Diabetes and the Heart: Cardiomyopathy, Energy Utilization, and Ketosis

Obesity and diabetes are rampant — more than 40% of adults in the US are obese and approximately 1 in 10 have diabetes (1). An even greater number have “prediabetes”, indicating a large majority of adults are metabolically unhealthy. These conditions are sometimes considered twin epidemic s — as they can (and often do) occur in conjunction. While neither are necessary nor sufficient for the other to occur, the metabolic causes and consequences often overlap.

We usually think of obesity and diabetes in their metabolic terms — using phrases like high blood glucose, insulin resistance, and body fatness to typify them. However, both diseases can have profound adverse effects on the cardiovascular system in addition to their metabolic consequences.

One of the primary findings in both obesity and diabetes is something called cardiomyopathy — a disease of the heart muscle. One manifestation of this is what is known as left-ventricular diastolic dysfunction, in which the main pumping chamber of the heart (the left ventricle, or LV) loses its ability to relax. Relaxation (diastole) is necessary for our heart to fill with blood before contraction (systole) ejects the blood out of the aorta and into our circulation.

The obese/diabetic heart has reduced ability to relax, and therefore doesn’t fill properly. In turn, this can lead to systolic dysfunction — a reduced ability to contract and eject blood. The dangerous cycle of diastolic and systolic dysfunction makes it so that circulation in the heart is drastically impaired.

This loss of function is accompanied by some pretty major structural changes to the heart. Diabetes and obesity can cause the walls of the heart to thicken — termed cardiac hypertrophy. These thick, muscular walls lose some of their elastic ability. Stiffer walls are worse at contracting and relaxing. Wall thickening occurs because individual heart cells (known as cardiomyocytes) actually grow larger themselves. As each cell grows (hypertrophies), the wall thickens in proportion.

Ventricle size also increases in diabetic and obesity cardiomyopathy, expanding in size and volume. This process is known as dilatation, and most often occurs in the left ventricle, though the right ventricle also experiences dilatation to some degree.

A final structural change involves a process known as fibrosis. Fibrosis of the heart is implicated in the process of thickening and stiffening. Our heart muscle is surrounded by a tissue layer called the extracellular matrix (ECM) — which is composed of proteins like collagen and elastin, vascular cells, and other immune and fibrotic cells that serve as a structural scaffold for the heart. In diabetes and obesity, the heart ECM becomes fibrotic — an abnormal amount of ECM accumulates and/or the composition changes; leading to a stiffer, fibrotic heart.

This structural remodeling is bad news for the heart. A large ventricle size may prevent adequate contraction, and thicker, stiffer walls prevent adequate contraction and relaxation, which is further impaired by fibrosis. As a result, the heart becomes less efficient at pumping blood, eventually leading to heart failure.

Normal (top) and hypertrophied/fibrotic heart (bottom) Source: Herum KM, Lunde IG, McCulloch AD et al. J Clin Med 2017

What causes these changes? Some of the pathophysiology is specific to either obesity or diabetes, but a lot of the mechanisms are shared.

In obesity, one of the primary causes of left ventricular hypertrophy is an increased load on the heart. Obese individuals have a higher metabolic activity and increased lean/fat mass, and this increases total blood volume and a hypercirculatory state. An increase in blood volume means that the heart experiences a greater filling volume and elevated systolic and diastolic pressure. The heart must also work harder (i.e. generate more force) to eject blood against these increased pressures. This means that the left ventricle work rate and wall stress are increased, leading to a thicker, hypertrophied muscle. The heart, just like a biceps or triceps muscle, grows larger with “training.”

Increased wall stress and elevated ventricular work rate means the heart has a higher demand for oxygen. In diabetes and obesity, as we will see later, oxygen supply may be reduced and therefore, the heart may be “starved” of oxygen.

