Insulin Signaling In the Heart

2021 ◽  
Author(s):  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Insulin Signaling ◽  
Ventricular Remodeling ◽  
Insulin Receptors ◽  
Multiple Roles ◽  
Substrate Uptake ◽  
Therapeutic Consequences ◽  
Cardiac Responses ◽  
Obesity And Diabetes ◽  
Heart Failure Progression

Insulin receptors are highly expressed in the heart and vasculature. Insulin signaling regulates cardiac growth, survival, substrate uptake, utilization and mitochondrial metabolism. Insulin signaling modulates the cardiac responses to physiological and pathological stressors. Altered insulin signaling in the heart may contribute to the pathophysiology of ventricular remodeling and heart failure progression. Myocardial insulin signaling adapts rapidly to changes in the systemic metabolic milieu. What may initially represent an adaptation to protect the heart from carbo-toxicity, may contribute to amplifying the risk of heart failure in obesity and diabetes. This review article presents the multiple roles of insulin signaling in cardiac physiology and pathology and discusses the potential therapeutic consequences of modulating myocardial insulin signaling.

scholarly journals Differential Regulation of ERK and mTOR Signaling Pathways in Failing Human Hearts

2020 ◽  
Author(s):  
Rebecca Autenried ◽  
Eric T. Weatherford ◽  
Yuan Zhang ◽  
Helena C. Kenny ◽  
Renata O. Pereira ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Human Heart ◽  
Ventricular Remodeling ◽  
Mtor Signaling ◽  
Heart Failure Patients ◽  
Healthy Donors ◽  
End Stage

STUCTURED ABSTRACTObjectivesWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into the pathophysiology of heart failure. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant.BackgroundPathologic ventricular remodeling accompanied by hypertrophic growth is a common characteristic of heart failure including in patients with diabetes. The contribution of aberrant insulin signaling in the pathophysiology of diabetes-associated heart failure and, ventricular hypertrophy is incompletely understood.MethodsHearts of twenty non-failing donor participants and thirty-one human cardiac transplant patients were assessed for insulin signaling. Samples were sorted into four groups: non-failing non-obese (NFN), non-failing obese (NFO), failing non-diabetic (FND), and failing diabetic (FDM). Ejection fraction was assessed by echocardiography and clinically relevant systolic dysfunction was defined as left ventricular ejection fraction <50%. A clinical diabetes diagnosis was obtained from chart review. As a proxy measure of prolonged glycemia, plasma fructosamine was determined by colorimetric assay. Insulin signaling, protein phosphorylation, and total protein levels were measured by immunoblot.ResultsWhen all groups were analyzed together, hyperglycemia correlated with increased cardiac size and decreased function. Cardiac size correlated with increased levels of insulin receptor (IRb) and phosphorylated ERK but with decreased levels of phosphorylated Akt and mTOR. IRb and p-Akt correlated with fructosamine, but p-ERK and p-mTOR did not. Cardiac hypertrophy correlated with decreased GLUT1 levels, increased Hexokinase I and repression mitochondrial complexes I, III and IV in concert with activation of AMPK.ConclusionsAltered insulin signaling, characterized by increased IRb content, activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart. Similar divergence of insulin signaling pathways have been previously described in vascular smooth muscle.CONDENSED ABSTRACTWe hypothesized that disruption of pathways downstream of insulin signaling characterize pathological ventricular remodeling and may provide insights into pathophysiology. To test this hypothesis, we examined components of the insulin signaling pathway in tissue explants from human hearts obtained from healthy donors and explants from heart failure patients with and without diabetes, receiving a heart transplant. We found that altered insulin signaling, characterized by increased IRb content and activation of ERK but repression of Akt and mTOR signaling pathways is present in the end-stage failing human heart.HIGHLIGHTSIn this cross-sectional analysis of end-stage failing human cardiac tissue, hyperglycemia correlated with cardiac dysfunction and increased cardiac hypertrophy.While myocardial insulin resistance may exist in the PI3K-Akt-mTOR pathway in end-stage failing human hearts, ERK signaling is induced, which may contribute to cardiac hypertrophy in a manner that is independent of plasma insulin.Differential activation of branches of insulin signaling in human failing hearts, supports the concept of selective insulin resistance.These findings have implications for the consequences of modulating systemic insulin sensitivity in patients with heart failure.

Research into the Effect of Sodium-Glucose Linked Transporter 2 Inhibition on Left Ventricular Remodeling in Patients with Heart Failure and Diabetes Mellitus

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 256-OR ◽  
Author(s):  
JAGDEEP S.S. SINGH ◽  
IFY MORDI ◽  
MOHAPRADEEP MOHAN ◽  
STEPHEN J. GANDY ◽  
EWAN PEARSON ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Patients With Heart Failure

Predictors of Left Ventricular Remodeling Post Acute Myocardial Infarction. Protocol for a Clinical Study

2019 ◽  
Vol 4 (3) ◽  
pp. 120-123
Author(s):  
Ioana Cîrneală ◽  
Diana Opincariu ◽  
István Kovács ◽  
Monica Chițu ◽  
Imre Benedek
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Speckle Tracking ◽  
Ventricular Remodeling ◽  
Speckle Tracking Echocardiography ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Serum Biomarkers ◽  
Remodeling Index

