Inhibition Of Glucose Oxidation Research Articles

Glycolysis modulation: New therapeutic strategies to improve pulmonary hypertension (Review).

Pulmonary hypertension (PH) is a progressive life‑threatening cardiopulmonary vascular disease involving various pathological mechanisms, including hypoxia, cellular metabolism, inflammation, abnormal proliferation and apoptosis. Specifically, metabolism has attracted the most attention. Glucose metabolism is essential to maintain the cardiopulmonary vascular function. However, once exposed to a noxious stimulus, intracellular glucose metabolism changes or switches to an alternative pathway more suitable for adaptation, which is known as metabolic reprogramming. By promoting the switch from oxidative phosphorylation to glycolysis, cellular metabolic reprogramming plays an important role in PH development. Suppression of glucose oxidation and secondary upregulation of glycolysis are responsible for various features of PH, including the proliferation and apoptosis resistance of pulmonary artery endothelial and smooth muscle cells. In the present review, the roles and importance of the glucose metabolism shift were discussed to aid in the development of new treatment approaches for PH.

Insulin-resistant female rat skeletal muscles display diacylglycerol-mediated protein kinase C activation and inflammation without ceramide accumulation.

This study investigated the role of diacylglycerol (DAG)-mediated protein kinase C (PKC) activation, ceramide accumulation and inflammation in insulin-resistant female oxidative and glycolytic skeletal muscles induced by an obesogenic high-fat sucrose-enriched (HFS) diet. The HFS diet impaired insulin-stimulated AKTThr308 phosphorylation and glycogen synthesis, whereas rates of fatty acid oxidation and basal lactate production were significantly elevated in soleus (Sol), extensor digitorum longus (EDL) and epitrochlearis (Epit) muscles. Insulin resistance was accompanied by increases in triacylglycerol (TAG) and DAG contents in Sol and EDL, whereas in Epit muscles only TAG content and markers of inflammation were associated with HFS diet-induced insulin resistance. Analysis of membrane-bound/cytoplasmic PKC fractions revealed that the HFS diet promoted activation/translocation of PKCδ and θ isoforms in Sol, EDL and Epit muscles. However, none of these muscles displayed alterations in ceramide content in response to HFS feeding. This could be explained by a significant increase in Dgat2 mRNA expression in Sol, EDL and Epit muscles, which likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis instead of ceramides. Overall, this study helps elucidate the molecular mechanisms underlying insulin resistance caused by diet-induced obesity in female skeletal muscles with distinct fibre type compositions. KEY POINTS: Feeding female Wistar rats a high-fat sucrose-enriched diet (HFS) led to diacylglycerol (DAG)-induced PKC activation and insulin resistance in oxidative and glycolytic skeletal muscles. HFS diet-induced toll-like receptor 4 (Tlr4) expression did not lead to increased ceramide content in female skeletal muscles. In highly glycolytic female muscles, elevated TAG content and markers of inflammation underlay HFS diet-induced insulin resistance. The HFS diet suppressed glucose oxidation and increased lactate production in oxidative and glycolytic female muscles. Increased Dgat2 mRNA expression likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis and prevented ceramide formation in skeletal muscles of HFS-fed female rats.

Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts.

Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

Calcium pyruvate attenuates fat deposition by augmenting fatty acid oxidation and inhibiting glucose oxidation in juvenile large yellow croaker (Larimichthys crocea) consuming a high-fat diet

