The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet

Introduction: Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. Methods: We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). Results: A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (−17%). Free water clearance was significantly decreased after 4 days (−74%) and 14 days (−41%). All changes reversed after dapagliflozin discontinuation. Conclusion: Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084)

Organic Fe speciation in the Eurasian Basins of the Arctic Ocean and its relation to terrestrial DOM

The bio-essential trace metal iron (Fe) has poor inorganic solubility in seawater, and therefore dissolution is dependent on organic complexation. The Arctic Ocean is subject to strong terrestrial influences which contribute to organic solubility of Fe, particularly in the surface. These influences are subject to rapid changes in the catchments of the main contributing rivers. Here we report concentrations and binding strengths of Fe-binding organic ligands in relation to spectral properties of Dissolved Organic Matter (DOM) and concentrations of humic substances. Full-depth profiles of Fe and Fe-binding organic ligands were measured for 11 stations, good agreement to previous studies was found with ligand concentrations between 0.9 and 2.2 equivalent nM of Fe (Eq. nM Fe) at depths > 200 m. We found nutrient-like profiles of Fe in the Atlantic-influenced Nansen basin, surface enrichment in the surface over the Amundsen and Makarov basins and scavenging effects in the deep Makarov basin. A highly detailed surface transect consisting of two sections crossing the surface flow from the Siberian continental shelf to the Fram Strait, the TransPolar Drift (TPD), clearly indicates the flow path of the riverine contribution to Fe and Fe-binding organic ligands with concentrations of 0.7 to 4.4 nM and 1.6 to 4.1 Eq. nM Fe, respectively. This is on average 4.5 times higher in DFe and 1.7 times higher in Fe-binding organic ligands than outside the TPD flow path. Conditional binding strengths of ligands in the entire dataset were remarkably similar at 11.45 ≤ LogK′ ≤ 12.63. Increased organic Fe-binding organic ligand concentrations were evident in the Arctic Ocean surface. To better identify the organic substances responsible for Fe complexation in the Arctic Ocean, diverse analytical approaches and a standard other than Suwannee River Fulvic Acid are recommended

Primary production and eddy correlation measurements of CO2 exchange over an intertidal estuary

Field measurements by eddy correlation indicate an average CO2 uptake of 1.9 g C m-2 d-1 by the intertidal Wadden Sea estuary in spring 2008. The flux did not show a dependency on the tide and fluxes during high and low tide were comparable. We hypothesize that biological production in the water column and in microbial mats that cover sediments lead to an undersaturation of CO2 that is strong enough to support the observed fluxes. The total carbon uptake by this intertidal estuary from day of the year 101–168 is estimated to be -1.7 Tg C. Extrapolation of this flux over three months in spring suggests that the uptake of CO2 by this estuary over this period is comparable to 24% of the yearly carbon flux over the North Sea and the European estuarie

Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy

Maternal thyroid function during early pregnancy is an important determinant of early fetal brain development because the fetal thyroid is unable to produce any T4 before 12-14 weeks' gestation. Overt maternal hypothyroidism as seen in severe iodine-deficient areas is associated with severely impaired neurological development of the offspring. At present, it is not known whether low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient areas may affect fetal neurodevelopment. Neurodevelopment was assessed at 10 months of age in a cohort of 220 healthy children, born after uncomplicated pregnancies and deliveries, using the Bayley Scales of Infant Development. Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks' gestation. Maternal gestational fT4 concentration was defined as an independent parameter for child development. Children of women with fT4 levels below the 5th ( <9.8 pmol/l, n = 11) and 10th ( <10.4 pmol/l, n = 22) percentiles at 12 weeks' gestation had significantly lower scores on the Bayley Psychomotor Developmental Index (PDI) scale at 10 months of age, compared to children of mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence interval (CI): 5.9-22 and 7.4, 95% CI: 1.1-13.9, respectively). At 32 weeks' gestation, no significant differences were found. In the group of women with the lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive correlation was found between the mothers' fT4 concentration and children's PDI scores (linear regression, R: 0.46, P = 0.03). After correction for confounding variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (RR): 5.8, 95% CI: 1.3-12.6). Low maternal plasma fT4 concentrations during early pregnancy may be an important risk factor for impaired infant developmen

The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet

Introduction: Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. Methods: We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). Results: A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (−17%). Free water clearance was significantly decreased after 4 days (−74%) and 14 days (−41%). All changes reversed after dapagliflozin discontinuation. Conclusion: Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084)