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1.
Eur J Nutr ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32072267

RESUMO

PURPOSE: Elevated plasma concentration of the vasopressin marker copeptin and low water intake are associated with elevated blood glucose and diabetes risk at a population level. Moreover, in individuals with low urine volume and high urine osmolality (u-Osm), water supplementation reduced fasting plasma (fp) copeptin and fp-glucose. In this observational study, we investigated if low total water intake or high u-Osm correlated with high fp-copeptin and components of the metabolic syndrome at the population level. METHODS: In the population-based Malmö Offspring Study (MOS, n = 2599), fp-copeptin and u-Osm from morning urine samples were measured, and diet and total water intake (from beverages and food moisture) was assessed by a 4-day web-based record. RESULTS: Increasing water intake by tertile was after adjustment for age and sex associated with low fp-triglycerides (p = 0.002) and high fp-HDL (p = 0.004), whereas there was no association with the other investigated metabolic traits (HbA1c, fp-glucose, BMI or waist circumference). Increasing u-Osm by tertile was, after adjustment for age and sex, associated with high fp-glucose (p = 0.007), and borderline significantly associated with high HbA1c (p = 0.053), but no association was observed with fp-HDL, fp-triglycerides, BMI or waist circumference. Fp-copeptin concentration correlated significantly with water intake (r = - 0.13, p < 0.001) and u-Osm (r = 0.27, p < 0.001). High copeptin was associated with all investigated metabolic traits (p < 0.001 for all). CONCLUSION: Low concentrations of the vasopressin marker copeptin is linked to high water intake, low u-Osm, and a favorable metabolic profile, suggesting that vasopressin lowering lifestyle interventions, such as increased water intake, may promote metabolic health.

3.
Endocrine ; 65(2): 304-311, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31230225

RESUMO

PURPOSE: Elevated copeptin, a vasopressin marker, is linked to metabolic disease, and obese rats with low-vasopressin concentration had a decreased risk of liver steatosis. We here investigated the association between copeptin and nonalcoholic fatty liver disease (NAFLD) and possible differences in copeptin concentration between ethnicities. METHODS: In this cross-sectional study of 361 South Africans (n = 172 African black, 189 = Caucasian) with a mean age of 45 years and 45% men, plasma copeptin was measured and associated with NAFLD according to a validated fatty liver index accounting for measures of BMI, waist, triglycerides, and gamma-glutamyltransferase. RESULTS: There was no significant difference in copeptin concentrations between ethnicities after age and gender adjustment (p = 0.24). Increasing copeptin tertile levels were significantly associated with obesity, overweight, and abdominal obesity, respectively, after multivariate adjustment for age, gender, ethnicity, and high HOMA-IR (p = 0.02 for all). Individuals in the second and third copeptin tertile had an increased odds (95% CI) of NAFLD of 1.77 (1.04-3.02) and 2.97 (1.74-5.06), respectively, compared to the bottom tertile (p < 0.001). The association between increasing copeptin tertile and NAFLD remained significant after adjustment for age, gender, ethnicity, high HOMA-IR, self-reported current alcohol intake, and statin treatment (p = 0.01). CONCLUSIONS: Elevated plasma copeptin is independently associated with NAFLD in a population with mixed ethnicities, pointing at the pharmacologically modifiable vasopressin system as a new mechanism behind NAFLD.