Calcium pyruvate (CP), known as an energetic aid, has been shown to enhance lipid utilization and prevent obesity in mammals. However, very few studies were conducted to evaluate the potential implications of CP for aquatic animals. This study examined the role of CP on fat deposition in large yellow croaker by feeding fish with high-fat diets containing four levels of dietary CP (0, 0.375%, 0.75% and 1.5%). After a 70-d feeding trial, fish fed higher doses of CP significantly decreased weight gain (WG) and hepatosomatic index (HSI). Lipid percentages and triglyceride (TG) contents of whole fish, liver and muscle were negatively correlated with dietary CP. Plasma TG, total cholesterol (TC), LDL-cholesterol (LDL-c) and non-esterified fatty acids (NEFAs) levels significantly decreased with increasing dietary CP, whereas plasma HDL-cholesterol (HDL-c) and β-hydroxybutyrate (β-HB) levels came to a climax in fish fed the 1.5% CP diet. The fish fed CP diets also exhibited smaller hepatic lipid droplet size. The expression of lipogenic genes (fatty acid synthase, fas; acetyl-CoA carboxylase, acc; diacylglycerol acyltransferase 2, dgat2) were significantly down-regulated in the liver and muscle of the CP-treated fish. Conversely, the expression of lipolytic genes (adipose triglyceride lipase, atgl; hormone-sensitive lipase, hsl; carnitine palmitoyltransferase 1, cpt1) were markedly elevated. This was accompanied by enhanced tricarboxylic acid (TCA) cycle capacity (citrate content; succinate dehydrogenase, SDH; malate dehydrogenase, MDH). Further Western blot analysis revealed that CP may dose-dependently induce phosphorylations of AMP-activated protein kinase (AMPK) and ACC in the liver and muscle, together with protein expression of CPT1 and fatty acid translocase 36 (CD36). Surprisingly, treatment with CP impaired glucose utilization, as evidenced by raised plasma glucose and weakened glucose metabolism-related enzymatic activities (hexokinase, HK; phosphofructokinase, PFK; pyruvate kinase, PK; pyruvate dehydrogenase, PDH) and gene expression (glucokinase, gk; hk; phosphofructokinase-liver type, pfkl; pyruvate kinase-muscle type, pkma) in the liver and muscle. Notably, increased plasma liver enzyme activities (alanine aminotransferase, ALT; aspartate aminotransferase, AST) and hepatic inflammation-related gene expression (interleukin-1 beta, il-1β and cyclooxygenase 2, cox-2) and reduced hepatic antioxidant capacity (total antioxidative capacity, T-AOC; catalase, CAT) were found in high-dose CP treatment. These findings indicated that dietary CP could attenuate fat deposition by stimulating β-oxidation through the AMPK-ACC-CPT1 cascade and inhibiting lipogenesis and glucose oxidation. Considering both lipid-lowering effect and growth performance, dietary supplementation with 0.375% ∼ 0.75% CP is suitable for alleviating fat deposition of juvenile large yellow croaker.

Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway–mediated antioxidant defense in a mouse model of cardiac arrest

ObjectiveThe aim of this study was to investigate the effect of the ketogenic diet (KD) on post-cardiac arrest brain injury in a mouse model of cardiac arrest and cardiopulmonary resuscitation. MethodsMice were fed a KD for 4 wk and then subjected to cardiac arrest and cardiopulmonary resuscitation. The HT22 cells after β-hydroxybutyrate (β-OHB) treatment were exposed to oxygen-glucose deprivation/reoxygenation. Survival and neurologic function were measured after return of spontaneous circulation. Positron emission tomography/computed tomography scanning, 13C-magnetic resonance spectroscopy analysis, and seahorse assay were performed to explore the mechanism underlying the phenotype. ResultsResults of this study demonstrated that KD improved neurologic function and reduced apoptotic neurons in cardiac arrest and cardiopulmonary resuscitation mice. With no alteration of glucose uptake, KD suppressed glucose oxidation in mouse brain. Consistently, the glycolytic capacity of the HT22 cells was also downregulated by β-OHB treatment. Moreover, KD increased nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate and reduced glutathione/oxidized glutathione couples and reduced reactive oxygen species in the brain, probably due to activation of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. Pharmacologic inhibition of pentose phosphate pathway totally abolished the influence of β-OHB on glycolysis, and post–oxygen-glucose deprivation/reoxygenation cell viability and reactive oxygen species production in HT22 cells. ConclusionKD improved survival and attenuated post-cardiac arrest brain injury, which was mediated by upregulation of pentose phosphate pathway and related antioxidant defense system.