Obesity and diabetes are often characterized by insulin resistance — the muscles and other tissues in the body fail to respond properly to insulin, and therefore blood glucose uptake and utilization is impaired. Insulin resistance leads to hyperglycemia, or high blood glucose. High blood glucose (blood sugar) can wreak havoc on the cardiovascular system — it increases oxidative stress and inflammation, reduces blood vessel function, and can lead to the production of advanced-glycation end products (AGEs). AGEs can be thought of as “sticky” molecules that attach to and cross-link proteins in the body, altering their function.

Insulin resistance also leads to a metabolic shift in the heart. Normally, the heart metabolizes glucose (also fatty acids, lactate, and ketone bodies) as a fuel substrate. Without proper insulin action, however, glucose can’t be transported into the myocytes.

Thus, the heart shifts from glucose oxidation to primarily fatty acid oxidation. For one, this increases the oxygen demand of the heart, since fatty acids require more oxygen for their metabolism than does glucose. Secondly, an increased flux of fatty acids into the myocytes can lead to something known as lipotoxicity and dyslipidemia; when supply of these molecules outpaces demand or utilization. Toxic byproducts of fatty acids and triglycerides can promote myocyte cell death and cardiac dysfunction.

Pathways of fatty acid and glucose metabolism in the heart. Source: Radcliffecardiology.org

Inflammation — characterized by increased presence of proinflammatory cytokines in the heart, is also elevated in both obesity and diabetes. This can be due to hyperglycemia, insulin resistance, or increased production of inflammatory cytokines from adipose (fat) tissue. Inflammation contributes in part to the cardiac hypertrophy and fibrosis involved in cardiac dysfunction.

A final shared mechanism among obesity and diabetes is overactivation of neurohumoral systems; including the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS).

In the body, the RAAS has several effects — causing vasoconstriction of blood vessels and sodium/fluid retention in order to maintain blood pressure. The main actor here is angiotensin II (ANG II), which causes these effects by binding to its receptors which are present throughout the cardiovascular system.

RAAS is overactive in obesity and diabetes. Several components of RAAS are found in high quantities in adipose tissue, meaning obese individuals have higher levels of angiotensin II than normal-weight individuals (even those with hypertension or cardiomyopathy). In diabetes, RAAS is also overactivated due to hyperglycemia, insulin resistance, and other factors.

When RAAS is chronically overactive, it has adverse effects including vasoconstriction of blood vessels, stimulation of reactive oxygen species (ROS), cell proliferation, and fibrosis. Angiotensin II is actually a pro-growth factor in the cardiovascular system, and high levels can promote cardiac hypertrophy.

Increased RAAS and insulin resistance can also lead to SNS activation. In the cardiovascular system, SNS activation induces many of the same pathways as does RAAS, including vasoconstriction, inflammation and oxidative stress, and cell proliferation.

One final common pathway involved in cardiomyopathy in obesity and diabetes involves endothelial dysfunction. Normally, our blood vessels regulate blood flow and pressure through vasoconstriction and vasodilation (relaxation). A healthy balance of molecules that promote dilation (nitric oxide, NO) and constriction (endothelin-1, ET-1) fine-tunes vascular tone to meet our metabolic needs. Many of the above mechanisms (RAAS, inflammation, hyperglycemia, SNS activation) can impair endothelial function. While it contributes to cardiomyopathy, endothelial dysfunction is also implicated in the progression of atherosclerosis, and has other effects such as reducing exercise capacity and cognitive function.

While these are only some of the mechanisms behind cardiomyopathy resulting from obesity and diabetes, the description illustrates a complex interaction between metabolic diseases and the cardiovascular system.

Let’s now switch from discussing structural abnormalities in the diabetic/obese heart to some functional changes that occur, in particular those related to energy metabolism. Specifically, there are some interesting new perspectives on the “inefficiency” of the diabetic heart related to its metabolism (or lack thereof) of ketone bodies. This is highly relevant given that ketogenic diets have long been prescribed as a treatment for diabetes.

