Dominic Stone
The heart is an insulin-dependent organ that requires the hormone to regulate cardiac metabolism, growth, and survival. Insulin resistance in the heart can lead to heart failure and cardiac dysfunction. Patients with coronary heart disease or heart failure have been found to be insulin-resistant, however, it is unclear whether the heart muscle is involved in this resistance. Insulin plays a crucial role in regulating the balance of metabolic fuels received by the myocardium and influencing blood flow and tissue blood flow.
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What You'll Learn
Insulin resistance in cardiac muscle
Insulin resistance occurs when there is a decrease in tissue response to insulin stimulation. This results in defects in glucose uptake and oxidation, a decrease in glycogen synthesis, and a reduced ability to suppress lipid oxidation. Insulin resistance is associated with cardiovascular disease (CVD), which is often linked to comorbidities such as obesity, abnormal lipid profiles, and insulin resistance.
Cardiac muscle insulin resistance is observed in patients with coronary heart disease and heart failure. In these patients, myocardial and muscle glucose uptake are significantly reduced compared to healthy controls. This reduction in glucose uptake is independent of blood flow, as similar myocardial and skeletal muscle blood flow rates were observed between patients and controls.
The mechanism underlying cardiac muscle insulin resistance is not fully understood, but it is believed to involve disruptions in myocardial fuel metabolism and bioenergetics. The heart primarily relies on fatty acids as fuel, but during insulin resistance, the capacity to utilize fatty acids is diminished, leading the heart to use alternative pathways for energy production.
Additionally, tumour necrosis factor-α (TNF-α) has been implicated in myocardial insulin resistance. TNF-α is a pro-inflammatory cytokine that is released after myocardial infarction, impairing insulin signalling and action. This results in reduced binding of phosphatidylinositol 3-kinase (PI3K) to IRS-1, which is essential for the regulation of glucose metabolism.
Furthermore, studies have shown that myocardial insulin resistance following myocardial ischemia contributes to post-ischemic heart failure. In a study using TCIRKO mice, it was found that knockout of heart insulin receptors led to LV dysfunction and dilation, which was exacerbated post-myocardial infarction. Insulin treatment improved cardiac function and inhibited LV dilation in littermate controls but not in TCIRKO mice, highlighting the role of myocardial insulin resistance in heart failure.
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Insulin's role in cardiac metabolism
Insulin is a key hormone that plays a crucial role in regulating cellular metabolism in various tissues in the human body, including the heart. Insulin signalling in the heart is important for maintaining cardiac metabolism and has unique roles that go beyond simple metabolic effects. Insulin promotes glucose uptake in the heart through glycolysis and also regulates long-chain fatty acid uptake, protein synthesis, and vascular tonicity.
The role of insulin in cardiac metabolism is complex and multifaceted. Insulin receptors (IRs) are abundantly expressed in cardiomyocytes, and they interact with insulin receptor substrate proteins (IRS1 and IRS2) to initiate signalling pathways. These signalling pathways have significant redundancy and overlap, indicating the importance of insulin in cardiac function. Insulin resistance in the myocardium can lead to damage through altered signalling transduction, impaired regulation of substrate metabolism, and dysregulation of lipid metabolism.
Insulin plays a pivotal role in regulating the balance of metabolic fuels received by the myocardium. It influences the supply of substrates for cardiac energy metabolism and affects myocardial perfusion. The ability of insulin to suppress protein degradation and promote protein synthesis has a profound impact on overall carbohydrate and nitrogen economy. Insulin deficiency can disrupt this balance, leading to an increase in amino acid supply from net protein catabolism, which contributes to the availability of substrates for the myocardium.
Additionally, insulin influences the availability of fatty acids by inhibiting adipose tissue triglyceride hydrolysis. This regulation is particularly important in insulin-dependent diabetes or cachexia, where a loss of control over adipose tissue lipolysis can lead to enhanced β-oxidation at the expense of pyruvate oxidation in cardiac myocytes. Cardiac glycogen metabolism is also influenced by insulin, with myocardial glycogen being preferentially oxidized compared to exogenous glucose, resulting in higher ATP production per mole of glucose metabolized.
Furthermore, insulin signalling has been linked to cardiac hypertrophy. Studies have shown that defects in exercise-induced hypertrophy were exacerbated by the loss of IRs in mice models. Both IRS1 and IRS2 play crucial roles in the hypertrophic and bioenergetic response to exercise training, and their loss prevents physiological hypertrophy.
In summary, insulin plays a critical role in cardiac metabolism by regulating glucose and fatty acid uptake, protein synthesis, and vascular functions. Insulin resistance and dysregulation can lead to metabolic alterations that contribute to cardiovascular disease. The intricate balance of insulin signalling and its effects on cardiac metabolism highlight the importance of understanding insulin's role in maintaining cardiac health.
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Insulin's impact on myocardial perfusion
Insulin resistance is defined as a decrease in tissue response to insulin stimulation. This results in defects in the uptake and oxidation of glucose, a decrease in glycogen synthesis, and a reduced ability to suppress lipid oxidation. Insulin resistance is associated with the development of cardiovascular disease, which is often accompanied by comorbidities such as obesity, abnormal lipid profiles, and insulin resistance.
Insulin impacts myocardial perfusion by regulating substrate utilization and promoting glucose uptake through glycolysis. Insulin also plays a role in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity. Under pathological conditions, such as type-2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signal transduction pathways are altered. These molecular signalling alterations are linked to atypical crosstalk with other signal transduction pathways.