Untargeted metabolomics profiling in a mouse model of lung cancer treated with thermal ablation

ABSTRACT Thermal ablation is widely used in the treatment of lung cancer and is beneficial for the overall survival of patients in clinic. However, there is barely a priority in which ablation system should be chosen under different periods of tumor progression in lung cancer. The present study investigated different modes of thermal ablation systems in mice with transplanted Lewis lung carcinoma tumors and their various biological effects in local regions using untargeted metabolomics. The results showed that thermal ablation could significantly suppress tumor growth and the differentially expressed metabolites of tumors after ablation relative to untreated tumors concentrated on organic compounds, organic acids and derivatives, nucleosides, nucleotides, and lipids. The upregulated metabolites indicated an inflammatory reaction in the ablation groups at an early stage after ablation. Steroid hormone and tryptophan metabolism, which are associated with immune responses, were modulated after both cryoablation and hyperthermal ablation. Characteristically, the results also indicated that cryoablation suppressed glucose oxidation and carbohydrate metabolism of tumor, while hyperthermal ablation suppressed lipid metabolism of tumor. In conclusion, thermal ablation could inhibit tumor growth under either freezing or heating modes with characteristic different biological effects on tumors.

A Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil.

A Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil.

The predominant role of glucose as a building block and precursor of reducing equivalents.

Stores of glucose (Glc) in our body are small compared with protein and lipid. Therefore, at times of famines or trauma/disease-related starvation, glucose utilization must be limited only to pathways that can only run with glucose carbon as substrate. We will try to outline how insulin resistance drives these pathways and inhibits glucose oxidation in the stressed organism. Glc is a basic substrate for a variety of other biomolecules like nucleic acids, amino acids, proteoglycans, mucopolysaccharides and lipids. It is essential for the formation of reducing equivalents, indispensable for anabolic, antioxidative, regulatory and immune processes. As a result, a continuous Glc turnover/cycle is essential to secure at all times the Glc requirements for nonoxidative pathways mentioned above but then requires introduction of extra glucose or other intermediates into the cycle. The production of ATP through complete Glc oxidation occurs only when Glc intake is higher than required for its nonoxidative metabolism. Insulin resistance and decreased Glc oxidation indicate that requirements of Glc for anabolic pathways are high. Glc is an important building block for anabolic reactions and substrate for reducing equivalents formation. Insulin resistance prevents irreversible Glc oxidation and stimulates Glc production during stress or growth. Glc is only oxidized when intake is in excess of its anabolic requirements.

Effect of unsaturated fatty acids on glycation product formation pathways

Glycation and lipid oxidation in high-nutrient foods are closely related and exhibit complex interactions. To evaluate the effect of unsaturated fatty acids (UFAs) on glycation pathways, glycation products in glucose-lysine-UFA models were detected by ultra performance liquid chromatography-tandem mass spectrometry and electron spin resonance spectroscopy, together with multivariate data analysis. Results indicated that UFAs inhibited glucose oxidation by decreasing the contents of carbonyl compounds about 73.85–86.19%. UFAs promoted the formation of glycation products mainly via production of active radical. In three models, linoleic acid (LA) exhibits stronger glycation activity than oleic acid and eicosapentaenoic acid. LA significantly promoted radical formation, as well as the formation and degradation of fructosyllysine (FL), the signal intensity of active radical increased 647.45% and FL increased 78.73%. The comparison of E(k3), E(k7) and variable importance in projection values of orthogonal projections to latent structures discriminant analysis in three models also proved these conclusions. By studying the characteristics of LA on glycation in three UFA, we hypothesized that unsaturation is not the key factor in evaluating their effects on glycation, the radical activity, UFA solubility, spatial structure and interaction should be considered as potentially important factors.

