Overview

Diabetes, scientifically known as diabetes mellitus (DM), is one of the most prevalent chronic diseases, affecting over 537 million adults worldwide – approximately 1 in 10 people. This figure is expected to increase to 643 million by 2030 and 783 million by 2045 (1 in 8).¹ Worryingly, up to 50% of those with diabetes mellitus are unaware they have the disease. 

A well-documented risk factor for several cardiovascular diseases (conditions affecting the heart and blood vessels), diabetes can significantly impact both the structure and function of the heart. One such potential effect is heart enlargement (cardiomegaly), which is associated with an increased risk of developing heart disease. Cardiomegaly poses serious risks to those affected as it can ultimately lead to heart failure or death. 

Given the close association between cardiomegaly and damaged blood vessels, it is significant that nearly half of the individuals with diabetes die of cardiovascular disease linked to damaged blood vessels.² Understanding the complex metabolic, molecular and inflammatory mechanisms linking diabetes mellitus to heart enlargement is vital for both the prevention and management of cardiac complications in those living with diabetes.  

Understanding diabetes mellitus and heart enlargement

Diabetes mellitus

Diabetes mellitus is a chronic, incurable metabolic condition characterised by elevated levels of glucose (sugar) in the blood, resulting from abnormal insulin secretion, insulin action or both. 

Insulin helps the body store glucose in the muscles, liver and adipose (fat) tissue. This can later be used as a source of energy.³ Diabetes can manifest in many forms, but the most common types, which comprise 98% of all diagnoses, are the following:³

• Type 1 diabetes mellitus (T1DM or juvenile diabetes): this form occurs when blood glucose levels are elevated because the pancreas is unable to produce insulin. Damage to the insulin-producing cells in the pancreas results in a complete halt in insulin production. Although it is typically diagnosed during childhood, type 1 diabetes can develop at any age with those whose parents or siblings have the disease being at higher risk
• Type 2 diabetes mellitus (T2DM or adult-onset diabetes): in this type, blood glucose levels rise either due to insufficient insulin production or because the body’s insulin is not used effectively. This is known as insulin resistance. It is usually diagnosed in those over the age of 25, often with a family history. Risk factors also include being overweight or obese and certain ethnicities
• Gestational diabetes: this form develops during pregnancy in women who have previously never been diagnosed with diabetes.  It typically goes away after giving birth

There are a range of other lesser-known types of diabetes, which comprise the remaining 2%. Examples include maturity onset diabetes of the young (MODY), neonatal diabetes, latent autoimmune diabetes in adults (LADA) and steroid-induced diabetes. These are caused by hormonal imbalances, surgery,  infections, drugs and genetic defects, among other causes.⁴ 

Heart enlargement (cardiomegaly)

Cardiomegaly, an enlarged heart, refers to an increase in the size of the heart, usually as a result of another medical condition which forces the heart to work harder. This is a form of cardiomyopathy, which is a term for when the walls of the heart become stiff, stretched or thickened, impairing the heart's ability to pump blood effectively throughout the body. Heart enlargement takes place in two ways:⁵

• Dilation: due to reduced blood flow to the heart muscles (cardiac ischemia), the walls of the heart stretch, become thinner and weaker. This is called dilated cardiomyopathy and results in an increase in the size of the heart’s chambers. Typically, damage occurs in the left ventricle, which is the chamber of the heart responsible for pumping oxygenated blood around the body. As the walls become thinner, the chamber increases in size. The chamber is unable to pump blood as forcefully, and the heart’s remaining 3 chambers are forced to carry the workload    
• Hypertrophy: the walls of the heart thicken due to increased workload for an extended period of time. This is called hypertrophic cardiomyopathy. The walls of the heart chambers as well as the walls separating them (the septa) can all be affected; however, the left ventricle is most commonly involved. Hypertrophic cardiomyopathy can lead to abnormal heart rhythms (arrhythmias) or in severe cases, a heart attack

Key mechanisms linking diabetes to heart enlargement

Metabolic effects of diabetes on the heart

Hyperglycemia-induced oxidative stress 

Chronic hyperglycemia (high blood sugar) is the hallmark of diabetes and has profound effects on the cardiovascular system.  One of the primary mechanisms by which hyperglycemia contributes to heart enlargement is through the production of advanced glycation end products (AGEs). AGEs are formed when excess glucose binds to proteins, nucleic acids and lipids, leading to the stiffening of tissues, including the myocardium (heart muscle).⁶ AGEs also hinder normal collagen turnover, leading to increased myocardial fibrosis, a key contributor to the thickening and stiffening of the heart wall, which can lead to heart enlargement.⁶

The AGEs formed during hyperglycemia promote oxidative stress through the overproduction of reactive oxygen species (ROS).⁷ Oxidative stress occurs when the amount of reactive oxygen species produced exceeds degradation, resulting in disrupted signalling pathways responsible for normal muscle function.⁷ ROS damage the endothelial cells lining the blood vessels and impair mitochondrial (the cell’s energy powerhouse) function in cardiac cells, reducing the heart’s ability to efficiently use energy. This mitochondrial dysfunction in diabetic patients leads to an imbalance between glucose and fatty acid metabolism, which can cause lipotoxicity (accumulation of toxic lipid molecules) in heart cells, further impairing cardiac function and structure.⁷

