Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention

Huggins, Catherine E.; Domenighetti, Andrea A.; Ritchie, Matthew E.; Khalil, Natalie; Favaloro, Jenny M.; Proietto, Joseph; Smyth, Gordon K.; Pepe, Salvatore; Delbridge, L.

doi:10.1016/j.yjmcc.2007.11.020

Cited by 49 publications

(39 citation statements)

References 33 publications

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“…Values of PCr and cytosolic creatine (Cr) obtained from high performance of liquid chromatography analysis were used for calculating cytosolic ADP and AMP. To calculate the cytosolic contents of ADP and AMP, the equilibrium reactions PCr+ADP+H + ↔ATP+Cr with a Keq=1.66×10 9 , whereas 2ADP↔ATP+AMP with a Keq=1.05, were used to calculate ADP and AMP, respectively, as described previously.…”

Section: Measurement Of High-energy Phosphatesmentioning

confidence: 99%

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Cardiac Insulin-Resistance and Decreased Mitochondrial Energy Production Precede the Development of Systolic Heart Failure After Pressure-Overload Hypertrophy

Zhang

Jaswal

Ussher

et al. 2013

Circ: Heart Failure

229

178

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The high energy demands of the heart are primarily met by the mitochondrial oxidation of fatty acids and carbohydrates (glucose and lactate). 1 The amount of ATP produced depends on overall mitochondrial oxidative capacity, oxygen supply to the myocardium, and the supply of substrates for oxidative metabolism.1 In hypertrophy and HF, a decrease in high-energy phosphates in the heart has been observed. 5,6 However, it is not clear whether this is attributable entirely to a decrease in mitochondrial oxidative capacity, a switch in energy substrate preference, or a less efficient use of energy. The question also arises as to whether these metabolic changes are a consequence of HF, per se, or whether they are an early event that may contribute to the development and progression of HF.Glucose use in the heart is highly dependent on insulin, and any decrease in responsiveness of the heart to insulin can create a state of cardiac insulin-resistance.7 Insulin facilitates glucose entry by inducing the translocation of glucose transporter 4 (GLUT4) from intracellular storage vesicles to the sarcolemmal membrane.8 Decreasing GLUT4 availability exacerbates Background-Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear. Methods and Results-Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E′), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP. Conclusions-The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

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Section: Measurement Of High-energy Phosphatesmentioning

confidence: 99%

“…9 As a result, myocardial insulin-resistance is an established risk factor for the development of cardiovascular diseases. 1,10 Chronic hyperinsulinemia associated with wholebody insulin-resistance can stimulate angiotensin II-induced pathological hypertrophy.…”

mentioning

confidence: 99%

Cardiac Insulin-Resistance and Decreased Mitochondrial Energy Production Precede the Development of Systolic Heart Failure After Pressure-Overload Hypertrophy

Zhang

Jaswal

Ussher

et al. 2013

Circ: Heart Failure

229

178

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“…By this approach, three groups of transcripts were identified: transcripts with a significant change in expression in insulin-treated animals compared with control, transcripts with a significant change in expression in X10-treated animals compared with control, and transcripts expressed at significantly different levels between insulin-and X10-treated animals. These groups comprised all transcripts identified as differentially expressed, irrespective of fold change, and in the further analysis we applied cutoff values for the definition of differentially expressed transcripts of R1.3-and R1.5-fold change in expression, which have been used in previous studies (Peart et al 2005, Huggins et al 2008, Raouf et al 2008). …”

Section: Microarraysmentioning

confidence: 99%

Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway

Hvid¹,

Fendt²,

Blouin³

et al. 2012

Endocrine-Related Cancer

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Recent evidence suggests that type II diabetes is associated with increased risk and/or aggressive behavior of several cancers, including those arising from the colon. Concerns have been raised that endogenous hyperinsulinemia and/or exogenous insulin and insulin analogs might stimulate proliferation of neoplastic cells. However, the mechanisms underlying possible growth-promoting effects of insulin and insulin analogs in cancer cells in vivo, such as changes in gene expression, are incompletely described. We observed that administration of the insulin analog X10 significantly increased tumor growth and proliferation in a murine colon cancer model (MC38 cell allografts). Insulin and X10 altered gene expression in MC38 tumors in a similar fashion, but X10 was more potent in terms of the number of genes influenced and the magnitude of changes in gene expression. Many of the affected genes were annotated to metabolism, nutrient uptake, and protein synthesis. Strikingly, expression of genes encoding enzymes in the serine synthesis pathway, recently shown to be critical for neoplastic proliferation, was increased following treatment with insulin and X10. Using stable isotopic tracers and mass spectrometry, we confirmed that insulin and X10 increased glucose contribution to serine synthesis in MC38 cells. The data demonstrate that the tumor growth-promoting effects of insulin and X10 are associated with changes in expression of genes involved in cellular energy metabolism and reveal previously unrecognized effects of insulin and X10 on serine synthesis.

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“…The increase of oxidative stress may not only stimulate cardiac hypertrophy but also promote fibrosis formation (57,97,98). Our data is supported by a cardiac insulin resistance study in which hearts with Glut4 knockout showed cardiac hypertrophy, impaired contractility and increased fibrosis (18,35,40) Human studies show that failing hearts have a lower PCrl ATP ratio, which is a marker of energy reserve and a predictor of mortality (69). The PCrl A TP ratio was significantly decreased in Mb-TAC hearts compared to FVB-TAC hearts ( Figure 5).…”

Section: Cardiac Structural Remodeling and Dysfunction After Tacsupporting

confidence: 74%

Cardiac abnormalities after transaortic constriction are worsened by changing glucose metabolism and benefited by repair of mitochondrial DNA.

Wang¹

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Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention

Cited by 49 publications

References 33 publications

Cardiac Insulin-Resistance and Decreased Mitochondrial Energy Production Precede the Development of Systolic Heart Failure After Pressure-Overload Hypertrophy

Cardiac Insulin-Resistance and Decreased Mitochondrial Energy Production Precede the Development of Systolic Heart Failure After Pressure-Overload Hypertrophy

Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway

Cardiac abnormalities after transaortic constriction are worsened by changing glucose metabolism and benefited by repair of mitochondrial DNA.

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