Two Liters a Day Keep the Doctor Away? Considerations on the Pathophysiology of Suboptimal Fluid Intake in the Common Population

Abstract

Suboptimal fluid intake may require enhanced release of antidiuretic hormone (ADH) or vasopressin for the maintenance of adequate hydration. Enhanced copeptin levels (reflecting enhanced vasopressin levels) in 25% of the common population are associated with enhanced risk of metabolic syndrome with abdominal obesity, type 2 diabetes, hypertension, coronary artery disease, heart failure, vascular dementia, cognitive impairment, microalbuminuria, chronic kidney disease, inflammatory bowel disease, cancer, and premature mortality. Vasopressin stimulates the release of glucocorticoids which in turn up-regulate the serum- and glucocorticoid-inducible kinase 1 (SGK1). Moreover, dehydration upregulates the transcription factor NFAT5, which in turn stimulates SGK1 expression. SGK1 is activated by insulin, growth factors and oxidative stress via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase PDK1 and mTOR. SGK1 is a powerful stimulator of Na⁺/K⁺-ATPase, carriers (e.g. the Na⁺,K⁺,2Cl^- cotransporter NKCC, the NaCl cotransporter NCC, the Na⁺/H⁺ exchanger NHE3, and the Na⁺ coupled glucose transporter SGLT1), and ion channels (e.g. the epithelial Na⁺ channel ENaC, the Ca²⁺ release activated Ca²⁺ channel Orai1 with its stimulator STIM1, and diverse K⁺ channels). SGK1 further participates in the regulation of the transcription factors nuclear factor kappa-B NFκB, p53, cAMP responsive element binding protein (CREB), activator protein-1, and forkhead transcription factor FKHR-L1 (FOXO3a). Enhanced SGK1 activity fosters the development of hypertension, obesity, diabetes, thrombosis, stroke, inflammation including inflammatory bowel disease and autoimmune disease, cardiac fibrosis, proteinuria, renal failure as well as tumor growth. The present brief review makes the case that suboptimal fluid intake in the common population may enhance vasopressin and glucocorticoid levels thus up-regulating SGK1 expression and favouring the development of SGK1 related pathologies.

Beta-Glycerophosphate-Induced ORAI1 Expression and Store Operated Ca2+ Entry in Megakaryocytes

“…As shown for other cell types, NFAT5 is up-regulated in further clinical disorders, such as dehydration 11 , diabetes mellitus 15 and inflammatory disease 16 . In those conditions the enhanced NFAT5 expression may lead to stimulation of SGK1 expression with subsequent upregulation of ORAI1, STIM1 and STIM2 in megakaryocytes and sensitization of blood platelets to activating stimuli.…”

Underhydration Is Associated with Obesity, Chronic Diseases, and Death Within 3 to 6 Years in the U.S. Population Aged 51–70 Years

“…Longitudinal data suggest parallel relationships between various correlates of osmotic stress on cells and risk of the metabolic syndrome. Behavioral determinants of hyperosmotic stress on cells, such as salt intake, lower absolute water intake, and intake of hypertonic beverages such as sugar-sweetened beverages instead of drinking water [97][98][99][100][101]; blood biomarker measures of hyperosmotic stress on cells, such as serum hypernatremia, hypertonicity, or hyperosmolality [26,32,33,38,88,102]; intracellular measures of biochemical response to hyperosmotic cell shrinkage such as upregulation of the serumand glucocorticoid-inducible kinase 1 (SGK1) [103,104]; and physiologic measures of response to hyperosmotic cell shrinkage, such as increases in plasma copeptin [18,19,[105][106][107][108], are independently associated with incident metabolic dysregulation and/or chronic disease risk.…”

Fluid Intake Habits in Type 1 Diabetes Individuals during Typical Training Bouts

“…Moreover, low total water intake in people with T2DM acutely impairs blood glucose response during an oral glucose tolerance test [28]. Suboptimal fluid intake is a known risk factor for several diseases, due to increased vasopressin concentration stimulating SGK1 expression, and fostering the development of hypertension, obesity, diabetes, thrombosis, stroke, inflammation, renal failure and tumor growth [29]. Although daily consumption of sweetened beverages is generally discouraged, individuals with diabetes often need to consume extra carbohydrates in order to avoid hypoglycemia [14].…”