4.
BMC Med ; 17(1): 85, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31035998

RESUMO

INTRODUCTION: Copeptin is the stable surrogate marker of vasopressin (VP), which is released in response to elevated plasma osmolality or low blood pressure. Elevated plasma copeptin levels are associated with higher risk of insulin resistance-related disorders, such as type 2 diabetes (T2DM), metabolic syndrome (MS), and cardiovascular disease, and experimental reduction of circulating VP levels is shown to significantly decrease hepatic fat content in obese rats, independently from body adiposity. However, the association between copeptin and non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) in humans has not been explored yet. The aim of this study was to explore the relationship between plasma copeptin and the presence/severity of NAFLD/NASH. METHODS: For this study, we recruited 60 obese patients candidate to bariatric surgery for clinical purposes in which intraoperative liver biopsies were performed for diagnosing NAFLD/NASH. Circulating copeptin levels were also assessed in 60 age- and sex-comparable non-obese individuals without NAFLD at liver ultrasonography. Plasma copeptin was measured by sandwich immunoluminometric assay (Thermo Fisher Scientific). RESULTS: Obese patients with biopsy-proven NAFLD (53%) had significantly higher copeptin levels than both obese individuals without NAFLD and non-obese subjects (ob/NAFLD+ 9.5 ± 4.9; ob/NAFLD- 6.4 ± 2.6; and non-ob/NAFLD- 7.4 ± 5.1 pmol/L; p = 0.004 and p = 0.01 respectively). Plasma copeptin concentration positively correlated with hepatic macro- and micro-vesicular steatosis (r = 0.36, p = 0.026; r = 0.31, p = 0.05), lobular inflammation (r = 0.37, p = 0.024) and significantly increased throughout degrees of NASH severity, as expressed as absence, borderline, and overt NASH at the liver biopsy (r = 0.35, p = 0.01). Greater circulating copeptin predicted the presence of NASH with OR = 1.73 (95% CI = 1.02-2.93) after multivariate adjustment for age, sex, renal function and presence of T2DM and MS components. CONCLUSIONS: Increased plasma copeptin is independently associated with the presence and severity of NAFLD and NASH, pointing to a novel mechanism behind human fatty liver disease potentially modifiable by pharmacological treatment and lifestyle intervention.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Glicopeptídeos/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Adulto , Animais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia
5.
Nephrol Dial Transplant ; 34(1): 74-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471407

RESUMO

Background: Plasma copeptin, a marker of vasopressin, is associated with renal function decline in the general population. Our aim was to study the links between elevated copeptin and future risk of kidney disease. Methods: Copeptin was measured in a sample of the Malmö Preventive Project (MPP) Reinvestigation (n = 5158) and in the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC) (n = 5162). According to national registers, 89 subjects in MPP and 180 in MDC-CC developed chronic kidney disease (CKD) during follow-up (8.7 and 19.6 years, respectively). Results: After multivariate adjustment (gender, age, body mass index, smoking status, estimated glomerular filtration rate, prevalent diabetes, systolic blood pressure and prevalent antihypertensive treatment), copeptin (beta-coefficient per 1 standard deviation increment of ln copeptin) was independently associated with increased risk of CKD during follow-up in both cohorts (MPP: (HR) 1.46, 95% confidence interval (CI) 1.18-1.80, P < 0.001; MDC-CC: HR 1.25, 95% CI 1.02-1.54, P = 0.03) among subjects free from prevalent kidney disease at baseline. Furthermore, in MPP, elevated copeptin predicted a specified diagnosis of kidney disease other than CKD (HR 1.31, 95% CI 1.08-1.59, P = 0.006) after multivariate adjustment. In a corresponding analysis in MDC-CC, copeptin was associated with a 10% increased risk, which, however, was non-significant (P = 0.25). A meta-analysis of the MPP and MDC-CC data showed significant association between elevated copeptin and a specified diagnosis of kidney disease other than CKD (HR 1.18, 95% CI 1.05-1.34, P = 0.008). Conclusion: An increased level of copeptin independently predicts development of both CKD and other specified kidney diseases, suggesting that copeptin can be used to identify individuals at risk for kidney disease development.


Assuntos
Biomarcadores/sangue , Glicopeptídeos/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Idoso , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
6.
Eur J Nutr ; 58(1): 315-324, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29242971

RESUMO

PURPOSE: High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. METHODS: Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. RESULTS: After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine ("water-responders"). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected. CONCLUSIONS: Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low-water drinkers with high copeptin concentration.