We mentioned earlier that, due to insulin resistance, the diabetic heart can undergo a metabolic shift to favor the breakdown of fatty acids as a fuel source. In diabetes, ketone body production by the liver and uptake of ketone bodies by the heart is often elevated. Initially, this would seem beneficial, as ketone bodies (including beta-hydroxybutyrate or BHB) are very efficient energy sources. However, animal data seem to suggest that the diabetic heart is still energy inefficient despite a high uptake of ketone bodies.

This inefficiency may occur because the process of producing ketone bodies (ketogenesis) and breaking down ketone bodies to produce energy (ketolysis) are inherently opposite processes — you can’t have high levels of both in a single organ such as the heart. In type 1 and type 2 diabetes, it appears that the breakdown of ketone bodies is reduced — either due to an increase in ketogenesis (type I diabetes) that inhibits ketolysis or a decrease in enzymes responsible for the breakdown of ketones (type 2). Low levels of insulin in type 1 diabetes promote increased ketone body production. High levels of insulin in type 2 diabetes (insulin resistant diabetes) reduce ketogenesis and also lower levels of ketolytic enzymes.

Here is a nice list of differences in the type 1 and type 2 diabetic heart that appears in a recent commentary article on the diabetic heart and energy (in)efficiency.

Type 1 diabetes

  • Low levels of insulin
  • High levels of ketone bodies (10-fold vs. non-diabetic heart)
  • Increased levels of ketogenesis enzymes
  • Reduced levels of ketolysis enzymes

Type 2 diabetes

  • High levels of insulin
  • Lower levels of ketone bodies vs. type I diabetes
  • No change in ketogenesis enzymes vs. a non-diabetic heart
  • Reduced levels of ketolysis enzymes

These metabolic abnormalities make it so that the diabetic heart can’t utilize ketone bodies for energy — at least not as well as a non-diabetic heart. Given the fact that glucose utilization is also impaired (due to low levels of insulin or insulin resistance), we have a situation where the diabetic heart is essentially “starved” of energy. As mentioned earlier, fatty acids are still an available source of energy, but these require more oxygen and highly-functioning mitochondria for adequate energy provision — something the diabetic heart also lacks. Indeed, mitochondrial dysfunction is also a characteristic of both type 1 and type 2 diabetes.

Why is all of this important? Well, to design treatment strategies targeting diabetes and in particular the diabetic heart, it’s useful to know the mechanisms of dysfunction. These data would suggest that ketogenic diets may NOT be useful for improving cardiac efficiency in the diabetic heart. Ketogenic diets are effective for improving weight/body fat and insulin sensitivity in people with diabetes, to be sure. However, from a cardiovascular perspective, the above discussion suggests that ketogenic diets may be not as useful for improving cardiac energetics due to a couple of reasons including:

  1. Ketone levels in diabetes are already high, and increasing levels further via a ketogenic diet may not improve the heart’s utilization of ketones or energetic efficiency.
  2. Ketolysis enzymes are reduced in diabetes and therefore increased ketone bodies will not lead to greater utilization of these ketones.
Mishra 2021: https://doi.org/10.1152/ajpheart.00260.2021

This brings up another interesting discussion about the use of exogenous ketones in people with diabetes. Exogenous ketones (ketone “supplements”) are a very popular research area right now, as they’ve been shown to improve aspects of athletic performance, cognition, aging, and may even be a potential countermeasure/supplement for cardiovascular health. The latter application relates to the fact that the heart can and will use ketones if they are provided. This may only apply to a “healthy” heart (a non-diabetic heart) given what we have just discussed, and suggests they may not have any application for diabetes. This is definitely an area that needs more research, however.

What can be done to improve health and energetics of the diabetic heart? That brings us to exercise. While the data on exercise in diabetes is beyond the scope of this post, it is well known that both aerobic and resistance exercise can benefit diabetes by improving weight and body composition, increasing insulin sensitivity and, relevant to our discussion today, likely improve cardiac efficiency and mitochondrial function. Together, exercise can increase the “efficiency” of the diabetic heart by allowing it to access more metabolic substrates through multiple different mechanisms.

All of life is energy, and how we use or misuse it has a profound effect on health.

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PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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Brady Holmer

Brady Holmer

PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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