Marek Kretowicz

25-hydroxyvitamin D, biomarkers of endothelial dysfunction and subclinical organ damage in adults with hypertension.

BACKGROUND The mechanism that underlies the association between low 25-hydroxyvitamin D [25(OH)D] and hypertension is not well understood; it seems to involve regulation of the renin-angiotensin-aldosterone system and the impact on endothelial function, cardiac remodeling, and subclinical organ damage. Vitamin D supplementation presents an ambiguous effect on endothelial function and arterial stiffness. We assess serum 25(OH)D3, biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule [sICAM], C-reactive protein [CRP], homocysteine [Hcy]) and subclinical organ damage in adults with newly diagnosed untreated hypertension. METHODS Patients were classified based on ambulatory blood pressure monitoring: 98 had hypertension, whereas in 60 persons BP was normal. Laboratory assays including serum 25(OH)D3, hsCRP, Hcy, sICAM, glucose, insulin, lipids, echocardiography, pulse wave velocity (PWV), intima-media thickness (IMT), and left-ventricular mass (LVM) measurements were performed. RESULTS 25(OH)D3 was significantly lower in hypertensive patients. The logistic regression analysis indicated that 25(OH)D3 reduced the probability of hypertension occurrence after adjusting for body mass index (BMI). 25(OH)D3 in those with hypertension correlated significantly with systolic BP (SBP; r = -0.39), PWV, IMT (r = -0.33), and diastolic BP (r = -0.26). Multiple regression analysis in patients with hypertension revealed that 25(OH)D3 and sICAM accounted for up to 27% of SBP variation after adjusting for age, BMI, and smoking. 25(OH)D3 and either PWV or IMT accounted for 23% of SBP variation. The impact of 25(OH)D3 was 10%. CONCLUSION The impact of 25(OH)D3 on SBP variation, mediated by its effect on endothelial dysfunction and subclinical organ damage, is modest but significant.

The Influence of Intravenous 1,25(OH)2D3 Therapy on Glucose Metabolism in Hemodialyzed Patients with Secondary Hyperparathyroidism

Glucose intolerance, insulin resistance and hyperinsulinemia are common findings in end‐stage renal disease patients. Parathormone (PTH) and vitamin D3 are linked with disturbances of glucose metabolism. Glycated hemoglobin (HbA1c) reflects long‐term glycemic control. HbA1c is a marker of increased risk of death in diabetic patients but also in general population. The aim of the study was to investigate the influence of 1,25(OH)2D3 therapy on long‐term control of glycemia in hemodialyzed (HD) patients with severe secondary hyperparathyroidism (SHP). Eight HD patients with SHP (PTH = 1088.6 ± 472.2) were given intravenous 1,25(OH)2D31–2 µg thrice a week, for 12 weeks (mean dose 4.5 µg/week). At baseline and after 12 weeks fasting blood was sampled for: glucose, insulin, HbA1c, PTH. Insulin/glucose ratio (I/G) was calculated as marker of insulin resistance. Results were compared with 14 healthy volunteers (controls) matched for age, sex and BMI. At baseline I/G was higher in HD vs controls 0.110 ± 0.045 vs 0.073 ± 0.021 (p = 0.02), and of borderline significance at follow‐up (0.106 ± 0.053, p = 0.05 vs controls). PTH decreased significantly to 506.1 ± 646.3 (p < 0.02) during therapy. Significant decrease of HbA1c in HD patients was observed (5.84 ± 0.40 vs 5.13 ± 0.51; p = 0.01), while fasting glucose, insulin and I/G did not change significantly. Intravenous 1,25(OH)2D3 therapy is successful, even in patients with severe secondary hyperparathyroidism. Significant decrease in HbA1c with stable insulin concentration may indicate positive impact of intravenous 1,25(OH)2D3 therapy on long‐term glucose metabolism.

The Impact of Fructose on Renal Function and Blood Pressure

Fructose is a sugar present in sucrose, high-fructose corn syrup, honey, and fruits. Fructose intake has increased markedly in the last two centuries, primarily due to increased intake of added sugars. Increasing evidence suggests that the excessive intake of fructose may induce fatty liver, insulin resistance, dyslipidemia, hypertension, and kidney disease. These studies suggest that excessive intake of fructose might have an etiologic role in the epidemic of obesity, diabetes, and cardiorenal disease.

