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1.
J Physiol ; 594(2): 307-20, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26574233

RESUMEN

KEY POINTS: Adaptation to hypoxia makes the heart more oxygen efficient, by metabolising more glucose. In contrast, type 2 diabetes makes the heart metabolise more fatty acids. Diabetes increases the chances of the heart being exposed to hypoxia, but whether the diabetic heart can adapt and respond is unknown. In this study we show that diabetic hearts retain the ability to adapt their metabolism in response to hypoxia, with functional hypoxia signalling pathways. However, the hypoxia-induced changes in metabolism are additive to abnormal baseline metabolism, resulting in hypoxic diabetic hearts metabolising more fat and less glucose than controls. This stops the diabetic heart being able to recover its function when stressed. These results demonstrate that the diabetic heart retains metabolic flexibility to adapt to hypoxia, but is hindered by the baseline effects of the disease. This increases our understanding of how the diabetic heart is affected by hypoxia-associated complications of the disease. ABSTRACT: Hypoxia activates the hypoxia-inducible factor (HIF), promoting glycolysis and suppressing mitochondrial respiration. In the type 2 diabetic heart, glycolysis is suppressed whereas fatty acid metabolism is promoted. The diabetic heart experiences chronic hypoxia as a consequence of increased obstructive sleep apnoea and cardiovascular disease. Given the opposing metabolic effects of hypoxia and diabetes, we questioned whether diabetes affects cardiac metabolic adaptation to hypoxia. Control and type 2 diabetic rats were housed for 3 weeks in normoxia or 11% oxygen. Metabolism and function were measured in the isolated perfused heart using radiolabelled substrates. Following chronic hypoxia, both control and diabetic hearts upregulated glycolysis, lactate efflux and glycogen content and decreased fatty acid oxidation rates, with similar activation of HIF signalling pathways. However, hypoxia-induced changes were superimposed on diabetic hearts that were metabolically abnormal in normoxia, resulting in glycolytic rates 30% lower, and fatty acid oxidation 36% higher, in hypoxic diabetic hearts than hypoxic controls. Peroxisome proliferator-activated receptor α target proteins were suppressed by hypoxia, but activated by diabetes. Mitochondrial respiration in diabetic hearts was divergently activated following hypoxia compared with controls. These differences in metabolism were associated with decreased contractile recovery of the hypoxic diabetic heart following an acute hypoxic insult. In conclusion, type 2 diabetic hearts retain metabolic flexibility to adapt to hypoxia, with normal HIF signalling pathways. However, they are more dependent on oxidative metabolism following hypoxia due to abnormal normoxic metabolism, which was associated with a functional deficit in response to stress.


Asunto(s)
Adaptación Fisiológica , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Miocardio/metabolismo , Estrés Oxidativo , Oxígeno/metabolismo , Animales , Hipoxia de la Célula , Glucógeno/metabolismo , Glucólisis , Ácido Láctico/metabolismo , Masculino , Mitocondrias Musculares/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Ratas , Ratas Wistar , Transducción de Señal
2.
Cardiovasc Diabetol ; 12: 136, 2013 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-24063408

RESUMEN

BACKGROUND: To study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes. METHODS AND RESULTS: Male Wistar rats were fed a high-fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15-25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin-stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function. CONCLUSIONS: High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15-25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Dieta Alta en Grasa , Metabolismo Energético , Miocardio/metabolismo , Animales , Biomarcadores/sangre , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inducido químicamente , Cardiomiopatías Diabéticas/sangre , Cardiomiopatías Diabéticas/etiología , Glucógeno/metabolismo , Glucólisis , Metabolismo de los Lípidos , Lípidos/sangre , Masculino , Miocardio/enzimología , Fenotipo , Ratas , Ratas Wistar , Factores de Tiempo
3.
Cardiovasc Res ; 113(7): 737-748, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28419197

RESUMEN

AIMS: The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress. METHODS AND RESULTS: Hearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels. CONCLUSIONS: Diabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.


Asunto(s)
Antígenos CD36/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/metabolismo , Ácidos Oléicos/farmacología , Sarcolema/efectos de los fármacos , Succinimidas/farmacología , Animales , Antígenos CD36/metabolismo , Hipoxia de la Célula , Ciclo del Ácido Cítrico/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/fisiopatología , Ácidos Grasos/metabolismo , Preparación de Corazón Aislado , Masculino , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Sarcolema/metabolismo , Factores de Tiempo , Triglicéridos/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacos
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