SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.

Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats.

High-fat-diet-induced hepatic insulin resistance attenuates murine lipogenesis.

Hepatic insulin resistance (IR) is often said to be "pathway-selective" with preserved insulin stimulation of lipogenesis (DNL) despite attenuated insulin signaling toward glucose metabolism. However, DNL has not been assessed in models of liver-specific IR. We studied mice with differential tissue-specific lipid-induced IR achieved by different durations of high-fat diet (HFD) feeding.

Preparing Nurse Educator Students for the New National Council of State Boards of Nursing NCLEX and AACN Essentials.

Background: Graduate nursing education students are required to complete essential core content (such as education theory, accreditation, evidence-based teaching strategies, and evaluation methods) to prepare them to transition into independent practice. The 2021-2022 academic year required a monumental change in the existing curriculum to incorporate the 2021 American Association of Colleges of Nursing and the Next Gen National Council Licensure Examination (NCLEX) content.

Method: An innovative, prioritized, learner-centered, backward design was used to update the existing curriculum to add the new core content to the nursing education student curriculum.

Comparison of Metabolic Response to Colonic Fermentation in Lean Youth vs Youth With Obesity.

Importance: Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention.

Objective: To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentation of dietary fibers and its production of acetate, gut-derived hormone secretion, and adipose tissue lipolysis.

Noninvasive Quantitative PET Imaging in Humans of the Pancreatic Beta-Cell Mass Biomarkers VMAT2 and Dopamine D2/D3 Receptors In Vivo.

Noninvasive quantitative imaging of beta-cells can provide information on changes in cellular transporters, receptors, and signaling proteins that may affect function and/or loss of mass, both of which contribute to the loss of insulin secretion and glucose regulation of patients with type 1 or type 2 diabetes (T1D/T2D). We have developed and optimized the use of two positron emission tomography (PET) radioligands, [F]FP-(+)-DTBZ and [C](+)-PHNO, targeting beta-cell VMAT2 and dopamine (D2/D3) receptors, respectively. Here we describe our optimized methodology for the clinical use of these two tracers for quantitative PET imaging of beta-cell biomarkers in vivo.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

Aims/hypothesis: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance.

Cells Adapt to Resist Fluoride through Metabolic Deactivation and Intracellular Acidification.

Fluoride is highly abundant in the environment. Many organisms have adapted specific defense mechanisms against high concentrations of fluoride, including the expression of proteins capable of removing fluoride from cells. However, these fluoride transporters have not been identified in all organisms, and even organisms that express fluoride transporters vary in tolerance capabilities across species, individuals, and even tissue types.

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC.

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6   6   6 m liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light.

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis.

SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis.

Sex- and strain-specific effects of mitochondrial uncoupling on age-related metabolic diseases in high-fat diet-fed mice.

Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria and may have evolved to protect cells against the production of damaging reactive oxygen species. Therefore, compounds that enhance mitochondrial uncoupling are potentially attractive anti-aging therapies; however, chronic ingestion is associated with a number of unwanted side effects. We have previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-directed and promotes oxidation of hepatic triglycerides by causing a subtle sustained increase in hepatic mitochondrial inefficiency.

MMAB promotes negative feedback control of cholesterol homeostasis.

Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans.

A ladder that matters: Conceptual development of a clinical ladder program for nurse practitioners and physician assistants.

Clinical ladders are professional enhancement models that encourage and reward participants for continued professional engagement and leadership development. They have the potential to affect patient care through improved provider retention, advanced and refined clinical skills, and increased engagement. Recent literature has demonstrated development and implementation of clinical ladder models for nurse practitioners (NPs) in the acute care setting.

Colonic Fermentation and Acetate Production in Youth with and without Obesity.

Background: In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications.

Objectives: In this study, we tested the following hypotheses: 1) lean youth and youth with obesity experience a different capability of their gut microbiota to ferment carbohydrates and produce acetate; and 2) colonic acetate may serve as a substrate for hepatic de novo lipogenesis (DNL).

Methods: Nineteen lean youth [mean ± SE BMI (in kg/m2): 21.

Measuring the Validity and Reliability of the Vascular Access Complication Staging and Treatment Instrument in a Pediatric Population.

A multiphase study designed with Delphi and observational components was conducted to establish the preliminary validity and reliability of the 2018 Vascular Access Complication Staging and Treatment Instrument in pediatric and neonatal populations from a single, free-standing academic children's hospital. The instrument uses objective measurement criterion to determine the severity of swelling and tissue damage to inform treatment decisions. The results of the study provided preliminary empirical evidence to support a pediatric and neonatal intravenous complication staging instrument to assess degree of swelling and severity of tissue injury.

Validation of a Gas Chromatography-Mass Spectrometry Method for the Measurement of the Redox State Metabolic Ratios Lactate/Pyruvate and β-Hydroxybutyrate/Acetoacetate in Biological Samples.

The metabolic ratios lactate/pyruvate and β-hydroxybutyrate/acetoacetate are considered valuable tools to evaluate the in vivo redox cellular state by estimating the free NAD+/NADH in cytoplasm and mitochondria, respectively. The aim of the current study was to validate a gas-chromatography mass spectrometry method for simultaneous determination of the four metabolites in plasma and liver tissue. The procedure included an o-phenylenediamine microwave-assisted derivatization, followed by liquid-liquid extraction with ethyl acetate and silylation with bis(trimethylsilyl)trifluoroacetamide:trimethylchlorosilane 99:1.

Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.

Objective: Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans.

Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference.

Alterations in muscle mitochondrial substrate preference have been postulated to play a major role in the pathogenesis of muscle insulin resistance. In order to examine this hypothesis, we assessed the ratio of mitochondrial pyruvate oxidation (V) to rates of mitochondrial citrate synthase flux (V) in muscle. Contrary to this hypothesis, we found that high-fat-diet (HFD)-fed insulin-resistant rats did not manifest altered muscle substrate preference (V/V) in soleus or quadriceps muscles in the fasting state.

Membrane-bound -1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice.

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-) mice and age-weight matched wild-type control mice.

A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.

Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance (HIR); however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum (ER), mitochondria, plasma membrane (PM), lipid droplets, and cytosol. Acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced HIR in rats.

Short report: sticks and stones may break my bones, but words can also hurt me: understanding language interpreters' perceptions of stress/growth and needs in a pediatric medical setting.

An increased focus on quality, trauma-informed patient care also warrants examination of providers' experiences of stress in medical settings. However, little is known about language interpreters' experiences of stress in the pediatric hospital setting, despite their involvement in acute and difficult patient encounters. This pilot study evaluated language interpreters' experiences and perceptions of stress in a large children's hospital.

Metabolic control analysis of hepatic glycogen synthesis in vivo.

Multiple insulin-regulated enzymes participate in hepatic glycogen synthesis, and the rate-controlling step responsible for insulin stimulation of glycogen synthesis is unknown. We demonstrate that glucokinase (GCK)-mediated glucose phosphorylation is the rate-controlling step in insulin-stimulated hepatic glycogen synthesis in vivo, by use of the somatostatin pancreatic clamp technique using [C]glucose with metabolic control analysis (MCA) in three rat models: 1) regular chow (RC)-fed male rats (control), 2) high fat diet (HFD)-fed rats, and 3) RC-fed rats with portal vein glucose delivery at a glucose infusion rate matched to the control. During hyperinsulinemia, hyperglycemia dose-dependently increased hepatic glycogen synthesis.