Elevated serum osmolarity, even mildly, is increasingly linked to various non-communicable diseases like hypertension, chronic kidney disease, heart failure, and age-related illnesses. The mechanisms are complex, likely involving the renin-angiotensin system (RAS), vasopressin, cortisol, and fructose metabolism pathways. While dehydration and heat stress are known to increase serum osmolarity, both salt and sugar (specifically fructose) acutely elevate it. Studies suggest that salt's acute blood pressure increase is due to the osmolarity change rather than salt load itself, and hydration can mitigate this effect. Hydration can also counteract salt-induced metabolic syndrome by blocking osmolarity-induced fructose generation. This study aimed to further investigate the effects of increased serum osmolarity on acute stress responses by comparing the effects of salt and fructose (from apple juice), given their frequent consumption in Western diets. The hypothesis was that both salt and fructose would induce comparable serum osmolarity increases and stress responses, with salt primarily activating the RAS and fructose affecting glucose and FGF21 metabolism.

Existing research demonstrates a strong correlation between even subtle elevations in serum osmolarity and an increased risk of various chronic diseases. Studies have implicated the stimulation of the renin-angiotensin system (RAS), vasopressin, cortisol, and fructose metabolic pathways in these mechanisms. Dehydration and heat stress are recognized factors increasing serum osmolarity, but the acute effects of salt and fructose consumption are also relevant. Evidence suggests that the acute increase in blood pressure following salt intake is primarily attributed to the resultant change in serum osmolarity rather than the direct effect of the sodium load. Furthermore, hydration has been shown to effectively counteract this blood pressure elevation by preventing the rise in serum sodium. The impact of hydration extends to the prevention of salt-induced metabolic syndrome by inhibiting osmolarity-induced fructose generation via the polyol pathway. These findings highlight the significance of investigating the metabolic consequences of both salt and fructose intake and the potential protective role of hydration.

Forty-four healthy individuals (BMI 19–25 kg/m²) with no systemic diseases or medications were recruited. Participants fasted overnight and were randomly assigned to one of four groups. Group 1 consumed 500 mL of lentil soup with added salt (5g), Group 2 consumed the same soup without added salt, Group 3 consumed 500 mL of 100% apple juice, and Group 4 consumed 500 mL of apple juice plus 500 mL of water. Blood pressure (BP), plasma sodium, and glucose levels were measured every 15 min for 2 h. Serum and urine osmolarity, serum uric acid, cortisol, FGF21, aldosterone, ACTH, and plasma renin activity (PRA) were measured at baseline and 2 h. The study protocol was approved by the Koc University School of Medicine ethics committee. Data were analyzed using linear mixed models, adjusting for baseline levels and demographic variables. Between-group comparisons were performed using the χ² test or one-way ANOVA. Time-repeated measurements were analyzed with linear mixed models including treatment, time, and the interaction term. Multiple group comparisons were adjusted using Bonferroni's method.

The study revealed no significant baseline differences in age and gender between the four groups; however, Groups 3 and 4 showed higher BMI than Group 2, and Group 4 had a higher BMI than Group 1. Systolic BP increased significantly across all groups over time (*p* < 0.001), with a significant difference in slopes between groups (*p* < 0.001). Groups 1 and 3 showed significant systolic BP increases compared to baseline at 30 min, lasting throughout the follow-up. Group 1 consistently displayed higher systolic BP than Groups 2 and 4 after the initial 15 min. At 30 min, Group 3's systolic BP was higher than Group 2's, and thereafter higher than Group 4's. Both acute salt and fructose intake increased serum osmolality (maximum ~4 mOsm/L peaking at 75 min), systolic and diastolic BP, PRA, aldosterone, ACTH, cortisol, plasma glucose, uric acid, and FGF21. Salt intake led to more significant RAS activation, while fructose intake resulted in greater increases in glucose and FGF21. Importantly, hydration (Group 4) prevented the increase in osmolality and largely blocked the acute stress response.

This study confirms that both acute salt and fructose intake significantly increase serum osmolality and trigger an acute stress response characterized by elevations in blood pressure, RAS activation, and markers of cortisol and glucose metabolism. The findings highlight the differential effects of salt and fructose: salt predominantly activates the RAS, while fructose significantly impacts glucose and FGF21 metabolism. Crucially, the results demonstrate the protective effect of hydration in mitigating these metabolic responses. By preventing the increase in serum osmolality, hydration effectively dampens the activation of the ACTH-cortisol axis, RAS, glucose metabolism, and uric acid axis. These findings underscore the potential health benefits of adequate hydration, even when consuming diets high in salt and fructose.

This study demonstrates that both salt and fructose acutely increase serum osmolality, leading to a significant stress response that includes increased blood pressure and activation of multiple metabolic pathways. However, hydration effectively mitigates these adverse effects. Future research should focus on long-term studies to determine if hydration can prevent the chronic diseases associated with high salt and sugar consumption. This could lead to the development of new dietary guidelines and interventions.

The study's relatively short duration (2 hours) limits the conclusions that can be drawn about the long-term effects of salt and fructose consumption. The sample size was relatively small, potentially limiting the generalizability of the findings to other populations. The study focused on healthy individuals; therefore, the results may not directly apply to individuals with pre-existing health conditions.