Assuntos
Glicemia/metabolismo , Glucagon/sangue , Glicopeptídeos/sangue , Insulina/sangue , Água/farmacologia , Adulto , Idoso , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Ingestão de Líquidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Água/administração & dosagem , Adulto Jovem
7.
J Clin Endocrinol Metab ; 104(6): 1917-1925, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566641

RESUMO

OBJECTIVE: Because elevated copeptin, a marker of vasopressin, is linked to low water intake and high diabetes risk, we tested the effect of water supplementation on copeptin and fasting glucose. DESIGN, SETTING, AND PARTICIPANTS: Thirty-one healthy adults with high copeptin (>10.7 pmol · L-1 in men and >6.1 pmol·L-1 in women) identified in a population-based survey from 2013 to 2015 and with a current 24-hour urine osmolality of >600 mOsm · kg-1 were included. INTERVENTION: Addition of 1.5 L water daily on top of habitual fluid intake for 6 weeks. MAIN OUTCOME MEASURE: Pre- and postintervention fasting plasma copeptin concentrations. RESULTS: Reported mean water intake increased from 0.43 to 1.35 L · d-1 (P < 0.001), with no other observed changes in diet. Median (interquartile range) urine osmolality was reduced from 879 (705, 996) to 384 (319, 502) mOsm · kg-1 (P < 0.001); urine volume increased from 1.06 (0.90, 1.20) to 2.27 (1.52, 2.67) L · d-1 (P < 0.001); and baseline copeptin decreased from 12.9 (7.4, 21.9) pmol · L-1 to 7.8 (4.6;11.3) pmol · L-1 (P < 0.001). Water supplementation reduced fasting plasma glucose from a mean (SD) of 5.94 (0.44) to 5.74 (0.51) (P = 0.04). The water-associated reduction of both fasting copeptin and glucose concentration in plasma was most pronounced in participants in the top tertile of baseline copeptin. CONCLUSIONS: Water supplementation in persons with habitually low water consumption and high copeptin levels is effective in lowering copeptin. It appears a safe and promising intervention with the potential of lowering fasting plasma glucose and thus reducing diabetes risk. Further investigations are warranted to support these findings.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/prevenção & controle , Ingestão de Líquidos/fisiologia , Glicopeptídeos/sangue , Água/administração & dosagem , Administração Oral , Adulto , Idoso , Glicemia/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Jejum/sangue , Jejum/fisiologia , Feminino , Glicopeptídeos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Projetos Piloto , Resultado do Tratamento , Urina/química , Urina/fisiologia , Vasopressinas/sangue , Vasopressinas/metabolismo , Adulto Jovem
8.
JCI Insight ; 3(13)2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997293

RESUMO

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition.


Assuntos
Progressão da Doença , Glicopeptídeos/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Albuminúria , Estudos de Coortes , Feminino , Seguimentos , França/epidemiologia , Taxa de Filtração Glomerular , Humanos , Incidência , Rim , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Suécia/epidemiologia , Vasopressinas/sangue
9.
Ann Nutr Metab ; 72 Suppl 2: 21-27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29925066

RESUMO

BACKGROUND: Type 2 diabetes, chronic kidney disease (CKD) and its cardiovascular complications are increasing as health problems worldwide. These diseases are interrelated with overlapping occurrence and once diabetes is established, the risk of cardiorenal disease is dramatically elevated. Thus, a search for unifying modifiable risk factors is key for effective prevention. SUMMARY: Elevated fasting plasma concentration of vasopressin, measured with the marker copeptin, predicts new onset type 2 diabetes as well as renal function decline. Furthermore, we recently showed that increased plasma copeptin concentration independently predicts the development of both CKD and other specified kidney diseases. In consequence, high copeptin is an independent risk factor for cardiovascular disease and premature mortality in both diabetes patients and in the general population. Vasopressin is released when plasma osmolality is high, and the easiest way to lower plasma vasopressin and copeptin concentration is to increase water intake. In a human water intervention experiment with 1 week of 3 L/day increased water intake, the one third of the participants with the greatest copeptin reduction (water responders) were those with a phenotype of low water intake (high habitual plasma copeptin and urine osmolality, and low urine volume). The water-responders had a copeptin reduction of 41% after 1 week of increased water intake compared to a control week; in contrast, a 3% reduction occurred in the other two thirds of the study participants. Among water responders, increased water intake also induced a reduction in fasting glucagon concentration. Key Messages: Elevated copeptin, a measure of vasopressin, is a risk marker of metabolic and cardiorenal diseases and may assist in the detection of individuals at higher risk for these diseases. Furthermore, individuals with high copeptin and other signs of low water intake may experience beneficial glucometabolic effects of increased water intake. Future randomized control trials investigating effects of hydration on glucometabolic and renal outcomes should focus on individuals with signs of low water intake including high plasma copeptin concentration.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Vasopressinas/sangue , Ingestão de Líquidos , Glicopeptídeos/sangue , Humanos , Estilo de Vida , Concentração Osmolar , Fatores de Risco , Vasopressinas/fisiologia
10.
Eur J Nutr ; 57(5): 1883-1890, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28578535

