Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes

Objectives: Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. Design: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26–47 years, BMI: 24.3–36.3 kg/m2) and 12 controls (age: 22–40 years, BMI: 30.1–37.0 kg/m2)]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. Results: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2–352.7) vs. 115.5 (60.5–188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3–0.6) vs. 0.8 (0.5–1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05). Conclusions: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points

Changes in carbon and nitrogen cycling in a floodplain lake over recent decades linked to littoral expansion, declining riverine influx, and eutrophication

This study aimed to understand changes in the biogeochemical processing of organic matter (OM) in response to multiple stressors (e.g., littoral area expansion, wastewater input, and hydrological regulation) in East Dongting Lake (Central China) over the past 60 years, using analyses of total organic carbon (TOC), total nitrogen (TN), C/N ratios, δ13C, δ15N, and diatoms from 2 sediment cores collected from the littoral and central parts of the lake. OM mainly originated from phytoplankton and C3 plant‐derived soil OM based on the ranges of C/N ratios (from 7 to 11) and δ13C (between −27‰ and −23‰). Littoral area expansion due to siltation caused an increasing influx of terrestrial soil OM in the 1980s and the 1990s, subsequently lowering δ13C values and rising C/N ratios in both sediment cores. Meanwhile, higher δ15N was linked to a high influx of isotopically heavy nitrate from urban and agricultural wastewaters. After 2000, slight decreases in TOC and TN in the littoral area were attributable to reducing inputs of external OM, likely linked to declining sediment influx from the upper reaches resulting from the Three Gorges Dam impoundment. Contrasting increases in TOC, TN, and C/N ratios in the central part indicated a high influx of terrestrial soil OM due to the declining distance from the shoreline with littoral area expansion. Declining δ15N values after 2000 indicated an increase in N2‐fixing cyanobacteria with eutrophication. Changes in diatom assemblages in both the littoral and central zones reflected nutrient enrichment and hydrological alterations. These results indicate that littoral expansion, declining riverine influx, and anthropogenic nutrient inputs are potential driving forces for the biogeochemical processing of OM in floodplain lakes. This study provides sedimentary biogeochemical clues for tracking past limnological conditions of floodplain lakes that are subjected to increasing disturbances from hydrological regulation and eutrophication

Exercise Increases Serum Fibroblast Growth Factor 21 (FGF21) Levels

Fibroblast growth factor 21 (FGF21) increases glucose uptake. It is unknown if FGF21 serum levels are affected by exercise.This was a comparative longitudinal study. Anthropometric and biochemical evaluation were carried out before and after a bout of exercise and repeated after two weeks of daily supervised exercise. The study sample was composed of 60 sedentary young healthy women. The mean age was 24±3.7 years old, and the mean BMI was 21.4±7.0 kg/m². The anthropometric characteristics did not change after two weeks of exercise. FGF21 levels significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6) vs. (460.8 (298.2-742.1), p<0.0001)). The delta (final-basal) log of serum FGF21, adjusted for BMI, showed a significant positive correlation with basal glucose (r = 0.23, p = 0.04), mean maximal heart rate (MHR) (r = 0.54, p<0.0001), mean METs (r = 0.40, p = 0.002), delta plasma epinephrine (r = 0.53, p<0.0001) and delta plasma FFAs (r = 0.35, p = 0.006). A stepwise linear regression model showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently associated with the increment in FGF21 after the exercise program (F = 4.32; r² = 0.64, p<0.0001).Serum FGF21 levels significantly increased after two weeks of physical activity. This increment correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise.ClinicalTrials.gov NCT01512368

Diurnal Variations of Mouse Plasma and Hepatic Bile Acid Concentrations as well as Expression of Biosynthetic Enzymes and Transporters

Diurnal fluctuation of bile acid (BA) concentrations in the enterohepatic system of mammals has been known for a long time. Recently, BAs have been recognized as signaling molecules beyond their well-established roles in dietary lipid absorption and cholesterol homeostasis.The current study depicted diurnal variations of individual BAs detected by ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) in serum and livers collected from C57BL/6 mice fed a regular chow or a chow containing cholestyramine (resin). Circadian rhythms of mRNA of vital BA-related nuclear receptors, enzymes, and transporters in livers and ilea were determined in control- and resin-fed mice, as well as in farnesoid X receptor (FXR) null mice. The circadian profiles of BAs showed enhanced bacterial dehydroxylation during the fasting phase and efficient hepatic reconjugation of BAs in the fed phase. The resin removed more than 90% of BAs with β-hydroxy groups, such as muricholic acids and ursodeoxycholic acid, from serum and livers, but did not exert as significant influence on CA and CDCA in both compartments. Both resin-fed and FXR-null mouse models indicate that BAs regulate their own biosynthesis through the FXR-regulated ileal fibroblast growth factor 15. BA flux also influences the daily mRNA levels of multiple BA transporters.BA concentration and composition exhibit circadian variations in mouse liver and serum, which influences the circadian rhythms of BA metabolizing genes in liver and ileum. The diurnal variations of BAs appear to serve as a signal that coordinates daily nutrient metabolism in mammals

Investigating molecular changes in organic matter composition in two Holocene lake-sediment records from central Sweden using pyrolysis-GC/MS

This research was supported by grants from the Swedish Research Council (dnr. 2014-5219) and from the Umeå University research environment ‘The environment’s chemistry’. We would like to thank Umeå Plant Science Center for making the Py-GC/MS available to us, and Alexandra Rouillard and one anonymous reviewer for constructive comments on the manuscript. All data presented in the figures in the main manuscript can be found in the supporting information. Raw data will be provided upon request from the corresponding authors.Peer reviewedPublisher PD

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics

Assessing human impact on Rostherne Mere, UK, using the geochemistry of organic matter

This study investigates recent changes in the geochemistry of organic material from a hypereutrophic lake (Rostherne Mere, United Kingdom) using the geochemical and molecular composition of radiometrically dated sediment cores. Modern samples suggest that recent sedimentation is dominated by algal production; however, a minor component of allochthonous organic material is present. Sediment cores reveal that absolute proxy values and the magnitude of observed changes are broadly homogenous across the lake basin. A transition to environmental conditions favouring enhanced algal productivity in recent sediments is suggested by higher total organic carbon (TOC) and lower carbon to nitrogen ratio (C/N), carbon isotope composition of organic matter (δ13Corg), and average n-alkane chain length. A strong covariance between TOC and Rock-Eval Hydrogen Index implies this transition is driven by an increasing algal contribution rather than being a response to variations in the source of organic matter. Decadal trends and abrupt shifts in organic geochemical proxies are suggested to be directly related to changes in external anthropogenic nutrient loading following the construction and decommissioning of sewage treatment plants. The development of hypereutrophic conditions likely occurred in stages, where rapid transitions are associated with the commencement of sewage effluent input in the 1930s, population increases in the 1980s, and a dramatic reduction in external nutrient loads in the 1990s. Recovery of the lake ecosystem is limited by internal nutrient recycling, and organic proxies indicate that the geochemistry of sediments has remained relatively constant since effluent diversion. This study highlights the utility of organic geochemical parameters in tracing recent eutrophication processes in lakes to provide evidence for the timing and scale of anthropogenic environmental change