The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

Биосенсор для экспресс-оценки интегральной токсичности товаров из полимерных и текстильных материалов

Biosensors to assess integral toxicity, which consist of an oxygen electrode and immobilized bacteria (Gluconobacter оxydans B-1280 and Escherichia coli К802) or yeast (Saccharomyces cerevisiae Y-1173) have been designed. Model toxic pollutants (phenol, n-nitrophenol, formaldehyde and heavy metal ions Pb2+, Cu2+, Hg2+ and Cr2O72) were chosen to estimate the concentration, at which 50% inhibition of glucose oxidation (ЕC50) was observed. It was shown that a biosensor based on G. оxydans cells provides the most sensitive detection of toxic pollutants, exhibits long operational stability (36 days) and can be used for the detection of integral toxicity. It was shown that the assessment of the toxicity of industrially manufactured polymer- and textile-based products using the developed biosensors and standard test systems (duckweed Lemna minor and protozoa ciliates Stylonychia mytilus) gave similar results. The proposed biosensors can significantly reduce the analysis time compared to the normatively fixed biotesting methods and can be used as a prototype of serial integral toxicity analyzers. biosensor, toxicity, immobilized bacteria Gluconobacter оxydans, Escherichia coli and yeast Saccharomyces cerevisiae, biotesting This research was supported by the State Task of the Ministry of Science and Higher Education of the Russian Federation (no. FEWG-2020-0008).

Transcriptome analysis identified long non-coding RNAs involved in the adaption of yak to high-altitude environments.

The mechanisms underlying yak adaptation to high-altitude environments have been investigated using various methods, but no report has focused on long non-coding RNA (lncRNA). In the present study, lncRNAs were screened from the gluteus transcriptomes of yak and their transcriptional levels were compared with those in Sanjiang cattle, Holstein cattle and Tibetan cattle. The potential target genes of the differentially expressed lncRNAs between species/strains were predicted using cis and trans models. Based on cis-regulated target genes, no KEGG pathway was significantly enriched. Based on trans-regulated target genes, 11 KEGG pathways in relation to energy metabolism and three KEGG pathways associated with muscle contraction were significantly enriched. Compared with cattle strains, transcriptional levels of acyl-CoA dehydrogenase, acyl-CoA-binding protein, 3-hydroxyacyl-CoA dehydrogenase were relatively higher and those of glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate mutase 1, pyruvate kinase and lactate/malate dehydrogenase were relatively lower in yak, suggesting that yaks activated fatty acid oxidation but inhibited glucose oxidation and glycolysis. Besides, NADH dehydrogenase and ATP synthase showed lower transcriptional levels in yak than in cattle, which might protect muscle tissues from deterioration caused by reactive oxygen species (ROS). Compared with cattle strains, the higher transcriptional level of glyoxalase in yak might contribute to dicarbonyl stress resistance. Voltage-dependent calcium channel/calcium release channel showed a lower level in yak than in cattle strains, which could reduce the Ca2+ influx and subsequently decrease the risk of hypertension. However, levels of EF-hand and myosin were higher in yak than in cattle strains, which might enhance the negative effects of reduced Ca2+ on muscle contraction. Overall, the present study identified lncRNAs and proposed their potential regulatory functions in yak.

The Importance of Fatty Acids as Nutrients during Post-Exercise Recovery.

It is well recognized that whole-body fatty acid (FA) oxidation remains increased for several hours following aerobic endurance exercise, even despite carbohydrate intake. However, the mechanisms involved herein have hitherto not been subject to a thorough evaluation. In immediate and early recovery (0–4 h), plasma FA availability is high, which seems mainly to be a result of hormonal factors and increased adipose tissue blood flow. The increased circulating availability of adipose-derived FA, coupled with FA from lipoprotein lipase (LPL)-derived very-low density lipoprotein (VLDL)-triacylglycerol (TG) hydrolysis in skeletal muscle capillaries and hydrolysis of TG within the muscle together act as substrates for the increased mitochondrial FA oxidation post-exercise. Within the skeletal muscle cells, increased reliance on FA oxidation likely results from enhanced FA uptake into the mitochondria through the carnitine palmitoyltransferase (CPT) 1 reaction, and concomitant AMP-activated protein kinase (AMPK)-mediated pyruvate dehydrogenase (PDH) inhibition of glucose oxidation. Together this allows glucose taken up by the skeletal muscles to be directed towards the resynthesis of glycogen. Besides being oxidized, FAs also seem to be crucial signaling molecules for peroxisome proliferator-activated receptor (PPAR) signaling post-exercise, and thus for induction of the exercise-induced FA oxidative gene adaptation program in skeletal muscle following exercise. Collectively, a high FA turnover in recovery seems essential to regain whole-body substrate homeostasis.

