Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells.

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks.

Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts.

Electrokinetic transport of CTAB induces multiphasic behavior during capillary adsorption and desorption.

Cationic surfactant coatings (e.g., CTAB) are commonly used in CE to control EOF and thereby improve separation efficiencies.

Fatty acids and inflammatory stimuli induce expression of long-chain acyl-CoA synthetase 1 to promote lipid remodeling in diabetic kidney disease.

Fatty acid handling and complex lipid synthesis are altered in the kidney cortex of diabetic patients. We recently showed that inhibition of the renin-angiotensin system without changes in glycemia can reverse diabetic kidney disease (DKD) and restore the lipid metabolic network in the kidney cortex of diabetic (db/db) mice, raising the possibility that lipid remodeling may play a central role in DKD. However, the roles of specific enzymes involved in lipid remodeling in DKD have not been elucidated.

Cross-sectional associations between prenatal maternal per- and poly-fluoroalkyl substances and bioactive lipids in three Environmental influences on Child Health Outcomes (ECHO) cohorts.

Background: Per- and poly-fluoroalkyl substances (PFAS) exposure can occur through ingestion of contaminated food and water, and inhalation of indoor air contaminated with these chemicals from consumer and industrial products. Prenatal PFAS exposures may confer risk for pregnancy-related outcomes such as hypertensive and metabolic disorders, preterm birth, and impaired fetal development through intermediate metabolic and inflammation pathways.

Objective: Estimate associations between maternal pregnancy PFAS exposure (individually and as a mixture) and bioactive lipids.

Tubular dysfunction impairs renal excretion of pseudouridine in diabetic kidney disease.

Plasma nucleosides-pseudouridine (PU) and -dimethyl guanosine (DMG) predict the progression of type 2 diabetic kidney disease (DKD) to end-stage renal disease, but the mechanisms underlying this relationship are not well understood. We used a well-characterized model of type 2 diabetes ( mice) and control nondiabetic mice ( mice) to characterize the production and excretion of PU and DMG levels using liquid chromatography-mass spectrometry. The fractional excretion of PU and DMG was decreased in mice compared with control mice at 24 wk before any changes to renal function.

Inhibition of neutrophil extracellular trap formation alleviates vascular dysfunction in type 1 diabetic mice.

While neutrophil extracellular traps (NETs) have previously been linked to some diabetes-associated complications, such as dysfunctional wound healing, their potential role in diabetic vascular dysfunction has not been studied. Diabetic Akita mice were crossed with either or mice to generate NET-deficient diabetic mice. By 24 weeks of age, Akita aortae showed markedly impaired relaxation in response to acetylcholine, indicative of vascular dysfunction.

Transcriptomic analysis of diabetic kidney disease and neuropathy in mouse models of type 1 and type 2 diabetes.

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background.

Role of succinate in airway epithelial cell regulation following traumatic lung injury.

Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA.

Clustering-based spatial analysis (CluSA) framework through graph neural network for chronic kidney disease prediction using histopathology images.

Machine learning applied to digital pathology has been increasingly used to assess kidney function and diagnose the underlying cause of chronic kidney disease (CKD). We developed a novel computational framework, clustering-based spatial analysis (CluSA), that leverages unsupervised learning to learn spatial relationships between local visual patterns in kidney tissue. This framework minimizes the need for time-consuming and impractical expert annotations.

Developmental programming: Impact of preconceptional and gestational exposure to a real-life environmental chemical mixture on maternal steroid, cytokine and oxidative stress milieus in sheep.

Background: Gestational exposure to environmental chemicals (ECs) is associated with adverse, sex-specific offspring health effects of global concern. As the maternal steroid, cytokine and oxidative stress milieus can have critical effects on pregnancy outcomes and the programming of diseases in offspring, it is important to study the impact of real-life EC exposure, i.e.

Nanofluidic diodes based on asymmetric bio-inspired surface coatings in straight glass nanochannels.

