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Therapeutic inhibition of the sodium–glucose co-transporter 2 (SGLT2) leads to substantial loss of energy (in the form of glucose) and additional solutes (in the form of Na+ and its accompanying anions) in urine. However, despite the continuously elevated solute excretion, long-term osmotic diuresis does not occur in humans with SGLT2 inhibition. Rather, patients on SGLT2 inhibitor therapy adjust to the reduction in energy availability and conserve water. The metabolic adaptations that are induced by SGLT2 inhibition are similar to those observed in aestivation — an evolutionarily conserved survival strategy that enables physiological adaptation to energy and water shortage. Aestivators exploit amino acids from muscle to produce glucose and fatty acid fuels. This endogenous energy supply chain is coupled with nitrogen transfer for organic osmolyte production, which allows parallel water conservation. Moreover, this process is often accompanied by a reduction in metabolic rate. By comparing aestivation metabolism with the fuel switches that occur during therapeutic SGLT2 inhibition, we suggest that SGLT2 inhibitors induce aestivation-like metabolic patterns, which may contribute to the improvements in cardiac and renal function observed with this class of therapeutics.SGLT2 inhibitors induce a number of metabolic adaptations in response to increased glucose and Na+ excretion. This Perspective article describes how these adaptations suggest that SGLT2 inhibition triggers a body water-conserving mechanism, and discusses how these metabolic adjustments may contribute to the favourable cardiovascular and renal outcomes of this class of therapeutics.

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

The idea that increasing salt intake increases drinking and urine volume is widely accepted. We tested the hypothesis that an increase in salt intake of 6 g/d would change fluid balance in men living under ultra-long-term controlled conditions. Over the course of 2 separate space flight simulation studies of 105 and 205 days' duration, we exposed 10 healthy men to 3 salt intake levels (12, 9, or 6 g/d). All other nutrients were maintained constant. We studied the effect of salt-driven changes in mineralocorticoid and glucocorticoid urinary excretion on day-to-day osmolyte and water balance. A 6-g/d increase in salt intake increased urine osmolyte excretion, but reduced free-water clearance, indicating endogenous free water accrual by urine concentration. The resulting endogenous water surplus reduced fluid intake at the 12-g/d salt intake level. Across all 3 levels of salt intake, half-weekly and weekly rhythmical mineralocorticoid release promoted free water reabsorption via the renal concentration mechanism. Mineralocorticoid-coupled increases in free water reabsorption were counterbalanced by rhythmical glucocorticoid release, with excretion of endogenous osmolyte and water surplus by relative urine dilution. A 6-g/d increase in salt intake decreased the level of rhythmical mineralocorticoid release and elevated rhythmical glucocorticoid release. The projected effect of salt-driven hormone rhythm modulation corresponded well with the measured decrease in water intake and an increase in urine volume with surplus osmolyte excretion. Humans regulate osmolyte and water balance by rhythmical mineralocorticoid and glucocorticoid release, endogenous accrual of surplus body water, and precise surplus excretion. Federal Ministry for Economics and Technology/DLR; the Interdisciplinary Centre for Clinical Research; the NIH; the American Heart Association (AHA); the Renal Research Institute; and the TOYOBO Biotechnology Foundation. Food products were donated by APETITO, Coppenrath und Wiese, ENERVIT, HIPP, Katadyn, Kellogg, Molda, and Unilever.

Background We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. Methods The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. Results Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. Conclusions Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. Trial registration : The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29). Graphical abstract

ObjectivePatients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation.MethodsIn a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequential T1-weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation.ResultsIMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%–13.39% vs 2.65%, 1.15%–4.61%, median, IQR, p<0.001) and remained significant after adjustment for age, sex, race and body mass index (p<0.001). In patients with SLE, IMAT accumulation did not differ significantly among corticosteroid users and non-users (p=0.48). In the study cohort (patients and controls), IMAT was positively correlated with self-reported fatigue score (rho=0.52, p<0.001) and inversely correlated with self-reported walking distance (rho=−0.60, p<0.001). Several markers of inflammation were associated with IMAT accumulation in patients with SLE, and gene ontology analysis showed significant enrichment for pathways associated with macrophage migration and activation in relation to IMAT.ConclusionPatients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE.