Gender differences in association of serum nesfatin-1 with selected metabolic risk factors in normoglycemic subjects: A preliminary study.

In recent years, many new proteins and hormones involved in the regulation of adipose tissue metabolism and activity of the hunger/satiety center in the central nervous system have been discovered. Nesfatin-1, first described by Oh-I et al. in 2006, is an 82-amino acid polypeptide encoded in the N-terminal region of Nucleobindin 2 (NUCB2) that exhibits an anorexigenic effect. Although nesfatin-1/NUCB2 production was initially considered to occur mainly in hypothalamic nuclei, studies have revealed highest expression in endocrine cells of the gastric mucosa, as well as in other peripheral tissues, like pancreatic islets, adipose tissue, and reproductive organs. Several animals studies have described insulinotropic effect of nesfatin-1/NUCB2 and its ability to decrease blood glucose levels via activation of L-type calcium channels in pancreatic β-cells or altering AKT phosphorylation and glucose transporter GLUT4 translocation into the cell membrane in muscles, adipocytes, and the liver. However, these findings have not been confirmed in humans. In the present study we investigated whether serum nesfatin-1/NUCB2 may be a novel candidate biomarker of impaired glucose metabolism in subjects without diabetes. The study was performed on 80 normoglycemic, nonobese (body mass index [BMI] 17.5–28 kg/m), nonsmoking subjects aged 25–40 years (32 women, 48 men). Fasting plasma glucose, HbA1c, serum lipid profile, insulin, C-reactive protein, and apolipoproteins AI and B were measured using autoanalyzers (Architect ci8200; Abbott Laboratories, Abbott Park, IL, USA; Cobas e411; Roche Diagnostics, Indianapolis, IN, USA). Adiponectin (human adiponectin; BioVendor R&D, Brno, Czech Republic) and nesfatin-1/NUCB2 (Nesfatin-1 (1–82) human; Phoenix Pharmaceuticals, Burlingame, CA, USA) concentrations were determined by ELISA. Nesfatin-1/NUCB2 concentrations were significantly higher in women than men (1.28 vs 0.82 ng/mL; P = 0.02). Different associations between nesfatin-1/ NUCB2 and glucose insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and HbA1c were found in women and men (Table 1), which may indicate that its activity depends on gender and BMI. In women,

Gender differences in association of serum nesfatin-1 with selected metabolic risk factors in normoglycemic subjects: A preliminary study在血糖正常的受试者中血清nesfatin-1与选定的代谢危险因素之间关系的性别差异：一项初步研究

In recent years, many new proteins and hormones involved in the regulation of adipose tissue metabolism and activity of the hunger/satiety center in the central nervous system have been discovered. Nesfatin-1, first described by Oh-I et al. in 2006, is an 82-amino acid polypeptide encoded in the N-terminal region of Nucleobindin 2 (NUCB2) that exhibits an anorexigenic effect. Although nesfatin-1/NUCB2 production was initially considered to occur mainly in hypothalamic nuclei, studies have revealed highest expression in endocrine cells of the gastric mucosa, as well as in other peripheral tissues, like pancreatic islets, adipose tissue, and reproductive organs. Several animals studies have described insulinotropic effect of nesfatin-1/NUCB2 and its ability to decrease blood glucose levels via activation of L-type calcium channels in pancreatic β-cells or altering AKT phosphorylation and glucose transporter GLUT4 translocation into the cell membrane in muscles, adipocytes, and the liver. However, these findings have not been confirmed in humans. In the present study we investigated whether serum nesfatin-1/NUCB2 may be a novel candidate biomarker of impaired glucose metabolism in subjects without diabetes. The study was performed on 80 normoglycemic, nonobese (body mass index [BMI] 17.5–28 kg/m), nonsmoking subjects aged 25–40 years (32 women, 48 men). Fasting plasma glucose, HbA1c, serum lipid profile, insulin, C-reactive protein, and apolipoproteins AI and B were measured using autoanalyzers (Architect ci8200; Abbott Laboratories, Abbott Park, IL, USA; Cobas e411; Roche Diagnostics, Indianapolis, IN, USA). Adiponectin (human adiponectin; BioVendor R&D, Brno, Czech Republic) and nesfatin-1/NUCB2 (Nesfatin-1 (1–82) human; Phoenix Pharmaceuticals, Burlingame, CA, USA) concentrations were determined by ELISA. Nesfatin-1/NUCB2 concentrations were significantly higher in women than men (1.28 vs 0.82 ng/mL; P = 0.02). Different associations between nesfatin-1/ NUCB2 and glucose insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and HbA1c were found in women and men (Table 1), which may indicate that its activity depends on gender and BMI. In women,

