American Journal of Physiology. Endocrinology and Metabolism

AIMS: Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alfa cell response are also part of the islet dysfunction. METHODS: A three-phase (euglycemia, hyperglycemia and hyperglycemia + glucagon-like peptide 1) clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase...

Metabolic flexibility (MetFlex) describes the ability to respond and adapt to changes in metabolic demand and substrate availability. The relationship between physical (in)activity and MetFlex is unclear. This study aimed to determine whether sedentary time, physical activity (PA), and cardiorespiratory fitness associate with MetFlex. Sedentary time, standing, and PA were measured with accelerometers for four weeks in 64 sedentary adults with metabolic syndrome (37 women, 27 men; 58.3 [SD 6.8] years). Fitness (VO2 max [mL·kg-1 ·min-1 ]) was measured with graded maximal cycle ergometry...

Obesity and its related metabolic complications represent a significant global health challenge. Central to this is the dysregulation of glucolipid metabolism, with a predominant focus on glucose metabolic dysfunction in current research, while adipose metabolism impairment garners less attention. Exosomes (EXs), small extracellular vesicles (EVs) secreted by various cells, have emerged as important mediators of intercellular communication and have the potential to be biomarkers, targets, and therapeutic tools for diverse diseases...

Larsucosterol (25-Hydroxycholesterol 3-sulfate, 25HC3S), a potent endogenous epigenetic regulator, has been reported to play a significant role in lipid metabolism, inflammatory responses, and cell survival. Administration of 25HC3S has been shown to decrease lipid accumulation in hepatocytes, suppress LPS- and TNFα-induced inflammatory responses in macrophages, alleviate LPS- and ATMP-induced multiple organ injury, and decreases mortalities in animal models. Results from phase 1 and 2 clinical trials have shown that 25HC3S has potential as a biomedicine for the treatment of acute and chronic liver diseases...

NAFLD is characterized by excess lipid accumulation which can progress to inflammation (NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly employed as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum (β-HB) levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142)...

Incretin-based pharmacotherapies provide novel efficient and safe therapeutic options to curb appetite and produce weight loss in obese patients. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioural mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss...

T2D prevalence in adults at a younger age has increased but the disease status may go unnoticed. This study aimed to determine whether the onset age and subsequent diabetic complications can be attributed to the polygenic architecture of T2D in the Taiwan Han population. A total of 9,627 cases with T2D and 85,606 controls from the Taiwan Biobank were enrolled. Three diabetic polygenic risk scores (PRSs)-PRS_EAS and PRS_EUR, and a trans-ancestry PRS (PRS_META)-calculated using summary statistic from East Asian and European populations...

We previously demonstrated impaired placental nutrient transfer in chorionic somatomammotropin (CSH) RNA interference (RNAi) pregnancies, with glucose transfer being the most impacted. Thus, we hypothesized that despite experimentally elevating maternal glucose, diminished umbilical glucose uptake would persist in CSH RNAi pregnancies, demonstrating the necessity of CSH for adequate placental glucose transfer. Trophectoderm of sheep blastocysts (9 days of gestational age; dGA) were infected with a lentivirus expressing either non-targeting control (CON RNAi; n = 5) or CSH-specific shRNA (CSH RNAi; n = 7), prior to transfer into recipient sheep...

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met not only by muscle glycogenolysis, but also by accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose...

The tricarboxylic acid (TCA) cycle metabolite fumarate non-enzymatically reacts with the amino acid cysteine to form S-(2-succino)cysteine (2SC), referred to as protein succination. The immunometabolite itaconate accumulates during lipopolysaccharide (LPS) stimulation of macrophages and microglia. Itaconate non-enzymatically reacts with cysteine residues to generate 2,3-dicarboxypropylcysteine (2,3-DCP), referred to as protein dicarboxypropylation. Since fumarate and itaconate levels dynamically change in activated immune cells, the levels of both 2SC and 2,3-DCP reflect the abundance of these metabolites and their capacity to modify protein thiols...

Background. Resveratrol (RSV), a natural polyphenol compound contained in numerous plants, has been proposed as a treatment for obesity-related disease processes such as insulin resistance. However, in humans there are conflicting results concerning the efficacy of RSV in improving insulin action; the purpose of the present study was to determine if obesity status (lean, severely obese) affects the response to RSV in human skeletal muscle. Methods. Primary skeletal muscle cells were derived from biopsies obtained from age-matched lean and insulin-resistant women with severe obesity and incubated with RSV (1µM) for 24-hours...

Background: Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. Methods : In a single-blind, randomized, cross-over design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-hour postabsorptive period followed by a 3-hour hyperinsulinemic-euglycemic clamp (HEC)...

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies...

Vitamin D(VD) is a fat-soluble sterol that possesses a wide range of physiological functions. The present study aimed to evaluate the effects of VD on folate metabolism in zebrafish and further investigate the underlying mechanism. Wild-type (WT) zebrafish were fed with the diet containing 0 IU/kg VD3 or 800 IU/kg VD3 for 3 weeks. Meanwhile, cyp2r1 mutant zebrafish with impaired VD metabolism served as another model of VD deficiency. Our results showed that VD deficiency in zebrafish suppressed the gene expression of folate transporters, including reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) in the intestine...

The hypothalamus is a key integrating centre that is involved in the initiation of the corticosteroid stress response, and in regulating nutrient homeostasis. While cortisol, the principal glucocorticoid in humans and teleosts, plays a central role in the feeding regulation, the mechanisms are far from clear. We tested the hypothesis that the metabolic changes to cortisol exposure signal an energy excess in the hypothalamus, leading to feeding suppression during stress in fish. Rainbow trout ( Oncorhynchus mykiss ) were administered a slow-release cortisol implant for three days, and the metabolite profiles in the plasma, hypothalamus, and the rest of the brain were assessed...

Several clinical studies observed a surprising beneficial effect of obesity to increase immunotherapy responsiveness in melanoma patients, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug used to treat diabetes by sequestering fatty acids in the metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-Programmed Cell Death Protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, a murine melanoma model that is initially sensitive to immunotherapy...

This study aimed to evaluate the role of skeletal muscle-derived interleukin (IL)-15 in the regulation of skeletal muscle autophagy using IL-15 knockout (KO) and transgenic (TG) mice. Male C57BL/6 wild type (WT), IL-15 KO, and IL-15 TG mice were used in this study. Changes in muscle mass, forelimb grip strength, succinate dehydrogenase (SDH) activity, gene and protein expression levels of major regulators and indicators of autophagy, comprehensive gene expression, and DNA methylation in the gastrocnemius muscle were analyzed...

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Nicotinamide adenine dinucleotide (NAD+ ) is an essential pyridine nucleotide cofactor that is present in cells and in several important biological processes, including oxidative phosphorylation and production of adenosine triphosphate, DNA repair, calcium-dependent secondary messenger and gene expression. The purpose of this systematic review is to examine whether the coenzyme formulae NAD+ and NADH are safe and effective when acting as a supplement to humans. This systematic review of randomized clinical trials performed a search in six electronic databases: PubMed, MEDLINE ( ovid ), Embase, Cochrane CENTRAL (clinical trials), Web of Science, and Scopus...