Abstract Disclosure: A. Marton: None. H. Tran: None. N. Morisawa: None. I.B. Osman: None. S. Saffari: None. R.S. Foo: None. P. Khong: None. T. Lim: None. A.M. Nagel: None. J. Titze: None. T. Puar: None. Introduction: Primary aldosteronism (PA) causes sodium retention and potassium loss. In the index patient described by Jerome Conn, a muscle biopsy performed during adrenalectomy demonstrated increased muscle sodium (Na+) and reduced muscle potassium (K+), reflecting physiological intracellular sodium and potassium derangements. Sodium (23Na)-MRI imaging is available to assess muscle Na+ content non-invasively. Methodology: Patients with suspicion of PA: hypertension and hypokalaemia, severe hypertension (blood pressure 150/100mmHg), resistant hypertension, young hypertension (age <40 years), and adrenal incidentaloma with hypertension are recruited from the Endocrinology outpatient clinics in Singapore. All patients undergo the standard PA diagnostic procedures including intravenous seated saline-loading test (SLT), and receive oral potassium supplementation to achieve serum K+ levels of 4mmol/L over 4-6 weeks prior to SLT. Eligible patients additionally attend 3 study visits: at baseline, after oral K supplementation but before the SLT (4-6 weeks) and after PA confirmation and treatment (6-12 months). During each study visit 23NaMRI imaging for muscle sodium quantification is performed and blood and 24h urine samples are collected for analysis. Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) are measured by liquid-chromatography tandem mass spectrometry. Patients will be confirmed with PA if post-SLT PAC is 5ng/dL or greater with suppressed PRA (1ng/ml/hr or lower). The trial was approved by the SingHealth Centralised Institutional Review Board, Singapore, and was registered on ClinicalTrials.gov (NCT06569589). Results: We prospectively recruited 28 patients, with 15 females (53.6%), median age 51 years, and BMI of 26.6 kg/m2. At baseline visit 1, systolic blood pressure (BP) was 137.6±12.4 mmHg, diastolic BP 91.0±10.0 mmHg, and heart rate was 78.7 ±10.5 beats per minute. Plasma Na+ and K+ were 141.9±1.9 and 3.44±0.4 mmol/L; 24h Na+ and K+ excretion were 142.0±54.7 and 40.3±13.6 mmol/d. Baseline median PAC was 7.3 ng/dL (IQR: 3.3-10.3) and urinary aldosterone 4.8 μg/d (IQR: 2.7-6.6), and PRA was 0.88 ng/ml/hr (IQR: 0.4-2.2). Muscle Na+ content was 24.3 (IQR: 22.6-26.4) mmol/L tissue volume. Oral K+ supplementation instituted was 3.7±1.6 g/d prior to SLT. Summary and Conclusion: We will test the hypothesis that compared to patients diagnosed with essential hypertension, patients with hyperaldosteronism have a 10-20% higher muscle Na content (primary outcome 1). Secondary outcome measures are the effect of oral K+ supplementation, MR blockade, and surgical removal of aldosterone-producing adenoma on muscle Na+ content in the study participants. Presentation: Monday, July 14, 2025

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary [Na.sup.+] excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid- driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

Individuals’ socio-demographic and economic characteristics crucially shape the spread of an epidemic by largely determining the exposure level to the virus and the severity of the disease for those who got infected. While the complex interplay between individual characteristics and epidemic dynamics is widely recognised, traditional mathematical models often overlook these factors. In this study, we examine two important aspects of human behaviour relevant to epidemics: contact patterns and vaccination uptake. Using data collected during the COVID-19 pandemic in Hungary, we first identify the dimensions along which individuals exhibit the greatest variation in their contact patterns and vaccination uptake. We find that generally higher socio-economic groups of the population have a higher number of contacts and a higher vaccination uptake with respect to disadvantaged groups. Subsequently, we propose a data-driven epidemiological model that incorporates these behavioural differences. Finally, we apply our model to analyse the fourth wave of COVID-19 in Hungary, providing valuable insights into real-world scenarios. By bridging the gap between individual characteristics and epidemic spread, our research contributes to a more comprehensive understanding of disease dynamics and informs effective public health strategies. Contact patterns influence the spread of infectious diseases, but mathematical models of epidemics typically only account for age differences in contacts. Here, the authors investigate the importance of other sociodemographic characteristics in shaping contact patterns and vaccine uptake using survey data from Hungary.

Vaccinations are fundamental public health interventions. Yet, inequalities in vaccine uptake across socioeconomic groups can significantly undermine their impact. Moreover, heterogeneities in vaccination coverage across socioeconomic strata are typically neglected by epidemic models and considered, if at all, only at posteriori. This limitation reduces their ability to predict and assess the effectiveness of vaccination campaigns. Here, we study the impact of socioeconomic inequalities in vaccination uptake on disease burden, measured as attack rate. We consider a modeling framework based on generalized contact matrices that extend traditional age-stratified approaches to incorporate socioeconomic status (SES) variables. We simulate epidemic dynamics under two scenarios. In the first, vaccination campaigns are concurrent with epidemics. In the second, instead, vaccinations are completed before the onset of infection waves. By using both synthetic and empirical generalized contact matrices, we find that inequalities in vaccine uptake can lead to non-linear effects on disease outcomes and exacerbate disease burden in disadvantaged groups of the population. We demonstrate that simpler models ignoring SES heterogeneity produce incomplete or biased predictions of attack rates. Additionally, we show how inequalities in vaccine coverage interact with non-pharmaceutical interventions (NPIs), compounding differences across subgroups. Overall, our findings highlight the importance of integrating SES dimensions, alongside age, into epidemic models to inform more equitable and effective public health interventions and vaccination strategies.

Background: Hispanic children and men carry a high burden for obesity and associated medical conditions. Healthy Dads Healthy Kids was the first obesity prevention intervention targeting fathers and demonstrated weight loss among fathers and behavior change among fathers and children in Australia. The aim of this study was to assess the feasibility of a culturally adapted version of the program for Hispanic families, Papás Saludables Niños Saludables. Methods: A randomized waitlist controlled trial with a process evaluation was conducted to assess the feasibility of Papás Saludables Niños Saludables (NCT03532048). Fathers, their partner (mother), and one to three children were enrolled. A priori feasibility criteria were: (1) recruit 40 Hispanic fathers and their families in ≤4 months; (2) retain 80% of participants for pre- and postassessments; (3) maintain ≥70% attendance to the 10 sessions; (4) obtain 80% “excellent” or “good” satisfaction from participants; and (5) collect anthropometric and behavioral data on ≥75% of participants at baseline and follow-up. Results: The study enrolled 90% (n = 36) of the goal from one local pediatric clinic between May and August 2018; retained 75% of participants for postassessment; maintained 72% attendance among those who started the program; and achieved 100% “excellent/good” satisfaction ratings among the participating fathers and mothers. One hundred percent of participants had most anthropometric and behavioral data at baseline and 72% at follow-up. Conclusions: With oversampling and improvements in the recruitment strategies, Papás Saludables Niños Saludables is feasible for a randomized controlled clinical trial to address whether a father-targeted lifestyle program is efficacious among low-income Hispanic men and their children.