RESUMO

PURPOSE: Inter-individual variation in median plasma copeptin is associated with incident type 2 diabetes mellitus, progression of chronic kidney disease, and cardiovascular events. In this study, we examined whether 24-h urine osmolality was associated with plasma copeptin and whether increasing daily water intake could impact circulating plasma copeptin. METHODS: This trial was a prospective study conducted at a single investigating center. Eighty-two healthy adults (age 23.6 ± 2.9 years, BMI 22.2 ± 1.5 kg/m2, 50% female) were stratified based upon habitual daily fluid intake volumes: arm A (50-80% of EFSA dietary reference values), arm B (81-120%), and arm C (121-200%). Following a baseline visit, arms A and B increased their water intake to match arm C for a period of 6 consecutive weeks. RESULTS: At baseline, plasma copeptin was positively and significantly associated with 24-h urine osmolality (p = 0.002) and 24-h urine specific gravity (p = 0.003) but not with plasma osmolality (p = 0.18), 24-h urine creatinine (p = 0.09), and total fluid intake (p = 0.52). Over the 6-week follow-up, copeptin decreased significantly from 5.18 (3.3;7.4) to 3.90 (2.7;5.7) pmol/L (p = 0.012), while urine osmolality and urine specific gravity decreased from 591 ± 206 to 364 ± 117 mOsm/kg (p < 0.001) and from 1.016 ± 0.005 to 1.010 ± 0.004 (p < 0.001), respectively. CONCLUSIONS: At baseline, circulating levels of copeptin were positively associated with 24-h urine concentration in healthy young subjects with various fluid intakes. Moreover, this study shows, for the first time, that increased water intake over 6 weeks results in an attenuation of circulating copeptin. CLINICAL TRIAL REGISTRATION NUMBER: NCT02044679.


Assuntos
Ingestão de Líquidos , Glicopeptídeos/sangue , Glicopeptídeos/urina , Concentração Osmolar , Urinálise , Adulto , Feminino , França , Humanos , Masculino , Estudos Prospectivos
11.
Am J Nephrol ; 44(1): 22-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27347674

RESUMO

BACKGROUND: Our aim was to test if plasma copeptin, a stable surrogate marker of arginine vasopressin, predicts decline of glomerular filtration rate (GFR) and risk of chronic kidney disease (CKD). METHODS: We measured copeptin and renal function at the Malmö Diet and Cancer Cardiovascular Cohort baseline exam and reassessed renal function after a follow-up time of 16.6 ± 1.5 years (n = 3,186). Furthermore, we defined CKD based on an estimated GFR (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) <60 (CKD_60MDRD), <45 (CKD_45MDRD) and <30 (CKD_30MDRD) ml/min/1.73 m2. RESULTS: After multivariate adjustment (gender, age, baseline eGFR, smoking status, systolic blood pressure, antihypertensive treatment and follow-up time), copeptin (beta-coefficient per 1 SD increment of copeptin) was independently associated with significantly greater annual decline of eGFR (ml/min/1.73 m2) according to the MDRD formula (OR 0.057, 95% CI 0.022-0.093; p = 0.001) as well as according to the CKD Epidemiology Collaboration (CKD-EPI) formula (OR 0.050, 95% CI 0.022-0.077; p < 0.001). Each SD increment of copeptin independently predicted incident CKD_60MDRD (OR 1.19, 95% CI 1.04-1.36; p = 0.010), CKD_45MDRD (OR 1.33, 95% CI 1.04-1.71; p = 0.026) and CKD_30MDRD (OR 3.69, 95% CI 1.41-9.66; p = 0.008). The relationship between copeptin and CKD defined by CKD-EPI gave similar results. CONCLUSION: Our data suggest that increased levels of copeptin independently predict decline in eGFR and greater risk of new-onset CKD.


