Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients:results of the TransplantLines Biobank and cohort Studies

BACKGROUND: New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. METHODS: This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1–5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). RESULTS: Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5–1.2] mmol/L vs. 0.6 [0.4–0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64–3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). CONCLUSIONS: This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors

Quantum Sensing of Free Radicals in Primary Human Granulosa Cells with Nanoscale Resolution

Cumulus granulosa cells (cGCs) and mural granulosa cells (mGCs), although derived from the same precursors, are anatomically and functionally heterogeneous. They are critical for female fertility by supporting oocyte competence and follicular development. There are various techniques used to investigate the role of free radicals in mGCs and cCGs. Yet, temporospatial resolution remains a challenge. We used a quantum sensing approach to study free radical generation at nanoscale in cGCs and mGCs isolated from women undergoing oocyte retrieval during in vitro fertilization (IVF). Cells were incubated with bare fluorescent nanodiamonds (FNDs) or mitochondria targeted FNDs to detect free radicals in the cytoplasm and mitochondria. After inducing oxidative stress with menadione, we continued to detect free radical generation for 30 min. We observed an increase in free radical generation in cGCs and mGCs from 10 min on. Although cytoplasmic and mitochondrial free radical levels are indistinguishable in the physiological state in both cGCs and mGCs, the free radical changes measured in mitochondria were significantly larger in both cell types, suggesting mitochondria are sites of free radical generation. Furthermore, we observed later occurrence and a smaller percentage of cytoplasmic free radical change in cGCs, indicating that cGCs may be more resistant to oxidative stress.</p

Quantum Sensing of Free Radicals in Primary Human Granulosa Cells with Nanoscale Resolution

Cumulus granulosa cells (cGCs) and mural granulosa cells (mGCs), although derived from the same precursors, are anatomically and functionally heterogeneous. They are critical for female fertility by supporting oocyte competence and follicular development. There are various techniques used to investigate the role of free radicals in mGCs and cCGs. Yet, temporospatial resolution remains a challenge. We used a quantum sensing approach to study free radical generation at nanoscale in cGCs and mGCs isolated from women undergoing oocyte retrieval during in vitro fertilization (IVF). Cells were incubated with bare fluorescent nanodiamonds (FNDs) or mitochondria targeted FNDs to detect free radicals in the cytoplasm and mitochondria. After inducing oxidative stress with menadione, we continued to detect free radical generation for 30 min. We observed an increase in free radical generation in cGCs and mGCs from 10 min on. Although cytoplasmic and mitochondrial free radical levels are indistinguishable in the physiological state in both cGCs and mGCs, the free radical changes measured in mitochondria were significantly larger in both cell types, suggesting mitochondria are sites of free radical generation. Furthermore, we observed later occurrence and a smaller percentage of cytoplasmic free radical change in cGCs, indicating that cGCs may be more resistant to oxidative stress.</p

Preconception insulin resistance and neonatal birth weight in women with obesity:role of bile acids

Research question: Does maternal preconception insulin resistance affect neonatal birth weight among women with obesity? Is insulin resistance associated with circulating bile acids? Do bile acids influence the association between maternal preconception insulin resistance and neonatal birth weight? Design: An exploratory post-hoc analysis of the LIFEstyle randomized controlled trial comparing lifestyle intervention with conventional infertility treatment in women with a BMI of ≥29 kg/m2. Fasting blood samples were collected at randomization and after 3 and 6 months in 469 women. Insulin resistance was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). Bile acid sub-species were determined by liquid chromatography with tandem mass spectrometry. Singletons were included (n = 238). Birth weight Z-scores were adjusted for age, offspring gender and parity. Multilevel analysis and linear regressions were used. Results: A total of 913 pairs of simultaneous preconception HOMA-IR (median [Q25; Q75]: 2.96 [2.07; 4.16]) and total bile acid measurements (1.79 [1.10; 2.94]) µmol/l were taken. Preconception HOMA-IR was positively associated with total bile acids (adjusted B 0.15; 95% CI 0.09 to 0.22; P < 0.001) and all bile acid sub-species. At the last measurement before pregnancy, HOMA-IR (2.71 [1.91; 3.74]) was positively related to birth weight Z-score (mean ± SD 0.4 ± 1.1; adjusted B 0.08; 95% CI 0.01 to 0.14; P = 0.03). None of the preconception bile acids measured were associated with birth weight. Conclusion: Maternal preconception insulin resistance is an important determinant of neonatal birth weight in women with obesity, whereas preconception bile acids are not