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Elevated copeptin, a surrogate marker of vasopressin, is linked to low water intake and increased diabetes risk. Water supplementation in habitual low-drinkers with high copeptin significantly lowers both fasting plasma (fp) copeptin and glucose. This study aims at investigating possible underlying mechanisms. Thirty-one healthy adults with high copeptin (&gt; 10.7 pmol·L −1  (men), &gt; 6.1 pmol −1  (women)) and 24-h urine volume of   600 mOsm·kg −1  were included. The intervention consisted of addition of 1.5 L water daily for 6 weeks. Fp-adrenocorticotropic hormone (ACTH), fp-cortisol, 24-h urine cortisol, fasting and 2 h (post oral glucose) insulin and glucagon were not significantly affected by the water intervention. However, decreased (Δ baseline-6 weeks) fp-copeptin was significantly associated with Δfp-ACTH (r = 0.76,  p  &lt; 0.001) and Δfp-glucagon (r = 0.39,  p  = 0.03), respectively. When dividing our participants according to baseline copeptin, median fp-ACTH was reduced from 13.0 (interquartile range 9.2–34.5) to 7.7 (5.3–9.9) pmol L −1 ,  p  = 0.007 in the top tertile of copeptin, while no reduction was observed in the other tertiles. The glucose lowering effect from water may partly be attributable to decreased activity in the hypothalamic–pituitary–adrenal axis.  ClinicalTrials.gov: NCT03574688.

Investigation of possible underlying mechanisms behind water-induced glucose reduction in adults with high copeptin