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The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HF...
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Context 1
... nonmetabolized fraction of [ F]FTHA in plasma was determined using thin-layer chromatography from blood samples taken 1, 2, 3, 5, 10, 20, and 30 min after [ 18 F]FTHA injection (Fig. 2 A ), and the metabolite-corrected input curve (Fig. 2 B ) was calculated by linear interpolation and used to correct the plasma input function (17). Myocardial NEFA fractional uptake ( K i ) and K m were determined by a Patlak graphical analysis (35, 40) ROI( C p ( t ) t ) ϭ ͫ ( k K 2 ϩ 1 · k k 3 2 ) 2 ͬ ϩ ͩ k K 2 1 ϩ · k k 3 3 ͪ ϫ ͫ ͐ C C p p ( ( t t )d( ) t ) ͬ where ROI( t ) is [ 18 F]FTHA tissue ROI activity at time t , C p ( t ) is the [ 18 F]FTHA plasma activity at time t , and ͐ C p ( t ) · d t is the integrated plasma [ 18 F]FTHA activity up to time t corrected for the presence of plasma [ 18 F]FTHA metabolites. The relation between ROI( t )/C p ( t ) and [ ͐ C p ( t ) · d( t )]/C p ( t ) is linear for [ 18 F]FTHA in the myocardium, and the term ( K 1 · k 3 )/( k 2 ϩ k 3 ) ϭ K i , which is the steady-state trapping rate of the tracer in the myocardium. Thus the slope ( K i ) of this relationship represents tissue NEFA fractional uptake (in ml·g Ϫ 1 · min Ϫ 1 ). Therefore NEFA uptake NEFA ( K m ) ϭ K i ϫ ...
Context 2
... nonmetabolized fraction of [ F]FTHA in plasma was determined using thin-layer chromatography from blood samples taken 1, 2, 3, 5, 10, 20, and 30 min after [ 18 F]FTHA injection (Fig. 2 A ), and the metabolite-corrected input curve (Fig. 2 B ) was calculated by linear interpolation and used to correct the plasma input function (17). Myocardial NEFA fractional uptake ( K i ) and K m were determined by a Patlak graphical analysis (35, 40) ROI( C p ( t ) t ) ϭ ͫ ( k K 2 ϩ 1 · k k 3 2 ) 2 ͬ ϩ ͩ k K 2 1 ϩ · k k 3 3 ͪ ϫ ͫ ͐ C C p p ( ( t t )d( ) t ) ͬ where ROI( t ) is [ 18 F]FTHA tissue ROI activity at time t , C p ( t ) is the [ 18 F]FTHA plasma activity at time t , and ͐ C p ( t ) · d t is the integrated plasma [ 18 F]FTHA activity up to time t corrected for the presence of plasma [ 18 F]FTHA metabolites. The relation between ROI( t )/C p ( t ) and [ ͐ C p ( t ) · d( t )]/C p ( t ) is linear for [ 18 F]FTHA in the myocardium, and the term ( K 1 · k 3 )/( k 2 ϩ k 3 ) ϭ K i , which is the steady-state trapping rate of the tracer in the myocardium. Thus the slope ( K i ) of this relationship represents tissue NEFA fractional uptake (in ml·g Ϫ 1 · min Ϫ 1 ). Therefore NEFA uptake NEFA ( K m ) ϭ K i ϫ ...
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Background:
The hyperinsulinemic euglycemic clamp is the gold standard for assessment of insulin resistance and requires frequent, accurate measurements of blood glucose concentrations, typically utilizing the YSI 2300 STAT Plus™ glucose analyzer (YSI, Inc., Yellow Springs, OH). Despite its accuracy, the YSI has several limitations, including its...
Citations
... The hypothesis that MetS is associated with an abnormal cardiac substrate utilization has been recently highlighted in a pig model of MetS, in which a severely reduced availability of glycolytic cycle pathway metabolites has been shown (6). Cardiac metabolism abnormalities have also been observed in mouse models of diabetic cardiomyopathy, in which cardiac uptake and oxidation of fatty acids is increased because of impaired glucose transport (7,8). ...
OBJECTIVE
Experimental evidence suggests that metabolic syndrome (MetS) is associated with changes in cardiac metabolism. Whether this association occurs in humans is unknown.
RESEARCH DESIGN AND METHODS
821 asymptomatic individuals from the Progression of Early Subclinical Atherosclerosis (PESA) study (50.6 [46.9–53.6] years, 83.7% male) underwent two whole-body 18F-fluorodeoxyglucose positron emission tomography-magnetic resonance (18F-FDG PET-MR) 4.8 ± 0.6 years apart. Presence of myocardial 18F-FDG uptake was evaluated qualitatively and quantitatively. No myocardial uptake was grade 0, while positive uptake was classified in grades 1–3 according to target-to-background ratio tertiles.
