Abstract
Context:Prior studies suggested a role for the arginine vasopressin (AVP) system in the pathogenesis of diabetes. Prospective studies on the association between copeptin (the C-terminal fragment of AVP hormone) and incident diabetes are limited.Objective:We have examined the association between plasma copeptin and the risk of incident diabetes in older men.Design:The British Regional Heart Study was a prospective study with an average of 13 years follow-up.Setting:General practices in the United Kingdom were studied.Participants:Participants were 3226 men aged 60 to 79 years with no prevalent diabetes.Outcome:We measured 253 patients with incident diabetes.Results:Copeptin was positively and significantly associated with renal dysfunction, insulin resistance (homeostasis model assessment of insulin resistance), metabolic risk factors (waist circumference, blood pressure, triglycerides, and liver function), C-reactive protein, tissue plasminogen activator, and von Willebrand factor (endothelial dysfunction) but not with plasma glucose. The risk of incident diabetes was significantly elevated only in men in the top fifth of the copeptin distribution (>6.79 pmol/L), and this risk persisted after adjustment for several diabetes risk factors including metabolic risk factors and C-reactive protein (adjusted hazard ratio in the top fifth vs the rest = 1.78 [95% confidence interval, 1.34–2.37]). Risk was markedly attenuated although it remained significant after further adjustment for homeostasis model assessment of insulin resistance and plasma glucose (adjusted hazard ratio = 1.47 [1.11–1.97]). The increased risk was seen even when the analysis was restricted to men with no chronic kidney disease or to men with no impaired fasting glucose (<6.1 mmol/L).Conclusion:Copeptin is associated with a significantly increased risk of diabetes in older men. The association is partly mediated through lower insulin sensitivity. The findings suggest a potential role of the AVP system in diabetes.
Highlights
Context: Prior studies suggested a role for the arginine vasopressin (AVP) system in the pathogenesis of diabetes
Among the 3 prospective studies that have examined the association between copeptin and the risk of incident diabetes, The Malmö Diet and Cancer (MDC) Study showed an association independent of fasting insulin and blood glucose [14], whereas the FINRISK97 Study showed no independent association between copeptin and diabetes after adjustment for metabolic risk factors [16]
Insulin resistance is associated with systemic inflammation and markers of endothelial dysfunction, including tissue plasminogen antigen and von Willebrand factor [17, 18], which have been related to diabetes incidence [18, 19]
Summary
The British Regional Heart Study (BRHS) is a prospective study of cardiovascular disease (CVD) involving 7735 men aged 40 to 59 years, selected from the age-sex registers of 1 general practice in each of 24 British towns, who were screened between 1978 and 1980 [20]. Follow-up All men have been followed up for all-cause mortality, cardiovascular morbidity, and development of type 2 diabetes from the initial examination to July 2012 [29], and follow-up has been achieved for 99% of the cohort This analysis is based on follow-up from rescreening in 1998 to 2000, a mean follow-up period of 13 years (12–14 years). Receiver operating characteristic curves and areas under the curve (C-statistic) were used to assess the incremental value of copeptin to predict diabetes beyond a basic score, which included routine risk factors for diabetes readily obtainable in clinical practice, eg, age, WC, smoking, hypertension, use of statins, antihypertensive drugs, preexisting CVD, renal function, GGT, triglycerides, and fasting blood glucose. Tests for differences between the C-statistics for the risk function models with and without copeptin were performed using an SAS macro (% receiver operating characteristic curve) with SAS software (version 9.3)
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