Chromatin bound by survivin regulates the glycolytic switch in interferon-γ producing CD4+ T cells

Upon activation, CD4+ T cells adapt metabolically to fulfill their effector function in autoimmunity. Here we show that nuclear survivin is essential for transcriptional regulation of glucose utilization. We found that the glycolytic switch in interferon (IFN) g–producing CD4+ cells is dependent on a complex of survivin with interferon regulatory factor 1 (IRF1), and Smad3 and was reversed by survivin inhibition. Transcriptome analysis of CD4+ cells and sequencing of survivin-bound chromatin identified a hub of metabolism regulating genes whose transcription depended on survivin. Direct binding of survivin to IRF1 and SMAD3 promoted IRF1-mediated transcription, repressed SMAD3 activity, and lowered PFKFB3 production. Inhibiting survivin upregulated PFKFB3, restored glycolysis, and reduced glucose uptake, improving control over IFNg-dependent T-cell functions. Thus, IRF1-survivin-SMAD3 interactions are important for metabolic adaptation of CD4+ cells and provide an attractive strategy to counteract IFNg-dependent inflammation.

Tissue specific responses that constrain glucose oxidation and increase lactate production with the severity of hypoxemia in fetal sheep

Fetal hypoxemia decreases insulin and increases cortisol and norepinephrine concentrations and may restrict growth by decreasing glucose utilization and altering substrate oxidation. Specifically, we hypothesized that hypoxemia would decrease fetal glucose oxidation and increase lactate and pyruvate production. We tested this by measuring whole-body glucose oxidation and lactate production, and molecular pathways in liver, muscle, adipose, and pancreas tissues of fetuses exposed to maternal hypoxemia for 9 days (HOX) compared with control fetal sheep (CON) in late gestation. Fetuses with more severe hypoxemia had lower whole-body glucose oxidation rates, and HOX fetuses had increased lactate production from glucose. In muscle and adipose tissue, expression of the glucose transporter GLUT4 was decreased. In muscle, pyruvate kinase (PKM) and lactate dehydrogenase B (LDHB) expression was decreased. In adipose tissue, LDHA and lactate transporter (MCT1) expression was increased. In liver, there was decreased gene expression of PKLR and MPC2 and phosphorylation of PDH, and increased LDHA gene and protein abundance. LDH activity, however, was decreased only in HOX skeletal muscle. There were no differences in basal insulin signaling across tissues, nor differences in pancreatic tissue insulin content, beta cell area, or genes regulating beta cell function. Collectively, these results demonstrate coordinated metabolic responses across tissues in the hypoxemic fetus that limit glucose oxidation and increase lactate and pyruvate production. These responses may be mediated by hypoxemia induced endocrine responses including increased norepinephrine and cortisol, which inhibit pancreatic insulin secretion resulting in lower insulin concentrations and decreased stimulation of glucose utilization.

Adaptations in metabolism and protein translation give rise to the Crabtree effect in yeast

Aerobic fermentation, also referred to as the Crabtree effect in yeast, is a well-studied phenomenon that allows many eukaryal cells to attain higher growth rates at high glucose availability. Not all yeasts exhibit the Crabtree effect, and it is not known why Crabtree-negative yeasts can grow at rates comparable to Crabtree-positive yeasts. Here, we quantitatively compared two Crabtree-positive yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, and two Crabtree-negative yeasts, Kluyveromyces marxianus and Scheffersomyces stipitis, cultivated under glucose excess conditions. Combining physiological and proteome quantification with genome-scale metabolic modeling, we found that the two groups differ in energy metabolism and translation efficiency. In Crabtree-positive yeasts, the central carbon metabolism flux and proteome allocation favor a glucose utilization strategy minimizing proteome cost as proteins translation parameters, including ribosomal content and/or efficiency, are lower. Crabtree-negative yeasts, however, use a strategy of maximizing ATP yield, accompanied by higher protein translation parameters. Our analyses provide insight into the underlying reasons for the Crabtree effect, demonstrating a coupling to adaptations in both metabolism and protein translation.