Branched chain amino acids exacerbate myocardial ischemia/reperfusion vulnerability via enhancing GCN2/ATF6/PPAR-α pathway-dependent fatty acid oxidation.

Rationale: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury.Methods: Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation. Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.Results: We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing.Conclusions: We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.

High-fat diet improves tolerance to myocardial ischemia by delaying normalization of intracellular PH at reperfusion

Reports on the effect of obesity on the myocardial tolerance to ischemia are contradictory. We have described that obesity induced by high-fat diet (HFD) reduces infarct size in B6D2F1 mice submitted to transient coronary occlusion. In this study, we analysed the mechanism by which dietary obesity modifies the susceptibility to myocardial ischemia and the robustness of this effect. B6D2F1 (BDF), C57BL6/J (6J), C57BL6/N (6N) male mice and BDF female mice were fed with a HFD or control diet for 16 weeks. In all three strains, HFD induced obesity with hyperinsulinemia and hypercholesterolemia and without hyperglycemia, hypertension, ventricular remodelling or cardiac dysfunction. In obese mice from all three strains PDK4 was overexpressed and HSQC NMR spectroscopy showed reduced 13C-glutamate and increased 13C-lactate and 13C-alanine, indicating uncoupling of glycolysis from glucose oxidation. In addition, HFD induced mild respiratory uncoupling in mitochondria from BDF and 6N mice in correlation with UCP3 overexpression. In studies performed in isolated perfused hearts submitted to transient ischemia these changes were associated with reduced ATP content and myocardial PCr/ATP ratio at baseline, and delayed pHi recovery (31PNMR) and attenuated hypercontracture at the onset of reperfusion. Finally, in mice subjected to 45 min of coronary occlusion and 24 h of reperfusion, HFD significantly reduced infarct size respect to their respective control diet groups in male BDF (39.4 ± 6.1% vs. 19.9 ± 3.2%, P = 0.018) and 6N mice (38.0 ± 4.1 vs. 24.5 ± 2.6%, P = 0.017), and in female BDF mice (35.3 ± 4.4% vs. 22.3 ± 2.5%, P = 0.029), but not in male 6J mice (40.2 ± 3.4% vs. 34.1 ± 3.8%, P = 0.175). Our results indicate that the protective effect of HFD-induced obesity against myocardial ischemia/reperfusion injury is influenced by genetic background and appears to critically depend on inhibition of glucose oxidation and mild respiratory mitochondrial uncoupling resulting in prolongation of acidosis at the onset of reperfusion.

Cardiac branched-chain amino acid oxidation is reduced during insulin resistance in the heart.

