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Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one's risk for both diabetes and cardiovascular disease (e.g., angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). Eight-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15 weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet-fed mice at 4 weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7 weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D. Key words: ranolazine, hepatic steatosis, non-alcoholic fatty liver disease, pyruvate dehydrogenase, obesity, type 2 diabetes. La steatose hepatique non alcoolique (SHNA) se caracterise par l'accumulation de matieres grasses en exces dans le foie en absence d'alcool et entraine un accroissement du risque de diabete comme de maladies cardiovasculaires (p. ex., l'angine). Nous avons montre que la ranolazine, un medicament antiangineux de seconde intention, permet d'attenuer la SHNA entrainee par l'obesite, et nous avions pour but d'etablir si ces actions de la ranolazine s'appliquent aussi a la SHNA associee avec le diabete de type 2 (DT2). Nous avons administre a des souris C57BL/6J males de 8 semaines un regime alimentaire a basse teneur en matieres grasses ou a teneur elevee en matieres grasses pendant 15 semaines, avec chez les souris de ce dernier groupe l'administration a 4 semaines d'une dose unique de streptozotocine (STZ; 75 mg/kg) en vue de provoquer un DT2 experimental. Les souris temoins ont recu le vehicule et les autres de la ranolazine au cours des 7 dernieres semaines (50 mg/kg une fois par jour). Nous avons evalue la glycemie a l'aide de la surveillance de la tolerance au glucose, de la tolerance a l'insuline de meme que de la tolerance a l'acide pyruvique, tandis que nous avons evalue la steatose hepatique par la quantification des taux de triacylglycerol. Nous avons observe que la ranolazine ne permettait pas d'ameliorer la glycemie chez les souris du groupe DT2 experimental, et qu'elle n'avait pas d'incidence non plus sur les taux de triacylglycerol dans le foie. Par consequent, les actions salutaires de la ranolazine contre la SHNA pourraient etre limitees aux sujets obeses, mais etre absentes chez ceux qui sont atteints de DT2. [Traduit par la Redaction] Mots-cles : ranolazine, steatose hepatique, steatose hepatique non alcoolique, pyruvate deshydrogenase, obesite, diabete de type 2., Introduction Non-alcoholic fatty liver disease (NAFLD) is a condition characterized by excess fat accumulation (>5% in hepatocytes) in the absence of excessive alcohol consumption or other conditions known to promote [...]

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D. [ABSTRACT FROM AUTHOR]

This article discusses the relationship between cardiac energy metabolism and cardiac function in obesity and type 2 diabetes. It highlights the advancements in studying cardiac energy metabolism, including the use of imaging techniques and the discovery of fatty acids as the primary fuel source for the heart. The article revisits a classic study by Aasum et al. that examined how obesity and type 2 diabetes affect cardiac energy metabolism. The study found that alterations in cardiac energy metabolism can directly lead to cardiac dysfunction. These findings have had a significant impact on our understanding of cardiac energy metabolism in obesity and type 2 diabetes. The article also discusses potential targets for pharmacotherapy to alleviate cardiovascular disease associated with obesity and type 2 diabetes. Future research in this field aims to explore the molecular mechanisms underlying these metabolic alterations and their effects on cardiac function. [Extracted from the article]

Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Previous studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-h exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane glucose transporter type 4 (GLUT4) translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake: a racemic mixture of the two β-hydroxybutyrate enantiomers (d and l) appeared to decrease basal glucose uptake, while 3 mM d -β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets). NEW & NOTEWORTHY: A limited number of studies investigate the effect of ketone bodies at concentrations reflective of both typical fasting and ketoacidosis. We tested a mix of physiologically relevant concentrations of ketone bodies, which allowed us to highlight the differential effects of d - and l -β-hydroxybutyrate and acetoacetate on skeletal muscle cell glucose uptake. Our findings will assist in better understanding the mechanisms that contribute to muscle insulin resistance and provide guidance on recommendations regarding ketogenic diets. [ABSTRACT FROM AUTHOR]

Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy, referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. Herein, we provide an overview on the key mediators of DbCM, with an emphasis on the role for perturbations in cardiac substrate metabolism. We discuss key mechanisms regulating metabolic dysfunction in DbCM, with additional focus on the role of metabolites as signaling molecules within the diabetic heart. Furthermore, we discuss the preclinical approaches to target these perturbations to alleviate DbCM. With several advancements in our understanding, we propose the following as a new definition for, or approach to classify, DbCM: "diastolic dysfunction in the presence of altered myocardial metabolism in a person with diabetes but absence of other known causes of cardiomyopathy and/or hypertension." However, we recognize that no definition can fully explain the complexity of why some individuals with DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due to DbCM sharing pathological features with heart failure with preserved ejection fraction (HFpEF), the latter of which is more prevalent in the population with diabetes, it is imperative to determine whether effective management of DbCM decreases HFpEF prevalence. Article Highlights: Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction and perturbations in cardiac substrate metabolism and is more prevalent in people with diabetes than previously recognized. Optimizing cardiac substrate metabolism is often associated with improvements in DbCM, and this improvement may be related to changes in flux, mitochondrial function, bioenergetics, and/or metabolite-regulated signaling processes. Heart failure with preserved ejection fraction (HFpEF) is also more prevalent in people with diabetes and is characterized by diastolic dysfunction, and the question of whether interventions aimed specifically at treating DbCM can decrease the risk or progression of HFpEF is an important area for future investigation. [ABSTRACT FROM AUTHOR]

The article explores the vascular regenerative benefits of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, particularly focusing on semaglutide, in individuals with type 2 diabetes and high cardiovascular risk. Topics include the increase in vascular regenerative progenitor cell content associated with GLP-1R agonist treatment, the comparison with sodium-glucose cotransporter-2 (SGLT2) inhibitors, and the broader cardioprotective effects of GLP-1R agonists beyond weight loss.