Response to “The Putative Role of Vitamin D in Essential Hypertension: Stepping Into the Light?”

To the Editor: In their letter, “The Putative Role of Vitamin D in Essential Hypertension: Stepping Into the Light?,” Gkaliagkousi et al. seem to question the use of traditional circulating biomarkers such as soluble intercellular adhesion molecule (sICAM), C-reactive protein (CRP), and homocysteine (Hcy) for the evaluation of endothelial dysfunction. They point out the latest position statement1 and recent European Society of Hypertension guidelines2 as a source of information on methods for the evaluation of endothelial dysfunction. It is obvious, however, that guidelines do not explicitly define which biomarkers should be used, and the position statement presents different methods for evaluating endothelial function, including the measurement of biomarkers we used,3 with the special focus on emerging biomarkers. We strongly disagree with Gkaliagkousi et al.’s criticism because we measured the circulating biomarkers that are widely and commonly used by others as determinants of endothelial dysfunction.4–6 Serum biomarkers of the endothelial origin reflect endothelial function; higher levels are thought to mirror the endothelial activation or damage.4 It has been reported that activated endothelial cells show enhanced expression and release of cell-surface adhesion molecules. sICAM-1 concentration correlates with its cell expression and was confirmed recently to be a sensitive marker of inflammatory vascular activation in hypertensive adolescents.7 Within the past 10 years the association between CRP and other inflammatory markers (including s-ICAM-1, Hcy) with prehypertension, hypertension, and arterial stiffness has been demonstrated.5 CRP is not only a biomarker of inflammation but, as recently unraveled,6 also actively and directly participates in the development of the endothelial dysfunction, which stands in stark contrast to the criticism of Dr Gkaliagkousi. Besides an array of traditional biomarkers, several modern but expensive methods may be used to assess the endothelial status: imaging methods and measurement of endothelial progenitor cells, circulating endothelial cells, and endothelial-derived microparticles (EMPs).1 Interestingly, a recent study8 demonstrated that sICAM-1 correlated significantly with EMPs measured by flow cytometry, which unequivocally substantiates its use as a surrogate marker of endothelial dysfunction. The emerging evidence suggests that blood EMPs may serve as both specific markers and contributors to pathology; however, their accurate quantification is a substantial challenge. EMPs and ECPs (endothelial progenitor cells) may be attractive biomarkers, but their measurement by multicolor flow cytometry or proteomic analysis by mass spectrometry is not widely available. Furthermore, progress in standardization of measurement of the emerging biomarkers is crucial to establish their clinical interest for the assessment of endothelial dysfunction. In the recent European Society of Hypertension guidelines, the term “BP variability” obviously refers to visit-tovisit blood pressure variability or blood pressure variability assessed by ambulatory blood pressure measurement. The mathematical definition of “variation” describes a function that relates the values of one variable to those of other variables, and in this sense we assessed variables of significance for the prediction of systolic blood pressure variation that was adjusted for possible confounders. In fact, both terms “variation” and “variability” are used interchangeably, which does not necessarily have to be correct because the R2 value explains the variability in the statistics. 25-Hydroxyvitamin D might mediate various biological effects, and it regulates physiological functions such as the expression of adhesion molecules and endothelium-dependent vasoconstriction. The endothelial dysfunction was associated with 25(OH) D deficiency; moreover, 25(OH)D deficiency was propounded to promote endothelial dysfunction. We presented potential mechanisms relating to the role of 25(OH)D and its influence on the endothelial dysfunction in hypertension. The putative causal relationships remain to be elucidated.