Abstract Heart failure is a clinical syndrome that appears as a consequence of a structural disease, and the most common cause of left ventricular systolic dysfunction results from myocardial ischemia. Cardiac remodeling and neuroendocrine activation are the major compensatory mechanisms in heart failure. The main objective of the study is to identify the association between serum biomarkers illustrating the extent of myocardial necrosis (highly sensitive troponin as-says), left ventricular dysfunction (NT-proBNP), and systemic inflammatory response (illustrated via serum levels of hsCRP and interleukins) during the acute phase of a myocardial infarction, and the left ventricular remodeling process at 6 months following the acute event, quantified via speckle tracking echocardiography. The study will include 400 patients diagnosed with acute myocardial infarction without signs and symptoms of heart failure at the time of enrollment that will undergo a complex clinical examination and speckle tracking echocardiography. Serum samples from the peripheral blood will be collected in order to determine the inflammatory serum biomarkers. After 6 months, patients will be divided into 2 groups according to the development of ventricular remodeling, quantified by speckle tracking echocardiography: group 1 will consist of patients with a remodeling index lower than 15%, and group 2 will consist of patients with a remodeling index higher than 15%. All clinical and imaging data obtained at the baseline will be compared between these two groups in order to determine the features associated with a higher risk of deleterious ventricular remodeling and heart failure.

The Pattern of Ventricular Remodeling Influences the Level of Oxidative Stress in Heart Failure Patients

2017 ◽  
Vol 68 (7) ◽  
pp. 1506-1511
Author(s):  
Cerasela Mihaela Goidescu ◽  
Anca Daniela Farcas ◽  
Florin Petru Anton ◽  
Luminita Animarie Vida Simiti
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Clinical Laboratory ◽  
Left Ventricular ◽  
Control Group ◽  
Reactive Protein ◽  
Lv Mass ◽  
Few Data

Oxidative stress (OS) is increased in chronic diseases, including cardiovascular (CV), but there are few data on its effects on the heart and vessels. The isoprostanes (IsoP) are bioactive compounds, with 8-iso-PGF25a being the most representative in vivo marker of OS. They correlate with the severity of heart failure (HF), but because data regarding OS levels in different types of HF are scarce, our study was aimed to evaluate it by assessing the urinary levels of 8-iso-PGF2aand its correlations with various biomarkers and parameters. Our prospective study included 53 consecutive patients with HF secondary to ischemic heart disease or dilative cardiomyopathy, divided according to the type of HF (acute, chronic decompensated or chronic compensated HF). The control group included 13 hypertensive patients, effectively treated. They underwent clinical, laboratory - serum NT-proBNP, creatinine, uric acid, lipids, C reactive protein (CRP) and urinary 8-iso-PGF2a and echocardiographic assessment. HF patients, regardless the type of HF, had higher 8-iso-PGF2a than controls (267.32pg/�mol vs. 19.82pg/�mol, p[0.001). The IsoP level was directly correlated with ejection fraction (EF) (r=-0.31, p=0.01) and NT-proBNP level (r=0.29, p=0.019). The relative wall thickness (RWT) was negatively correlated with IsoP (r=-0.55, p[0.001). Also 8-iso-PGF25a was higher by 213.59pg/�mol in the eccentric left ventricular (LV) hypertrophy subgroup comparing with the concentric subgroup (p=0.014), and the subgroups with severe mitral regurgitation (MR) and moderate/severe pulmonary hypertension (PAH) had the highest 8-iso-PGF2a levels. Male sex, severe MR, moderate/severe PAH, high LV mass and low RWT values were predictive for high OS level in HF patients.Eccentric cardiac remodeling, MR severity and PAH severity are independent predictors of OS in HF patients.

scholarly journals Heart failure—emerging roles for the mitochondrial pyruvate carrier

2021 ◽  
Author(s):  
Mariana Fernandez-Caggiano ◽  
Philip Eaton
Keyword(s):  
Heart Failure ◽  
Warburg Effect ◽  
Translational Regulation ◽  
Hypertrophic Growth ◽  
Metabolic Adaptations ◽  
Mitochondrial Pyruvate Carrier ◽  
Heart Failure Progression ◽  
Mitochondrial Oxidation ◽  
Human And Mouse ◽  
The Warburg Effect

AbstractThe mitochondrial pyruvate carrier (MPC) is the entry point for the glycolytic end-product pyruvate to the mitochondria. MPC activity, which is controlled by its abundance and post-translational regulation, determines whether pyruvate is oxidised in the mitochondria or metabolised in the cytosol. MPC serves as a crucial metabolic branch point that determines the fate of pyruvate in the cell, enabling metabolic adaptations during health, such as exercise, or as a result of disease. Decreased MPC expression in several cancers limits the mitochondrial oxidation of pyruvate and contributes to lactate accumulation in the cytosol, highlighting its role as a contributing, causal mediator of the Warburg effect. Pyruvate is handled similarly in the failing heart where a large proportion of it is reduced to lactate in the cytosol instead of being fully oxidised in the mitochondria. Several recent studies have found that the MPC abundance was also reduced in failing human and mouse hearts that were characterised by maladaptive hypertrophic growth, emulating the anabolic scenario observed in some cancer cells. In this review we discuss the evidence implicating the MPC as an important, perhaps causal, mediator of heart failure progression.

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