Assuntos
Glicopeptídeos/sangue , Insuficiência Renal Crônica/sangue , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
12.
Eur J Endocrinol ; 174(1): 69-75, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26503846

RESUMO

OBJECTIVE: Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM. DESIGN: Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996. METHODS: Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort). RESULTS: In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (ß-coefficient ± s.e.m.; 0.30 ± 0.14, P=0.03) and waist (0.78 ± 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 ± 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04). CONCLUSIONS: Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation.


Assuntos
Diabetes Mellitus/genética , Variação Genética/genética , Sobrepeso/genética , Receptores de Vasopressinas/genética , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Genótipo , Glicopeptídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade Abdominal/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Suécia
13.
Heart ; 102(2): 127-32, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26661323

RESUMO

OBJECTIVE: In a middle-aged population, it was recently shown that the stable vasopressin marker plasma copeptin (copeptin) predicts development of diabetes mellitus, diabetic heart disease and death. Here, it was hypothesised whether copeptin predicts a risk of coronary artery disease (CAD), and cardiovascular mortality in an older population. METHODS: Between 2002 and 2006, fasting plasma copeptin was examined and measured in 5386 participants of a population-based longitudinal study (mean age 69.4±6.2 years, 69.8% males) and related copeptin to risk of CAD (first myocardial infarction or coronary revascularisation), cardiovascular and total mortality during a mean follow-up time of 6.5 years using multivariate adjusted (age, gender, systolic blood pressure, antihypertensive therapy, smoking, diabetes, low-density lipoprotein and high-density lipoprotein cholesterol) Cox proportional hazards models. RESULTS: Among subjects free from CAD at baseline, the multivariate adjusted HR (95% CI) per 1 SD increment of log-transformed copeptin for risk of CAD development was 1.20 (1.08 to 1.33) (p=0.001). There was a borderline significant interaction between diabetes and copeptin on CAD risk (p=0.08) with higher copeptin-associated risk in subjects with diabetes (1.49 (1.14 to 1.95); p=0.004) than in non-diabetic subjects (1.15 (1.02 to 1.50); p=0.02). Moreover, each SD increment of copeptin independently predicted total mortality (1.31 (1.21 to 1.41); p<0.001), an effect driven by the copeptin association with cardiovascular mortality (1.36 (1.21 to 1.53); p<0.001). The absolute risks for CAD were 4.9%, 9.3% and 2.9%, total and CV mortality were 4.9%, 9.3% and 2.9% in quartile 1, 7.1%, 9.4% and 3.5% in quartile 2, 8.3%, 14.2% and 5.6% in quartile 3, and 10.3%, 23.3% and 9.1% in quartile 4, respectively. CONCLUSIONS: Copeptin predicts development of CAD and cardiovascular mortality both in diabetics and non-diabetics.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Glicopeptídeos/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fumar/epidemiologia , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Suécia/epidemiologia
14.
Am J Emerg Med ; 33(10): 1335-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26321170