Gender differences in association of serum nesfatin-1 with selected metabolic risk factors in normoglycemic subjects: A preliminary study在血糖正常的受试者中血清nesfatin-1与选定的代谢危险因素之间关系的性别差异：一项初步研究: Letter to the editor

In recent years, many new proteins and hormones involved in the regulation of adipose tissue metabolism and activity of the hunger/satiety center in the central nervous system have been discovered. Nesfatin-1, first described by Oh-I et al. in 2006, is an 82-amino acid polypeptide encoded in the N-terminal region of Nucleobindin 2 (NUCB2) that exhibits an anorexigenic effect. Although nesfatin-1/NUCB2 production was initially considered to occur mainly in hypothalamic nuclei, studies have revealed highest expression in endocrine cells of the gastric mucosa, as well as in other peripheral tissues, like pancreatic islets, adipose tissue, and reproductive organs. Several animals studies have described insulinotropic effect of nesfatin-1/NUCB2 and its ability to decrease blood glucose levels via activation of L-type calcium channels in pancreatic β-cells or altering AKT phosphorylation and glucose transporter GLUT4 translocation into the cell membrane in muscles, adipocytes, and the liver. However, these findings have not been confirmed in humans. In the present study we investigated whether serum nesfatin-1/NUCB2 may be a novel candidate biomarker of impaired glucose metabolism in subjects without diabetes. The study was performed on 80 normoglycemic, nonobese (body mass index [BMI] 17.5–28 kg/m), nonsmoking subjects aged 25–40 years (32 women, 48 men). Fasting plasma glucose, HbA1c, serum lipid profile, insulin, C-reactive protein, and apolipoproteins AI and B were measured using autoanalyzers (Architect ci8200; Abbott Laboratories, Abbott Park, IL, USA; Cobas e411; Roche Diagnostics, Indianapolis, IN, USA). Adiponectin (human adiponectin; BioVendor R&D, Brno, Czech Republic) and nesfatin-1/NUCB2 (Nesfatin-1 (1–82) human; Phoenix Pharmaceuticals, Burlingame, CA, USA) concentrations were determined by ELISA. Nesfatin-1/NUCB2 concentrations were significantly higher in women than men (1.28 vs 0.82 ng/mL; P = 0.02). Different associations between nesfatin-1/ NUCB2 and glucose insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and HbA1c were found in women and men (Table 1), which may indicate that its activity depends on gender and BMI. In women,

The fructose tolerance test in patients with chronic kidney disease and metabolic syndrome in comparison to healthy controls

BackgroundFructose acutely raises serum uric acid in normal subjects, but the effect in subjects with metabolic syndrome or subjects with chronic kidney disease is unknown. The aim of the study was to evaluate changes in serum uric acid during the fructose tolerance test in patients with chronic kidney disease, metabolic syndrome with comparison to healthy controls.MethodsStudies were performed in 36 subjects with obesity (body mass index >30) and metabolic syndrome, 14 patients with stage 3 chronic kidney disease, and 25 healthy volunteers. The fructose tolerance test was performed in each patient. The change in serum uric acid during the fructose challenge was correlated with baseline ambulatory blood pressure, serum uric acid, metabolic, and inflammatory markers, and target organ injury including carotid intima media thickness and renal resistive index (determined by Doppler).ResultsAbsolute serum uric acid values were highest in the chronic kidney disease group, followed by the metabolic syndrome and then healthy controls. Similar increases in serum uric acid in response to the fructose tolerance test was observed in all three groups, but the greatest percent rise was observed in healthy controls compared to the other two groups. No significant association was shown between the relative rise in uric acid and clinical or inflammatory parameters associated with kidney disease (albuminuria, eGFR) or metabolic syndrome.ConclusionsSubjects with chronic kidney disease and metabolic syndrome have higher absolute uric acid values following a fructose tolerance test, but show a relatively smaller percent increase in serum uric acid. Changes in serum uric acid during the fructose tolerance test did not correlate with changes in metabolic parameters, inflammatory mediators or with target organ injury. These studies suggest that acute changes in serum uric acid in response to fructose do not predict the metabolic phenotype or presence of inflammatory mediators in subjects with obesity, metabolic syndrome or chronic kidney disease.Trial registrationThe study was registered in ClinicalTrials.gov. Identifier : NCT01332526. www.register.clinicaltrials.gov/01332526