Abstract 649: Does Chronic Increase of Glucose Uptake Cause Cardiac “glycotoxicity”?

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jie Yan ◽  
Ivan Luptak ◽  
Lei Cui ◽  
Mohit Jain ◽  
Ronglih Liao ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Functional Recovery ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Atp Depletion ◽  
Metabolic Phenotype ◽  
Acid Oxidation

A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile but its role in the pathogenesis of cardiac diseases is incompletely understood. We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared to wildtype (WT) littermates, the GLUT1-TG mice showed normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. When the hearts were subjected to ischemia-reperfusion, an age-related impairment in functional recovery was observed in WT; cardiac function recovered to 35% vs. 52% of the preischemic level in old (22 months) vs. young (3 months) WT hearts respectively (p<0.05). Ischemic tolerance was markedly enhanced in GLUT1-TG hearts, and importantly, the greater functional recovery in GLUT1-TG hearts was sustained at older age (83% vs. 86% for old and young GLUT1-TG, respectively, p=ns). 31 P NMR spectroscopic measurement showed delayed ATP depletion, reduced acidosis during ischemia and improved recovery of high energy phosphate content in old GLUT1-TG hearts (p<0.05 vs. old WT). These differences were found to be independent of alterations in the activations of Akt and AMPK by ischemia. During reperfusion, glucose oxidation was 3-fold higher while fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared to old WT (p<0.05) suggesting that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts. Thus, these results suggest that a normal heart is capable of adapting to chronic increases in basal glucose entry into cardiomyocytes without developing “glucotoxicity”, and furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.

Suppression of 5′-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts

2009 ◽  
Vol 297 (1) ◽  
pp. H313-H321 ◽  
Author(s):  
Clifford D. L. Folmes ◽  
Cory S. Wagg ◽  
Mei Shen ◽  
Alexander S. Clanachan ◽  
Rong Tian ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Functional Recovery ◽  
Recovery Of Function ◽  
High Energy ◽  
Acid Oxidation ◽  
Protein Kinase Activity ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Activation of 5′-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) α2-subunit of AMPK (AMPK-α2 DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-14C]glucose, 0.4 mM [9, 10-3H]palmitate, and 100 μU/ml insulin. AMPK-α2 DN hearts had reduced AMPK activity at the end of reperfusion (82 ± 9 vs. 141 ± 7 pmol·mg−1·min−1) with no changes in high-energy phosphates. Despite this, AMPK-α2 DN hearts had improved recovery of function during reperfusion (14.9 ± 0.8 vs. 9.4 ± 1.4 beats·min−1·mmHg·10−3). During reperfusion, fatty acid oxidation provided 44.0 ± 2.8% of total acetyl-CoA in AMPK-α2 DN hearts compared with 55.0 ± 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 ± 9.4% vs. 85.3 ± 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.

scholarly journals Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

Diabetes ◽  
2006 ◽  
Vol 55 (10) ◽  
pp. 2688-2697 ◽  
Author(s):  
A. L. Carey ◽  
G. R. Steinberg ◽  
S. L. Macaulay ◽  
W. G. Thomas ◽  
A. G. Holmes ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Interleukin 6 ◽  
Glucose Disposal ◽  
Acid Oxidation ◽  
Amp Activated Protein Kinase

scholarly journals MicroRNA-27b-3p regulates function and metabolism in insulin resistance cells by inhibiting receptor tyrosine kinase-like orphan receptor 1

2018 ◽  
Vol 16 ◽  
pp. 205873921876205
Author(s):  
Yong Liu ◽  
Guohui Wang ◽  
Xiangwu Yang ◽  
Pengzhou Li ◽  
Hao Ling ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Tyrosine Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Receptor Tyrosine Kinase ◽  
Cell Model ◽  
Orphan Receptor ◽  
Acid Oxidation ◽  
Metabolism Disorder