Metabolic effects of insulin resistance

In T2DM, insulin resistance alters metabolic processes of the heart, and thus, the manner in which energy is produced. Under normal conditions, the heart uses both glucose and fatty acids as energy sources. However, in insulin-resistant states, the heart relies heavily on fatty acid oxidation for energy, which is less efficient and generates toxic byproducts.⁸ This shift can lead to the accumulation of fatty acids within cardiac myocytes (heart cells), contributing to lipotoxicity, inflammation, and damage to the heart.⁸

Over time, these metabolic changes lead to cardiac hypertrophy as the myocardium (heart or cardiac muscle) adapts to the increased toxic byproduct production, elevated energy demands and inefficiencies. This adaptation promotes the thickening of the ventricular walls, particularly the left ventricle, leading to LVH and dilated cardiomyopathy.

Diabetic cardiomyopathy

Diabetic cardiomyopathy is characterised by structural and functional changes in the myocardium that occur independently of coronary artery disease or hypertension.⁹ Though poorly understood, it appears to be driven by cellular damage as a direct or indirect result of hyperglycemia and a combination of structural, metabolic and molecular changes in the myocardium.^9,10

Key features of diabetic cardiomyopathy include:

• Myocardial fibrosis: fibrotic tissue accummulates in the myocardium due to increased production of collagen and extracellular matrix proteins. This is primarily triggered by AGEs and chronic inflammation. This fibrosis reduces the elasticity of the heart muscle, leading to heart enlargement
• Impaired contractility: due to stiffening and fibrosis, the heart’s ability to pump blood efficiently is reduced, contributing to growth of the heart. With overreliance on fat to generate energy in DM, lipotoxicity (excess lipid or fat accumulation leading to toxic effects on cell function), is thought to play a significant role in reduced contractility of the heart muscle in diabetics, potentially leading to cardiomegaly
• Calcium dysregulation: in diabetes, calcium management in heart cells is disrupted in the presence of AGEs and ROS, leading to sporadic contraction and relaxation of the heart muscle. This is primarily due to damage to the calcium channels and calcium signalling pathways within cardiomyocytes. These dysfunctions contribute to heart muscle rigidity, reduced contractility, and cardiomegaly. As heart enlargement often results from chronic stress on the heart, in diabetic conditions, calcium dysregulation can lead to thickening of the heart walls. Elevated intracellular calcium is also thought to trigger excessive cardiac cell growth (myocyte hypertrophy), increasing the size of the heart while reducing its efficiency^11,12,13,14

Microvascular dysfunction

Microvascular dysfunction contributes to heart enlargement, particularly in the coronary microcirculation, the small blood vessels which supply blood to the heart muscle.¹⁵ In diabetes, chronic hyperglycemia damages the small blood vessels (microangiopathy), causing a reduction in the density of capillaries and dysfunction of the endothelium (the single layer of cells lining blood vessels).¹⁵ This limits the heart muscle’s supply of oxygen and nutrients, causing ischaemia (lack of oxygen). The result is myocardial fibrosis and hypertrophy.

Though not yet fully understood, the mechanisms by which endothelial dysfunction takes place are:^15,16

• Decreased concentration of nitric oxide (NO) in blood, a molecule responsible for dilating blood vessels
• Increased production of vasoconstrictors such as endothelin-1
• Reduced coronary blood flow: In response to poor circulation, back-up blood vessels called anastomoses are formed in diabetes to compensate. As the body’s blood passes through these new vessels, important vessels are bypassed, causing ischaemia (oxygen starvation) of the endothelium. Additionally, stress is put on the heart to accommodate this increase in demand, leading to poor blood flow in and around the heart and endothelial damage

Inflammation and cytokine activation

Hyperglycemia and insulin resistance activate various inflammatory pathways, leading to the release of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP). These cytokines contribute to myocardial inflammation and hypertrophy by stimulating fibrosis.¹⁷

Inflammation also activates the renin-angiotensin-aldosterone system (RAAS), which leads to fluid retention, narrowing of the blood vessels and increased blood pressure, further burdening the heart.¹⁸ Angiotensin II is largely responsible for this physical stress and damage to blood vessels and the resulting cardiac hypertrophy.¹⁸

Summary

The connection between diabetes mellitus and heart enlargement is highlighted by a complex relationship between metabolic disturbances, oxidative stress, inflammation, microvascular dysfunction, and hypertension.¹⁹ These mechanisms not only lead to structural changes in the heart, such as LVH and dilated cardiomyopathy, but also increase the risk of cardiovascular complications such as arrhythmias, coronary artery disease (CAD) and even heart failure. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies for diabetic patients to potentially improve cardiovascular outcomes.