RESUMO

RATIONALE: Patients with acute dyspnea are a large heterogeneous patient group where initial management is important for outcome. OBJECTIVES: The objective of the study is to investigate if venous blood gas parameters predict 1-year risk of readmission or death in patients admitted to the emergency department due to acute dyspnea. METHODS: We studied 283 patients with acute dyspnea and followed them up for 1 year regarding incidence of readmission or death. MEASUREMENTS AND MAIN RESULTS: In venous blood obtained immediately upon admission levels of total carbon dioxide (TCO2), base excess (BE), potential hydrogen (pH), and partial pressure of carbon dioxide (pCO2) were measured. In Cox proportional hazards models, patients belonging to top and bottom quartiles of TCO2, BE, pH, and pCO2 were compared to patients belonging to the 2 central quartiles and assessed for end point. After adjustment, top (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.08-2.04; P=.016) and bottom (HR, 1.54; 95% CI, 1.08-2.18; P=.017) quartiles of BE were associated with increased risk of readmission or death. The strongest predictor was top quartile of TCO2 (HR, 1.68; 95% CI, 1.21-2.35; P=.002). In the combined analysis, top quartile of TCO2 remained significantly related to the end point (HR, 1.59; 95% CI, 1.03-2.45; P=.035), whereas BE became nonsignificant. Comorbidities, for example, prevalent chronic obstructive pulmonary disease, did not explain the association. Neither pCO2 nor pH predicted the end point. CONCLUSIONS: A high value of TCO2 appears to be an easily accessible marker for 1-year readmission or death in patients with acute dyspnea and may thus add clinically important information for risk stratification and follow-up strategies.


Assuntos
Dióxido de Carbono/sangue , Dispneia/sangue , Serviço Hospitalar de Emergência/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Doença Aguda , Idoso , Biomarcadores/sangue , Gasometria , Dispneia/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco/métodos , Suécia/epidemiologia
15.
Am Heart J ; 169(4): 549-56.e1, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25819862

RESUMO

BACKGROUND: We previously discovered that high copeptin is associated with incidence of diabetes mellitus (diabetes), abdominal obesity, and albuminuria. Furthermore, copeptin predicts cardiovascular events after myocardial infarction in diabetic patients, but whether it is associated with heart disease and death in individuals without diabetes and prevalent cardiovascular disease is unknown. In this study, we aim to test whether plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin prohormone, predicts heart disease and death differentially in diabetic and nondiabetic individuals. METHODS: We related plasma copeptin to a combined end point composed of coronary artery disease (CAD), heart failure (HF), and death in diabetes (n = 895) and nondiabetes (n = 4187) individuals of the Malmö Diet and Cancer Study-Cardiovascular cohort. RESULTS: Copeptin significantly interacted with diabetes regarding the combined end point (P = .006). In diabetic individuals, copeptin predicted the combined end point (hazard ratio [HR] 1.32 per SD, 95% CI 1.10-1.58, P = .003) after adjustment for conventional risk factors, prevalent HF and CAD, and remained significant after additional adjustment for either fasting glucose (P = .02) or hemoglobin A1c (P = .02). Furthermore, in diabetic individuals, copeptin predicted CAD (HR 1.33 per SD, 95% CI 1.04-1.69, P = .02), HF (HR 1.62 per SD, 95% CI 1.09-2.41, P = .02), and death (HR 1.32 per SD, 95% CI 1.04-1.68, P = .02). Interestingly, among nondiabetic individuals, copeptin was not associated with any of the end points. CONCLUSIONS: Copeptin predicted heart disease and death, specifically in diabetes patients, suggesting copeptin and the vasopressin system as a prognostic marker and therapeutic target for diabetic heart disease and death.


Assuntos
Diabetes Mellitus/sangue , Cardiomiopatias Diabéticas/sangue , Glicopeptídeos/sangue , Biomarcadores/sangue , Causas de Morte/tendências , Diabetes Mellitus/mortalidade , Cardiomiopatias Diabéticas/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Suécia/epidemiologia
16.
Diabetologia ; 58(5): 1081-90, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25622862

RESUMO

AIMS/HYPOTHESIS: High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. METHODS: Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion. RESULTS: Compared with controls with normal VP, lean rats with high-VP had a higher fasting glycaemia after 4 weeks. In obese rats, high-VP promoted hyperinsulinaemia, glucose intolerance, assessed by glucose and insulin tolerance tests, and an impaired response to a pyruvate challenge. Conversely, treatment with a selective arginine vasopressin receptor 1A (V1aR) antagonist reduced glucose intolerance. Low-VP obese rats had unchanged glucose tolerance but exhibited a drastic decrease in liver steatosis compared with control obese rats, associated with low hepatic triacylglycerol and cholesterol content, and reduced expression of hepatic lipogenic genes. These effects were independent of changes in body adiposity, and plasma sodium and osmolality did not differ among groups. CONCLUSION/INTERPRETATION: These findings show a causal relationship between the VP-hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR.