Impact of muscle mass on blood glucose level

Objectives At present, diabetes is one of the leading causes of mortality across the world. It was hypothesized that muscle mass could have a significant influence on blood glucose level and this corelation if established successfully could pave way for novel treatment modalities for type 2 diabetes mellitus (T2DM). In the present study, the association between muscle mass and blood glucose level was examined in a healthy population who was not having T2DM at baseline and was undergoing a regular course of exercise. Methods The clinical study was performed involving 53 healthy male populations between 10 and 60 years of age. The participants were sampled in accordance with the quantitative experimental study design, using nonprobability sampling techniques. The independent variable measured among the subjects included muscle mass and blood glucose level, using bioelectrical impedance and a simple glucometer respectively. Subgroup analysis amongst different substantial parameters including body mass index (BMI), myostatin inhibitor usage, and age factor that could affect the muscle mass and glucose level correlation were also studied simultaneously. Results The study findings demonstrated a negative correlation between muscle mass and glucose utilization levels. There was a significant difference in the mean muscle mass of the participants which was 36.2453, and the mean glucose utilization level which was 15.1493%. Pearson correlation between the muscle mass and percentage of glucose utilization of the participants indicated a significant difference (since p-value <0.05) between these two studied parameters. Conclusions The study finding suggests an inverse association of the skeletal muscle mass with blood glucose level which encourages the implication of muscle-building exercises as the preventive measure for T2DM.

2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA

Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.

Effect of photobiomodulation therapy on the regulation of glucose uptake by lymphocytes in diabetes mellitus (Review)

For most cells, including lymphocytes, glucose is a primary energy source, and, therefore, it is vital to understand the regulatory mechanisms that control the work of glucose transporters. Lymphocytes are pivotal for mediation of immune and inflammatory responses. A feature of lymphocytes is increasing glucose utilization during activation of the immune function, which is strongly dependent on glucose uptake. Some studies show that elevated glucose concentration in diabetes mellitus affects lymphocytes’ glucose transporters expression, whichcorrelates with impaired immune functions and may become one of the predisposing factors of contracting infectious diseases. Recent studies have focused on glucose transporters as therapeutic targets for a variety of diseases, including diabetes mellitus. This review demonstrates the effect of photobiomodulationtherapy on glucose uptake by Na+-coupled glucose carrier SGLT1 and facilitated diffusion glucose carriers of the GLUT family (GLUT1, GLUT3, GLUT4) in normal and diabetic lymphocytes.

Pregnane-Oximino-Alkyl-Amino-Ether Compound as a Novel Class of TGR5 Receptor Agonist Exhibiting Antidiabetic and Anti-Dyslipidemic Activities

<b><i>Introduction:</i></b> The present study deals with the synthesis of pregnane-oximino-amino-alkyl-ethers and their evaluation for antidiabetic and anti-dyslipidemic activities in validated animal and cell culture models. <b><i>Methods:</i></b> The effect on glucose tolerance was measured in sucrose-loaded rats; antidiabetic activity was evaluated in streptozotocin (STZ)-induced diabetic rats and genetically diabetic <i>db</i>/<i>db</i> mice; the anti-dyslipidemic effect was characterized in high-fructose, high-fat diet (HFD)-fed dyslipidemic hamsters. The effect on glucose production and glucose utilization was analyzed in HepG2 liver and L6 skeletal muscle cells, respectively. <b><i>Results:</i></b> From the synthesized molecules, pregnane-oximino-amino-alkyl-ether (compound <b>14b)</b> improved glucose clearance in sucrose-loaded rats and exerted antihyperglycemic activity on STZ-induced diabetic rats. Further evaluation in genetically diabetic <i>db</i>/<i>db</i> mice showed temporal decrease in blood glucose, and improvement in glucose tolerance and lipid parameters, associated with mild improvement in the serum insulin level. Moreover, compound <b>14b</b> treatment displayed an anti-dyslipidemic effect characterized by significant improvement in altered lipid parameters of the high-fructose, HFD-fed dyslipidemic hamster model. In vitro analysis in the cellular system suggested that compound <b>14b</b> decreased glucose production in liver cells and stimulated glucose utilization in skeletal muscle cells. These beneficial effects of compound <b>14b</b> were associated with the activation of the G-protein-coupled bile acid receptor TGR5. <b><i>Conclusion:</i></b> Compound <b>14b</b> exhibits antidiabetic and anti-dyslipidemic activities through activating the TGR5 receptor system and can be developed as a lead for the management of type II diabetes and related metabolic complications.