Background Animal studies suggest that the arginine vasopressin (AVP) system may play a role in glucose metabolism, but data from humans are limited. Methods and Results We analysed plasma copeptin (copeptin), a stable C-terminal fragment of the AVP pro-hormone. Using baseline and longitudinal data from a Swedish population-based sample (n=4742, mean age 58 years, 60% women), we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes at baseline, insulin resistance (top quartile of fasting plasma insulin among non-diabetic subjects), and incident diabetes on long-term follow up using multivariable logistic regression. New-onset diabetes 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 (P=0.04) and insulin resistance (P<0.001). During 12.6 years of follow up 174 subjects (4%) developed new-onset diabetes. The odds of developing diabetes 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 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, independent of established clinical risk factors, including fasting glucose and insulin. These findings could have implications for risk assessment, novel anti-diabetic treatments, and metabolic side effects from AVP system modulation.

Copeptin independently predicts DM and abdominal obesity but not the cluster of MetS. Apart from predicting DM and abdominal obesity, elevated copeptin signals increased risk of microalbuminuria. Interestingly, the association between copeptin and later microalbuminuria was independent of both prevalent and incident DM and hypertension. Our findings suggest a relationship between a dysregulated vasopressin system and cardiometabolic risk, which could have implications for risk assessment and novel preventive treatments.