Type 2 diabetes mellitus (T2DM) is associated with insulin resistance-induced lipid and glucose metabolism disorder. The study was aimed to explore the potential functional role of microRNA (miR)-27b-3p in T2DM, as well as underlying mechanisms. An insulin resistance cell model was induced in HepG2 cells and then expression of miR-27b-3p and receptor tyrosine kinase-like orphan receptor 1 (ROR1) was analyzed. The expression of miR-27b-3p was overexpressed or silenced, and the relationship between ROR1 and miR-27b-3p was investigated. Thereafter, the effects of miR-27b-3p on percentage of glucose uptake, fatty acid oxidation and cell cycle were analyzed. The expressions of miR-27b-3p were significantly increased, while the ROR1 levels were statistically decreased in the cells of the model group. Overexpression of miR-27b-3p dramatically decreased the levels of ROR1 and the percentage of glucose uptake, but had no effects on fatty acid oxidation. ROR1 was a target of miR-27b-3p. Moreover, overexpression of miR-27b-3p could remarkably highlight the percentages of cells at G0/G1 phase, but decreased the percentages of cells at S phase. In conclusion, our results suggest that miR-27b-3p regulates the function and metabolism of insulin resistance cells by inhibiting ROR1. miR-27b-3p might be a potential drug target in treating T2DM.

scholarly journals Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

2018 ◽  
Vol 46 (1) ◽  
pp. 187-202 ◽  
Author(s):  
Jaume Amengual ◽  
Francisco J. García-Carrizo ◽  
Andrea Arreguín ◽  
Hana Mušinović ◽  
Nuria Granados ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Retinoic Acid ◽  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Kinase Inhibitor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Protective Effects

Background/Aims: All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. Methods: Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. Results: Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. Conclusion: These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status.

Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Yi Liu ◽  
Chao Xin ◽  
Weidong Huang ◽  
Lijian Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Glucose Utilization ◽  
C2c12 Cells ◽  
Time Dependent ◽  
Acid Oxidation ◽  
Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

Chikusetsu saponin IVa regulates glucose uptake and fatty acid oxidation: implications in antihyperglycemic and hypolipidemic effects

2015 ◽  
Vol 67 (7) ◽  
pp. 997-1007 ◽  
Author(s):  
Yuwen Li ◽  
Tiejun Zhang ◽  
Jia Cui ◽  
Na Jia ◽  
Yin Wu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation

AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle

1997 ◽  
Vol 273 (6) ◽  
pp. E1107-E1112 ◽  
Author(s):  
G. F. Merrill ◽  
E. J. Kurth ◽  
D. G. Hardie ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 μU/ml insulin, and 10 mM glucose with or without AICAR (0.5–2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.

Estrogen replacement stimulates fatty acid oxidation and impairs post-ischemic recovery of hearts from ovariectomized female rats

2002 ◽  
Vol 80 (10) ◽  
pp. 1001-1007 ◽  
Author(s):  
Mark Grist ◽  
Richard B Wambolt ◽  
Gregory P Bondy ◽  
Dean R English ◽  
Michael F Allard
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Corn Oil ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Female Rats ◽  
Acid Oxidation ◽  
Estrogen Replacement ◽  
Lipid Utilization ◽  
Intact Rats

Women less than 50 years of age, the majority of whom are likely premenopausal and exposed to estrogen, are at greater risk of a poor short-term recovery after myocardial ischemia than men and older women. Since estrogen enhances non-cardiac lipid utilization and increased lipid utilization is associated with poor post-ischemic heart function, we determined the effect of estrogen replacement on post-ischemic myocardial function and fatty acid oxidation. Female Sprague–Dawley rats, either intact (n = 15) or ovariectomized and treated with 17β-estradiol (0.1 mg·kg–1·day–1, s.c., n = 14) or corn oil vehicle (n = 16) for 5 weeks, were compared. Function and fatty acid oxidation of isolated working hearts perfused with 1.2 mM [9,10-3H]palmitate, 5.5 mM glucose, 0.5 mM lactate, and 100 mU/L insulin were measured before and after global no-flow ischemia. Only 36% of hearts from estrogen-treated rats recovered after ischemia compared with 56% from vehicle-treated rats (p > 0.05, not significant), while 93% of hearts from intact rats recovered (p < 0.05). Relative to pre-ischemic values, post-ischemic function of estrogen-treated hearts (26.3 ± 10.1%) was significantly lower than vehicle-treated hearts (53.4 ± 11.8%, p < 0.05) and hearts from intact rats (81.9 ± 7.0%, p < 0.05). Following ischemia, fatty acid oxidation was greater in estrogen-treated hearts than in the other groups. Thus, estrogen replacement stimulates fatty acid oxidation and impairs post-ischemic recovery of isolated working hearts from ovariectomized female rats.Key words: fatty acid oxidation, estrogen, ischemia, reperfusion.

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