RESULTS
One hundred fifty-six participants (19.0%) showed no myocardial 18F-FDG uptake, and this was significantly associated with higher prevalence of MetS (29.0% vs. 13.9%, P < 0.001), hypertension (29.0% vs. 18.0%, P = 0.002), and diabetes (11.0% vs. 3.2%, P < 0.001), and with higher insulin resistance index (HOMA-IR, 1.64% vs. 1.23%, P < 0.001). Absence of myocardial uptake was associated with higher prevalence of early atherosclerosis (i.e., arterial 18F-FDG uptake, P = 0.004). On follow-up, the associations between myocardial 18F-FDG uptake and risk factors were replicated, and MetS was more frequent in the group without myocardial uptake. The increase in HOMA-IR was associated with a progressive decrease in myocardial uptake (P < 0.001). In 82% of subjects, the categorization according to presence/absence of myocardial 18F-FDG uptake did not change between baseline and follow-up. MetS regression on follow-up was associated with a significant (P < 0.001) increase in myocardial uptake.
CONCLUSIONS
Apparently healthy individuals without cardiac 18F-FDG uptake have higher HOMA-IR and higher prevalence of MetS traits, cardiovascular risk factors, and early atherosclerosis. An improvement in cardiometabolic profile is associated with the recovery of myocardial 18F-FDG uptake at follow-up.
... Glucose, total NEFA, and TG were measured as previously described (29). Plasma C-peptide, insulin, and leptin were measured using Luminex xMAP-based immunoassays (Millipore, Etobicoke, Ontario, Canada). ...
Excessive lean tissue uptake of fatty acids (FA) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased non-esterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. Twenty-one individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]-fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]-palmitate. Hepatic (96 [range 39-213]mmol/6h vs. 75 [23-145]mmol/6h, P=0.05), but not cardiac (11 [range 4-24]mmol/6h vs. 7 [2-20]mmol/6h, P=0.1) uptake of most sources of postprandial FA (NEFA+DFA uptake) integrated over 6 hours was higher in IGT vs. NGT. DFA accounted for lower fractions of total cardiac (19 [5-47]% vs. 25 [10-40]%, P=0.08) and hepatic (22 [6-50]% vs. 29 [15-52]%, P=0.04) uptake in IGT vs. NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake, and was associated with higher total cardiac fatty acid uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182).
... This procedure is widely acknowledged by researchers worldwide because it simulates the natural history and metabolic features of T2DM [30,31]. Additionally, this method has been confirmed by previous studies on the induction of DCM models [31,32]. In line with previous researches [33,34], metabolic benefits of bariatric surgery were observed in our study, characterized by a reduced body weight, food intake, and blood glucose levels and restored glucose tolerance as well as insulin sensitivity postoperatively. ...
Diabetic cardiomyopathy (DCM) can develop in diabetes mellitus and is a major cause of morbidity and mortality. Surgical bariatric surgery procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes and have benefits regarding systolic and diastolic myocardial function. The NLR family pyrin domain containing 3 (NLRP3) inflammasome appears to participate in the development of DCM. However, whether SG surgery affects myocardial NLRP3 inflammasome-related pyroptosis to improve cardiac function remains unclear. This study was aimed at investigating the effect of SG surgery on NLRP3-associated pyroptosis in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a metabolic benefit of SG, including a reduced body weight, food intake, and blood glucose levels and restored glucose tolerance and insulin sensitivity postoperatively. We observed a marked decline in glucose uptake in rats with DCM, and this was restored after SG. Also, SG alleviated the dysfunction of myocardial contraction and diastole, delayed the progression of DCM, and reduced the NLRP3 inflammasome-mediated myocardial pyroptosis in vivo. H9c2 cardiomyocytes showed membrane disruption and DNA damage under a high glucose stimulus, which suggested myocardial pyroptosis. Using a ROS scavenger or chloride channel blocker in vitro restored myocardial NLRP3-mediated pyroptosis. Furthermore, we found that chloride efflux acted downstream of ROS generation. In conclusion, SG may ameliorate or even reverse the progression of DCM. Our study provides evidence that the SG operation alleviates NLRP3 inflammasome dysregulation in DCM. Clearance of ROS overburden and suppression of chloride efflux due to SG might act as the proximal event before inhibition of NLRP3 inflammasome in the myocardium, thus contributing to morphological and functional alleviation of DCM.
... Because it mimics the regular pathological progression of T2DM, this technique has been widely utilized by numerous specialists (Reed et al., 2000;Sahin et al., 2007;Skovsø, 2014). In addition, this method is ordinarily adopted in the induction of DCM models (Ménard et al., 2010;Ti et al., 2011). In accordance with the findings of previous research (Chambers et al., 2011), metabolic improvement of SG procedure was observed in our study, shown by a decreased body weight, food intake, and FBG level and improved glucose tolerance and insulin sensitivity post-operatively. ...
Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.
... Group II (vehicle-treated DCM; n=20) which was subdivided into 2 equal subgroups: Group IIa and Group IIb: Rats were fed a high-fat diet (15.6% protein, 57.5% fat, 26.9% carbohydrate, Faculty of Agriculture, Zagazig University) all through the experimental periods. Then, at the beginning of 5th week animals were treated with 25 mg/kg streptozotocin intraperitoneally (Sigma chemical-Aldrich, St Louis, MO) diluted into precooled citrate buffer solution (1ml per 30 mg STZ at pH 4.5) [15] . Blood glucose was monitored weekly via tail-tip blood samples; rats with persistent blood glucose levels higher than 250 mg/dl after STZ administration were considered diabetic rats [16] and rats were treated with oral saline for 8 weeks, from confirmation of diabetes in rats in group (IIa), and from the end 7th week in group (IIb). ...
... Due to the speci c metabolic fate and lipogenic property, fructose causes impairment in glucose metabolism, leading to insulin resistance, dyslipidemia and hepatic brosis, together with cardiac and renal dysfunctions [1][2][3]. During the course of excess sugar intake, wide range of stress and in ammatory responses are activated in metabolic tissues, such as pancreas, adipose tissue, skeletal muscles, and liver causing activation of c-Jun N-terminal kinase (JNK) and inhibitory κB kinase (IKK) pathways [4][5][6]. ...
Background: Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats.
Methods: Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay.
Results and Conclusion: HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
... With regards to impaired myocardial glucose utilization in obesity/T2D, cardiac myocytes isolated from adult ob/ob and db/db mice exhibit reduced insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake (Mazumder et al., 2004;Hafstad et al., 2006). Moreover, PET imaging with [ 18 F]fluorodeoxyglucose demonstrated marked reductions in myocardial glucose uptake during a euglycemichyperinsulinemic clamp in male Wistar rats fed a high-fat and high-fructose diet for 6 weeks (Menard et al., 2010). Similarly, PET imaging revealed decreased [ 18 F]fluorodeoxyglucose uptake in 12 h fasted male C57BL/6J mice fed a high-fat diet for at least 25 weeks (Battiprolu et al., 2012). ...
As the most metabolically demanding organ in the body, the heart must generate massive amounts of energy adenosine triphosphate (ATP) from the oxidation of fatty acids, carbohydrates and other fuels (e.g., amino acids, ketone bodies), in order to sustain constant contractile function. While the healthy mature heart acts omnivorously and is highly flexible in its ability to utilize the numerous fuel sources delivered to it through its coronary circulation, the heart’s ability to produce ATP from these fuel sources becomes perturbed in numerous cardiovascular disorders. This includes ischemic heart disease and myocardial infarction, as well as in various cardiomyopathies that often precede the development of overt heart failure. We herein will provide an overview of myocardial energy metabolism in the healthy heart, while describing the numerous perturbations that take place in various non-ischemic cardiomyopathies such as hypertrophic cardiomyopathy, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and the cardiomyopathy associated with the rare genetic disease, Barth Syndrome. Based on preclinical evidence where optimizing myocardial energy metabolism has been shown to attenuate cardiac dysfunction, we will discuss the feasibility of myocardial energetics optimization as an approach to treat the cardiac pathology associated with these various non-ischemic cardiomyopathies.
... Glucose and fatty acid uptake assays 14 C-bromopalmitate ([1-14 C]-2-bromopalmitic acid) and 3 H-deoxyglucose ([1,2-3H(N)]-Deoxy-D-glucose) were used to evaluate NEFA and glucose uptake respectively into BAT, VAT, muscle and liver as previously described in (Mé nard et al., 2010;Labbé et al., 2016). Both radioactive tracers (Moravek Biochemicals, Inc. Brea, CA, USA) were dissolved in normal saline supplemented with 4% bovine serum albumin (BSA). ...
mTORC2 controls glucose and lipid metabolism, but the mechanisms are unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT, and in a pathway distinct from its positive role in anabolic lipid synthesis. This facilitates FoxO1 nuclear retention, enhances lipid uptake and lipolysis, and potentiates UCP1 expression. We provide evidence that SIRT6 is the FoxO1 deacetylase suppressed by mTORC2 and show an endogenous interaction between SIRT6 and mTORC2 in both mouse and human cells. Our findings suggest a new paradigm of mTORC2 function filling an important gap in our understanding of this more mysterious mTOR complex.
... This method has been accepted by many researchers, as it simulates the natural history and metabolic characteristics of patients with type 2 diabetes [26][27][28] . Furthermore, this model is commonly used in research of DCM, and it was reported that 12-16 weeks of diabetes was sufficient to induce DCM in this model [29][30][31] . In the present study, after 16 weeks of diabetes, the diabetic rats showed both systolic and diastolic LV dysfunction before surgery, which makes it a suitable experimental model for investigating the effects of DJB on DCM. ...
... However, these studies suffered from a drawback that the measurements were carried out in vitro using isolated working hearts. Recently, PET has been used to evaluate myocardial energy substrate uptake, with the advantage of fully reflecting the physiological state in vivo 29,32 . ...
Aims/Introduction
Duodenal‐jejunal bypass (DJB) surgery has been reported to relieve diabetic cardiomyopathy (DCM) effectively. However, the specific mechanisms remain largely unknown. This study was designed to determine the alterations of myocardial glucose uptake (MGU) after DJB and their effects on DCM.
Materials and Methods
DJB and Sham surgeries were performed in diabetic rats induced by high fat diet and low dose of streptozotocin, with chow‐diet fed rats as control. Body weight, food intake, glucose homeostasis, and lipid profiles were measured at indicated time points. Cardiac function was evaluated by transthoracic echocardiography and hemodynamic measurement. Cardiac remodeling was assessed by series of morphometric analyses along with transmission electron microscopy. Positron emission tomography with fluorine‐18 labelled fluorodeoxyglucose was performed to evaluate the MGU in vivo. Furthermore, myocardial glucose transporters (GLUT1 and GLUT4), myocardial insulin signaling, and GLUT‐4 translocation related proteins were investigated to elucidate the underlying mechanisms.
Results
The DJB group showed restored systolic and diastolic cardiac function along with significant remission in cardiac hypertrophy, cardiac fibrosis, lipid deposit, and ultrastructural disorder independent of weight loss compared with the Sham group. Moreover, the DJB group demonstrated upregulated myocardial insulin signaling, hyperphosphorylation of AKT substrate of 160 kDa (AS160) and TBC1D1, along with preserved SNARE proteins, facilitating the GLUT‐4 translocation to myocardial cell surface and restoration of MGU.
Conclusions
Our findings provide evidence that restoration of MGU is implicated in the alleviation of DCM after DJB through facilitating GLUT‐4 translocation, suggesting a potential choice for treatment of human DCM if properly implemented.
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... This method has been used by many researchers, as it well simulates the natural history and metabolic characteristics of patients with T2DM (29,33,37). Furthermore, this model is commonly adopted in the induction of DCM (24,40) and suitable for investigating the mechanisms related to the therapeutic effects of bariatric surgery on DCM (46). ...
Bariatric surgery has been reported to relieve diabetic cardiomyopathy (DCM) effectively. However, the mechanisms remain largely unknown. To determine the effects of bariatric surgery on DCM via modulation of myocardial Ca2+ homeostasis and autophagy, sleeve gastrectomy (SG), duodenal-jejunal bypass (DJB) and SHAM surgeries were performed in diabetic rats induced by high fat diet and low dose of streptozotocin. Cardiac remodeling was assessed by series of morphometric and histological analyses. Transthoracic echocardiography and hemodynamic measurement were performed to determine cardiac function. The Ca2+ homeostasis was evaluated by measuring Ca2+ transients with Fura-2/AM in isolated ventricular myocytes, along with detecting abundance of Ca2+ regulatory proteins in myocardium. The myocardial autophagic flux was determined by expression of autophagy-related proteins in the absence and presence of chloroquine (CQ). Both SG and DJB surgery alleviated diabetic cardiomyopathy morphologically and functionally. Ca2+ transients exhibited significantly higher amplitude and faster decay after SG and DJB, which could be partially explained by increased expression of ryanodine receptor 2 (RyR2), sarco/endoplasmic reticulum Ca2+-2ATPase (SERCA2a), FKBP12.6, and hyperphosphorylation of phospholamban. In addition, lower level of light chain 3 B (LC3B)-II and higher level of p62 were detected after both SG and DJB, which was not reversed by CQ treatment and associated with activated mTOR and attenuated AMP-activated protein kinase (AMPK) signaling pathway. Collectively, these results provided evidence that bariatric surgery could alleviate DCM effectively, which may result, at least in part, from facilitated Ca2+ homeostasis and attenuated autophagy, suggesting a potential choice for treatment of DCM when properly implemented.
