Copeptin, Insulin Resistance, and Risk of Incident Diabetes in Older Men

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.