Recent studies have proposed that elevated branched-chain amino acids (BCAAs) may induce insulin resistance (IR) in muscle secondary to increased BCAA oxidation inhibiting glucose oxidation (GO) and fatty acid oxidation (FAO). However, BCAA oxidation rates have not been assessed in muscle IR, and cardiac FAO rates are actually already elevated in obesity-associated IR. We therefore directly examined cardiac BCAA oxidation in mice fed a high-fat diet (HFD) to induce insulin resistance to better understand the role of cardiac BCAA oxidation in cardiac IR. BCAA oxidation, GO, FAO, and glycolysis were measured in isolated working hearts from mice fed either a low-fat diet (LFD) or HFD for 10 wk. Insulin stimulation of cardiac GO and inhibition of FAO were blunted in HFD mice, resulting in a marked increase in FAO contribution to ATP production compared with LFD mice hearts (71.2% vs. 37.1%, respectively). Surprisingly, cardiac BCAA oxidation rate was reduced in HFD compared with LFD mice (33.5 ± 3.4 vs. 56.7 ± 7.1 nmol·min-1·g dry wt-1, respectively, P < 0.05, n = 9/group). In addition, BCAA oxidation contributed ~1% of the ATP production of the heart, and, as a result, alterations in BCAA oxidation could not significantly impact either GO or FAO rates. However, the decrease in BCAA oxidation was accompanied by an increase in BCAA concentration and impaired insulin signaling. These results suggest that cardiac IR is not due to an increase in BCAA oxidation and subsequent inhibition of GO and FAO. Rather, we propose that an inhibition of BCAA oxidation rate contributes to IR by leading to increased BCAA concentration, which negatively impacts insulin signaling.

Adrenergic receptor stimulation suppresses oxidative metabolism in isolated rat islets and Min6 cells.

Insulin secretion is stimulated by glucose metabolism and inhibited by catecholamines through adrenergic receptor stimulation. We determined whether catecholamines suppress oxidative metabolism in β-cells through adrenergic receptors. In Min6 cells and isolated rat islets, epinephrine decreased oxygen consumption rates compared to vehicle control or co-administration of epinephrine with α2-adrenergic receptor antagonist yohimbine. Epinephrine also decreased forskolin-stimulated oxygen consumption rates, indicating cAMP dependent and independent actions. Furthermore, glucose oxidation rates were decreased with epinephrine, independent of the exocytosis of insulin, which was blocked with yohimbine. We evaluated metabolic targets through proteomic analysis after 4 h epinephrine exposure that revealed 466 differentially expressed proteins that were significantly enriched for processes including oxidative metabolism, protein turnover, exocytosis, and cell proliferation. These results demonstrate that acute α2-adrenergic stimulation suppresses glucose oxidation in β-cells independent of nutrient availability and insulin exocytosis, while cAMP concentrations are elevated. Proteomics and immunoblots revealed changes in electron transport chain proteins that were correlated with lower metabolic reducing equivalents, intracellular ATP concentrations, and altered mitochondrial membrane potential implicating a new role for adrenergic control of mitochondrial function and ultimately insulin secretion.

Berberine inhibits glucose oxidation and insulin secretion in rat islets.

Glucose promotes insulin secretion primarily via its metabolism and the production of metabolic coupling factors in beta-cells. The activation of AMP-activated protein kinase (AMPK), an energy sensor, results in a decrease in insulin secretion from beta-cells, but its mechanism remains largely unknown. Berberine, an oral anti-diabetic drug, has been shown to activate AMPK in multiple peripheral tissues. Here, we examined the effects of berberine and AMPK activation on insulin secretion and glucose oxidation in rat islets. Our results showed that berberine inhibited glucose-stimulated insulin secretion from rat islets with AMPK activation. When glucose concentration was elevated to 25 mmol/L, the inhibitory action of berberine on insulin secretion disappeared. Furthermore, berberine significantly decreased oxygen consumption rate (OCR) and ATP production induced by high glucose in rat islets. Although adenovirus-mediated overexpression of constituent-activated AMPK markedly decreased GSIS and OCR in rat islets, the inhibition of AMPK by compound C did not reverse berberine-suppressed OCR. In addition, berberine attenuated glucose-stimulated expression of fatty acid synthase. These results indicate that berberine-mediated deceleration of glucose oxidation is tightly link to the decreased insulin secretion in islets independent of AMPK activation and inhibition of fatty acid synthesis may also contribute to the effect of berberine on insulin secretion.

Cardiac hypertrophy suppresses glucose oxidation in newborns with congenital heart defects

Cardiac hypertrophy suppresses glucose oxidation in newborns with congenital heart defects

Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion.

Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by 18F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury.