The effect of insulin on the uptake and metabolic fate of glucose in isolated perfused hearts of dyslipemic rats21This investigation was carried out under the auspices of University of Litoral (Secretaria de Ciencia y Técnica) and CONICET (Consejo Nacional de Investigaciones Cientı́fı́cas y Tecnológicas) by grants CAI + D # 12/B011/94, PMT-PICT # 0043/97, and PID # 4129/97, Argentina.22A preliminary report was presented at the VIth Meeting of the International Society of Heart Research (ISHR) Latinamerican

Montes, M. C.; Chicco, Adriana; Lombardo, Yolanda B.

doi:10.1016/s0955-2863(99)00068-6

Cited by 12 publications

(6 citation statements)

References 37 publications

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“…Isolated cardiomyocytes from MetS rats showed an impaired insulin response, evidenced by the absence of a significant increase in glucose uptake in response to this hormone (Fig 2). Impaired insulin-induced glucose uptake in heart has been reported in different studies, mainly conducted in Zucker fa/fa obese rats [37,50], a model widely used for the study of myocardial IR [51], and also in sucrose-fed rats [36]. However, in those studies, a diminished basal glucose uptake (without insulin stimulation) was reported, contrasting with our results, where no changes in this parameter were found.…”

Section: Impaired Insulin-induced Glucose Uptake and Akt Activation Icontrasting

confidence: 99%

“…After confirming the insulin resistance state in cardiomyocytes, evidenced by impaired glucose uptake, as reported in different models [36,37], we aimed to evaluate the insulin-induced Akt activation in cardiomyocytes isolated from our MetS model. As a first step for Akt activation, this kinase translocates towards the plasma membrane.…”

Section: Impaired Insulin-induced Akt Activation In Mets Cardiomyocytesmentioning

confidence: 83%

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Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes

et al. 2020

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Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors, with insulin resistance as a critical component for its development. Insulin signaling in the heart leads to Akt (also known as PKB) activation, a serine/threonine protein kinase, which regulates cardiac glucose metabolism and growth. Cardiac metabolic inflexibility, characterized by impaired insulin-induced glucose uptake and oxidation, has been reported as an early and consistent change in the heart of different models of MetS and diabetes; however, the evaluation of Akt activation has yielded variable results. Here we report in cardiomyocytes of MetS rats, diminished insulin-induced glucose uptake and Akt activation, evaluated by its impaired mobilization towards the plasma membrane and phosphorylation, and reflected in a redistribution of its interacting proteins, assessed by label-free mass spectrometry (data are available via ProteomeXchange with identifier PXD013260). We report 45 proteins with diminished abundance in Akt complex of MetS cardiomyocytes, mainly represented by energy metabolism-related proteins, and also, 31 Akt-interacting proteins with increased abundance, which were mainly related to contraction, endoplasmic reticulum stress, and Akt negative regulation. These results emphasize the relevance of Akt in the regulation of energy metabolism in the heart and highlight Akt-interacting proteins that could be involved in the detrimental effects of MetS in the heart.

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Section: Impaired Insulin-induced Glucose Uptake and Akt Activation Icontrasting

confidence: 99%

Section: Impaired Insulin-induced Akt Activation In Mets Cardiomyocytesmentioning

confidence: 83%

Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes

et al. 2020

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“…The M-CPT1 activity was expressed as the amount of CoASH released per min per mg of protein. The extract and assay of the PDHc activity from the heart muscle were measured as previously described [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, high sucrose, high fructose and/or high fat diets have been used to induce metabolic and physiological alterations in rodents, mimicking several aspects of the MS in humans such as dyslipidemia, IR and adiposity [ 14 ]. Furthermore, we have previously demonstrated that the cardiac muscle of rats chronically fed a sucrose-rich diet (SRD) showed a significant increase of lipid storage accompanied by a significant reduction of basal and insulin stimulated glucose uptake and metabolism (isolated perfusion according to Langendorff’s recirculating mode), as well as in the activities of key enzymes involved in glucose metabolism [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Involved in the Improvement of Lipotoxicity and Impaired Lipid Metabolism by Dietary α-Linolenic Acid Rich Salvia hispanica L (Salba) Seed in the Heart of Dyslipemic Insulin-Resistant Rats

Creus

Ferreira

Oliva

et al. 2016

JCM

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This study explores the mechanisms underlying the altered lipid metabolism in the heart of dyslipemic insulin-resistant (IR) rats fed a sucrose-rich diet (SRD) and investigates if chia seeds (rich in α-linolenic acid 18:3, n-3 ALA) improve/reverse cardiac lipotoxicity. Wistar rats received an SRD-diet for three months. Half of the animals continued with the SRD up to month 6. The other half was fed an SRD in which the fat source, corn oil (CO), was replaced by chia seeds from month 3 to 6 (SRD+chia). A reference group consumed a control diet (CD) all the time. Triglyceride, long-chain acyl CoA (LC ACoA) and diacylglycerol (DAG) contents, pyruvate dehydrogenase complex (PDHc) and muscle-type carnitine palmitoyltransferase 1 (M-CPT1) activities and protein mass levels of M-CPT1, membrane fatty acid transporter (FAT/CD36), peroxisome proliferator activated receptor α (PPARα) and uncoupling protein 2 (UCP2) were analyzed. Results show that: (a) the hearts of SRD-fed rats display lipotoxicity suggesting impaired myocardial lipid utilization; (b) Compared with the SRD group, dietary chia normalizes blood pressure; reverses/improves heart lipotoxicity, glucose oxidation, the increased protein mass level of FAT/CD36, and the impaired insulin stimulated FAT/CD36 translocation to the plasma membrane. The enhanced M-CPT1 activity is markedly reduced without similar changes in protein mass. PPARα slightly decreases, while the UCP2 protein level remains unchanged in all groups. Normalization of dyslipidemia and IR by chia reduces plasma fatty acids (FAs) availability, suggesting that a different milieu prevents the robust translocation of FAT/CD36. This could reduce the influx of FAs, decreasing the elevated M-CPT1 activity and lipid storage and improving glucose oxidation in cardiac muscles of SRD-fed rats.

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“…In the liver-specific KO mice, insulin sensitivity is enhanced and body weight is reduced on chow diet 76 . A low PDH activity leads to a decrease in glucose utilization and an increase in fatty acid utilization in ATP production 77 . PDH activity is reduced in diabetes or obesity conditions in various tissues in animals or patients 78,79 .…”

Section: Mitochondrial Pdh and Insulin Resistancementioning

confidence: 99%

Mitochondrial inhibitor as a new class of insulin sensitizer

Zhang

2012

Acta Pharmaceutica Sinica B

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Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

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Cited by 12 publications

References 37 publications

Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes

Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes

Mechanisms Involved in the Improvement of Lipotoxicity and Impaired Lipid Metabolism by Dietary α-Linolenic Acid Rich Salvia hispanica L (Salba) Seed in the Heart of Dyslipemic Insulin-Resistant Rats

Mitochondrial inhibitor as a new class of insulin sensitizer

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