In this study, we present nanofluidic diodes fabricated from straight glass nanochannels and functionalized using bio-inspired polydopamine (PDA) and poly-L-lysine (PLL) coatings. The resulting PDA coatings are shown to be asymmetric due to a combination of transport considerations which can be leveraged to provide a measure of control over the effective channel geometry. By subsequently introducing a layer of amine-bearing PLL chains covalently bound to the PDA, we enhance heterogeneities in the charge and ion distributions within the channel and enable significant current rectification between forward-bias and reverse-bias modes; our PDA-PLL-coated channels yielded a rectification ratio greater than 1000 in a 100 nm channel filled with 0.

Low concentrations of medium-sized HDL particles predict incident CVD in chronic kidney disease patients.

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional CVD risk factors cannot completely explain the increased risk. Altered HDL proteome is linked with incident CVD in CKD patients, but it is unclear whether other HDL metrics are associated with incident CVD in this population.

Crabtree effect in kidney proximal tubule cells via late-stage glycolytic intermediates.

The Crabtree effect is defined as a rapid glucose-induced repression of mitochondrial oxidative metabolism and has been described in yeasts and tumor cells. Using plate-based respirometry, we identified the Crabtree effect in normal (non-tumor) kidney proximal tubule epithelial cells (PTEC) but not in other kidney cells (podocytes or mesangial cells) or mammalian cells (C2C12 myoblasts). Glucose-induced repression of respiration was prevented by reducing glycolysis at the proximal step with 2-deoxyglucose and partially reversed by pyruvate.

The effect of surgical weight loss on diabetes complications in individuals with class II/III obesity.

Aims/hypothesis: The aim of this study was to determine the effect of bariatric surgery on diabetes complications in individuals with class II/III obesity (BMI > 35 kg/m).

Methods: We performed a prospective cohort study of participants with obesity who underwent bariatric surgery. At baseline and 2 years following surgery, participants underwent metabolic phenotyping and diabetes complication assessments.

The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease.

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression.

SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes.

The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs.

Present and future directions in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of kidney failure and is associated with substantial risk of cardiovascular disease, morbidity, and mortality. Traditionally, DKD prevention and management have focused on addressing hyperglycemia, hypertension, obesity, and renin-angiotensin system activation as important risk factors for disease. Over the last decade, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to meaningfully reduce risk of diabetes-related kidney and cardiovascular complications.

Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study.

Acetyl Co-A Carboxylase Inhibition Halts Hyperglycemia Induced Upregulation of De Novo Lipogenesis in Podocytes and Proximal Tubular Cells.

The effect of glycemic stress on de novo lipogenesis (DNL) in podocytes and tubular epithelial cells is understudied. This study is aimed (A) to show the effect of glycemic stress on DNL, and (B) to assess the effect of acetyl-Co A (ACC) inhibition on halting upregulation of DNL, on the expression of other lipid regulatory genes in the DNL pathway, and on markers of fibrosis and apoptosis in podocytes and tubular epithelial cells. We used cultured mouse primary tubular epithelial cells, mouse proximal tubular (BUMPT) cells, and immortal mouse podocytes and measured their percentage of labeled C-palmitate as a marker of DNL after incubation with C acetate in response to high glucose concentration (25 mM).

Electrooxidation of Phenol on Polyelectrolyte Modified Carbon Electrodes for Use in Insulin Pump Infusion Sets.

Background: Many type 1 diabetes patients using continuous subcutaneous insulin infusion (CSII) suffer from the phenomenon of unexplained hypoglycemia or "site loss." Site loss is hypothesized to be caused by toxic excipients, for example, phenolic compounds within insulin formulations that are used as preservatives and stabilizers. Here, we develop a bioinspired polyelectrolyte-modified carbon electrode for effective electrooxidative removal of phenol from insulin and eventual incorporations into an infusion set of a CSII device.