Assuntos
Ingestão de Líquidos/fisiologia , Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Obesidade/metabolismo , Vasopressinas/sangue , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Glicemia/metabolismo , Fígado Gorduroso/metabolismo , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Indóis/farmacologia , Masculino , Pirrolidinas/farmacologia , Ratos Zucker , Vasopressinas/farmacologia
17.
Int J Hypertens ; 2014: 641587, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25405024

RESUMO

This study investigated if copeptin is affected by high salt intake and whether any salt-induced changes in copeptin are related to the degree of salt sensitivity. The study was performed on 20 men and 19 women. In addition to meals containing 50 mmol NaCl daily, capsules containing 100 mmol NaCl and corresponding placebo capsules were administered during 4 weeks each, in random order. Measurements of 24 h blood pressure, body weight, 24 h urinary volume, and fasting plasma copeptin were performed at high and low salt consumption. Copeptin increased after a high compared to low dietary salt consumption in all subjects 3,59 ± 2,28 versus 3,12 ± 1,95 (P = 0,02). Copeptin correlated inversely with urinary volume, at both low (r = -0,42; P = 0,001) and high (r = -0,60; P < 0,001) salt consumption, as well as with the change in body weight (r = -0,53; P < 0,001). Systolic salt sensitivity was inversely correlated with salt-induced changes of copeptin, only in females (r = -0,58; P = 0,017). As suppression of copeptin on high versus low salt intake was associated with systolic salt sensitivity in women, our data suggest that high fluid intake and fluid retention may contribute to salt sensitivity.

18.
J Clin Endocrinol Metab ; 96(7): E1065-72, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21490073

RESUMO

CONTEXT: Arginine vasopressin (AVP) is known to affect liver glycogenolysis, insulin, and glucagon secretion and pituitary ACTH release. We previously showed that high copeptin, the stable C-terminal fragment of AVP prohormone, is independently associated with hyperinsulinemia and future development of diabetes mellitus. OBJECTIVE: The objective of the study was to examine whether plasma copeptin is associated with components of the metabolic syndrome (MetS) independently of insulin, diabetes mellitus, and environmental factors. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional, population-based sample of 4742 subjects, aged 46-68 yr, 60% women, in Malmö, Sweden. MAIN OUTCOME MEASURE: Using multivariable logistic and linear regression, plasma copeptin was associated with components of the MetS. RESULTS: Copeptin quartile (lowest quartile as reference) was, after adjustment for age, sex, insulin, and diabetes mellitus, associated with hypertension (odds ratios 1.04, 1.07, 1.31; P = 0.004), abdominal obesity (odds ratios 1.21, 1.16, 1.57; P = 0.002), obesity (odds ratios 1.25, 1.15, 1.49; P = 0.01), top quartile of c-reactive protein (odds ratios 1.11, 1.13, 1.32; P = 0.007), and MetS (adjusted for age and sex only) (odds ratios 1.53, 1.77, 1.86; P < 0.001). High copeptin levels were significantly associated with high fat intake, low physical activity, and borderline significantly associated with low socioeconomic status. The association between copeptin and components of the MetS was not affected after adjustment for these environmental factors. CONCLUSIONS: Our data suggest that increased activity of the AVP system is a unifying factor in the MetS and point to a new pharmacologically modifiable system of potential importance in the treatment of MetS and prevention of cardiovascular disease.


