THE VASOPRESSIN SYSTEM IN DIABETES MELLITUS, OBESITY AND THE METABOLIC SYNDROME

Background: Animal studies suggest that the arginine vasopressin (AVP) system plays a role in glucose and fat metabolism, but data from humans are limited.

Method and results: We analysed plasma copeptin (copeptin), a stable C-terminal fragment of the AVP pro-hormone in the large, Swedish, population-based cohort Malmö Diet and Cancer Study Cardiovascular Cohort (MDC-CC, n=6103). Using baseline (1991-1994) and longitudinal (register- and reinvestigation-based) data from MDC-CC (partly re-investigated 15.8 years later (n=2345)) we examined the association of increasing quartiles of copeptin (lowest quartile as reference) with prevalent diabetes (DM) and other components of the metabolic syndrome (MetS) at baseline, and incident DM, measures of obesity and microalbuminuria at follow up, using multivariable logistic regression. After adjusted for clinical and anthropometric risk factors, cystatin C, and C-reactive protein, increasing copeptin quartile (lowest quartile as reference) was associated with prevalent DM (Ptrend=0.04). Furthermore, copeptin quartile was after adjustment for age, sex, insulin and diabetes mellitus associated with prevalent hypertension (Ptrend=0.004), abdominal obesity (Ptrend=0.002), obesity (P=0.01), top quartile of CRP (Ptrend=0.007) and MetS (adjusted for age and sex only) (Ptrend<0.001).

During 12.6 years of register-based follow up 174 subjects (4%) developed new-onset diabetes. The odds of developing DM increased across increasing quartile of copeptin, even after additional adjustment for baseline fasting glucose and insulin (adjusted odds ratios 1.0, 1.37, 1.79, and 2.09; Ptrend =0.004). The association with incident DM 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; Ptrend=0.001).

When incident cases of DM were captured by a re-examination (n=2345) 15.8 years after baseline, increasing copeptin quartiles predicted DM (odds ratios 1.18, 1.32, 1.46; Ptrend=0.04), abdominal obesity (odds ratios 1.55, 1.30, 1.59; Ptrend=0.04), and microalbuminuria (odds ratios 1.05, 1.08, 1.65, Ptrend=0.02) but not MetS (Ptrend=0.19) after adjustment for age, gender and all MetS components at baseline.

Genetic polymorphisms in the human AVP receptor 1a gene (AVPR1A) and 1b gene (AVPR1B) were genotyped in MDC-CC. We found that genetic variance in AVPR1A was associated with high glucose and low triglyceride levels, as well as increased prevalence of DM in subjects with a high fat intake, features strongly resembling mice with selective deletion of the same receptor. Finally, we found that genetic variance in AVPR1B was associated with BMI. This finding was replicated in the MDC replication cohort (n=24344).

Conclusion: Elevated copeptin independently predicts DM and abdominal obesity but not the cluster of MetS. Our findings suggest a relationship between a dysregulated vasopressin system and cardiometabolic risk, which could have implications for risk assessment and novel preventive treatments.