the American Heart Association), the International Diabetes Federation (IDF), and the World Health Organization (WHO). The complication outcomes included coronary artery disease, renal failure, diabetes-related death, and the aggregate of these three major outcomes of diabetes (MOD). RESULTS Metabolic syndrome prevalence ranged from 8% (IDF) to 21% (WHO). All definitions showed reasonable specificity (> or = 83%) for each outcome, while the WHO definition had the highest sensitivity for all outcomes except renal failure, for which eGDR was most sensitive. However, the components of each definition predicted better than the overall syndrome. Microalbuminuria was clearly the strongest predictor of all individual measures, yielding hazard ratios of 9 and 6 for mortality and MOD, respectively. CONCLUSIONS Though the three metabolic syndrome classifications predict major complication outcomes in type 1 diabetes, their individual components predict better. Of the variables studied, including HbA1, microalbuminuria appears to be the best single predictor of MOD.
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Affiliation(s)
- Georgia Pambianco
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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25
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Ladeia AM, Stefanelli E, Ladeia-Frota C, Moreira A, Hiltner A, Adan L. Association between elevated serum C-reactive protein and triglyceride levels in young subjects with type 1 diabetes. Diabetes Care 2006; 29:424-6. [PMID: 16443901 DOI: 10.2337/diacare.29.02.06.dc05-2033] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Ana M Ladeia
- Bahian Medical and Public Health School and Post-Graduate of Bahian Medical and Public Health School, Science Development Foundation of Bahia, Bahia, Brazil.
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