Assuntos
Glicopeptídeos/sangue , Síndrome Metabólica/sangue , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Gorduras na Dieta/metabolismo , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Estilo de Vida , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Atividade Motora , Obesidade/sangue , Obesidade/complicações , Estudos Prospectivos , Classe Social , Suécia
19.
Circulation ; 121(19): 2102-8, 2010 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-20439785

RESUMO

BACKGROUND: Animal studies suggest that the arginine vasopressin system may play a role in glucose metabolism, but data from humans are limited. METHODS AND RESULTS: We analyzed plasma copeptin (copeptin), a stable C-terminal fragment of the arginine vasopressin prohormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742; mean age, 58 years; 60% women) and multivariable logistic regression, we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes mellitus at baseline, insulin resistance (top quartile of fasting plasma insulin among nondiabetic subjects), and incident diabetes mellitus on long-term follow-up. New-onset diabetes mellitus was ascertained through 3 national and regional registers. All models were adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein. In cross-sectional analyses, increasing copeptin was associated with prevalent diabetes mellitus (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow-up, 174 subjects (4%) developed new-onset diabetes mellitus. The odds of developing diabetes mellitus increased across increasing quartiles of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios, 1.0, 1.37, 1.79, and 2.09; P for trend=0.004). The association with incident diabetes mellitus remained significant in analyses restricted to subjects with fasting whole blood glucose <5.4 mmol/L at baseline (adjusted odds ratios, 1.0, 1.80, 1.92, and 3.48; P=0.001). CONCLUSIONS: Elevated copeptin predicts increased risk for diabetes mellitus independently of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel antidiabetic treatments, and metabolic side effects from arginine vasopressin system modulation.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Glicopeptídeos/sangue , Resistência à Insulina , Glicemia/metabolismo , Feminino , Seguimentos , Humanos , Insulina/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prevalência , Fatores de Risco , Suécia/epidemiologia
20.
Am J Clin Nutr ; 89(1): 400-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19056558

RESUMO

BACKGROUND: Male arginine vasopressin 1a receptor knockout mice (V1aR(-/-)) display a phenotype of low triglycerides and high glucose concentrations and high-fat-diet-induced obesity and diabetes. OBJECTIVE: We investigated whether genetic variation of the human arginine vasopressin 1A (AVPR1A) gene is associated with phenotypic features resembling those of the V1aR(-/-) mouse. DESIGN: In a population-based cross-sectional study in southern Sweden, middle-aged individuals (n = 6,055) were examined in 1991-1994. Associations between 4 AVPR1A tag single nucleotide polymorphisms (rs1042615, rs10784339, rs7308855, and rs10747983) and diabetes status, glucose and triglyceride concentrations, and BMI were analyzed. Furthermore, rs1042615 was related to diabetes status, glucose, and triglycerides within sex-specific quartiles of dietary fat intake (Q1(Fat)-Q4(Fat)) and BMI (Q1(BMI)-Q4(BMI)). RESULTS: Subjects carrying the T allele of rs1042615 had lower concentrations of triglycerides than did CC carriers (1.36 +/- 0.77 compared with 1.42 +/- 0.89 mmol/L; P = 0.014), especially in nondiabetic subjects (P = 0.001). Carriers of the rs1042615 T allele had higher fasting blood glucose (5.20 +/- 1.44 mmol/L compared with 5.12 +/- 1.22 mmol/L; P = 0.036) and a tendency toward an increased prevalence of diabetes (odds ratio: 1.22; 95% CI: 0.99, 1.51; P = 0.067) compared with CC carriers. The less common rs10784339, rs7308855, and rs10747983 were not consistently associated with metabolic variables. Among men, the rs1042615 T allele was associated with diabetes exclusively within Q4(Fat) (odds ratio: 2.22; 95% CI: 1.05, 4.71; P = 0.04) and Q4(BMI) (odds ratio: 1.81; 95% CI: 1.11, 2.93; P = 0.02). CONCLUSION: The rs1042615 T allele is associated with features resembling the phenotype of the V1aR(-/-) mouse, including uncoupling of the usual direct relation between glucose and triglycerides and an increased prevalence of diabetes in subjects with a high fat intake or who are overweight.


Assuntos
Diabetes Mellitus Tipo 2/genética , Gorduras na Dieta/administração & dosagem , Hipertrigliceridemia/genética , Polimorfismo de Nucleotídeo Único , Receptores de Vasopressinas/genética , Triglicerídeos/sangue , Alelos , Animais , Arginina/genética , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Gorduras na Dieta/efeitos adversos , Feminino , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/epidemiologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/genética , Prevalência , Estudos Prospectivos
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