In patients with coronary heart disease, myocardial blood flow and skeletal muscle blood flow were similar when compared to controls. However, myocardial and skeletal muscle glucose uptake were significantly reduced in patients compared to controls. This indicates that insulin resistance affects both the myocardium and skeletal muscle, independent of blood flow. Patients with a history of myocardial infarction and low ejection fraction exhibit insulin resistance, which impacts myocardial perfusion.
The impact of insulin on myocardial perfusion has been studied in non-diabetic patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Acute insulin resistance in the early post-PCI period was found to be common even in non-diabetic patients and was associated with impaired myocardial perfusion. Higher levels of insulin resistance were observed in obese patients with hyperinsulinemia, indicating a correlation between insulin resistance and impaired myocardial perfusion.
In summary, insulin resistance impacts myocardial perfusion by altering glucose metabolism and uptake in the myocardium. This can lead to reduced blood flow and oxygen delivery to the heart muscle, potentially contributing to the development of cardiovascular disease.
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Insulin and cardiac hypertrophy
Insulin plays a crucial role in the heart, regulating substrate utilisation. It promotes glucose uptake and utilisation through glycolysis and also regulates long-chain fatty acid uptake, protein synthesis, and vascular tonicity. Under pathological conditions such as type-2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signalling pathways are altered.
Cardiac insulin resistance is a significant risk factor for heart failure, independent of coronary artery disease. It is associated with a decline in myocardial glucose uptake capacity, reductions in endothelial nitric oxide synthase (eNOS) activity, and mitochondrial dysfunction. Myocardial insulin resistance has been observed in patients with post-ischemic heart failure and cardiac hypertrophy, even in the absence of hypertension, coronary artery disease, and diabetes. This suggests that insulin resistance may be a feature of the hypertrophied heart.
Animal studies have shown that left ventricular hypertrophy may be linked to insulin resistance and abnormalities in glucose transporters. In patients with cardiac hypertrophy due to aortic stenosis and normal coronary arteries, myocardial glucose uptake was measured and compared to a control group. The results indicated myocardial insulin resistance in the patient group, suggesting that cardiac hypertrophy may be associated with impaired glucose transport.
Furthermore, in patients with coronary heart disease, myocardial and skeletal muscle glucose uptake were significantly reduced compared to controls. While myocardial blood flow and skeletal muscle blood flow were similar between the two groups, indicating that the reduced glucose uptake was not due to reduced blood flow. These findings suggest that cardiac hypertrophy and coronary heart disease may contribute to insulin resistance and impaired glucose uptake in the heart and skeletal muscle.
Additionally, in patients with essential hypertension, whole-body and femoral glucose uptake rates were decreased compared to controls. However, heart glucose uptake was increased by 33% in the hypertensive group. This increase correlated with systolic blood pressure and the minute work index, suggesting a link between insulin resistance, glucose uptake, and blood pressure regulation in hypertension.
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Insulin's influence on blood flow
Insulin has a significant influence on blood flow, particularly in the context of cardiac and skeletal muscle function. Insulin's role in the heart is primarily focused on regulating substrate utilisation. It promotes glucose uptake and utilisation through glycolysis, as well as participating in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity.
Insulin has been found to increase myocardial blood flow in healthy individuals and those with conditions such as obesity, type 1 diabetes, and coronary artery disease. This increase in blood flow is thought to be due to insulin acting as a vasodilatory hormone in the coronary arteries, enhancing myocardial blood flow and decreasing coronary vascular resistance. The mechanism behind this involves insulin further enhancing endothelium-dependent vasodilation, which increases blood flow to the heart.
In addition, insulin resistance, which is characterised by impaired glucose uptake, has been linked to reduced blood flow. Patients with coronary artery disease or heart failure exhibit insulin resistance, and while it is unclear if reduced blood flow contributes to this resistance, there is a direct relationship between insulin-stimulated glucose uptake and blood flow in the heart and skeletal muscle. This suggests that factors influencing blood flow can impact insulin resistance.
Furthermore, insulin's influence on blood flow extends to skeletal muscle as well. Studies have shown that insulin can increase total blood flow to skeletal muscle, potentially enhancing its own action by improving the delivery of insulin and glucose to muscle cells. This increased blood flow is associated with improved insulin sensitivity, as seen in athletes, where increased blood flow, muscle glucose transport protein (GLUT-4) concentration, and glycogen synthase activity contribute to enhanced insulin sensitivity.
The impact of insulin on blood flow is mediated through its receptors and signalling cascades, specifically the IRS1/2/PI3K/Akt pathway and the Src/MAPK pathway. These pathways are crucial for the expression and distribution of metabolites, hormones, and cytokines. Disruptions in these pathways can lead to selective insulin resistance, contributing to endothelial dysfunction and vascular complications in conditions like diabetes.
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Frequently asked questions
Yes, the heart is an insulin-dependent organ. Insulin plays a role in regulating the balance of metabolic fuels received by the myocardium. It also promotes glucose uptake and its utilization via glycolysis.
Insulin plays a major role in regulating the balance of metabolic fuels received by the myocardium. It also promotes glucose uptake and its utilization via glycolysis. Insulin also participates in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity.
Insulin resistance in the heart is associated with heart failure. Heart failure patients suffer from cardiac energy deficiency, structural and functional dysfunction, and cardiac contractility.
