Individuals with diabetes may encounter a serious condition called diabetic cardiomyopathy. This condition develops gradually and cannot be solely attributed to high blood pressure or other heart diseases. It is often overlooked and is one of the primary causes of mortality among diabetic patients, impacting both type 1 and type 2 diabetes. Currently, there are no specific drug therapies or approved clinical guidelines to treat this condition.
A recent study featured in the journal Pharmacological Research highlights a possible target for developing new treatment strategies aimed at diabetic cardiomyopathy. The research indicates that stimulating a protein called PPARβ/δ, which is found in nearly all body cells and particularly prevalent in metabolically active organs like skeletal muscle, heart, liver, and fat tissue, may yield positive effects on the condition.
Manuel Vázquez-Carrera and Xavier Palomer from the Faculty of Pharmacy and Food Sciences at the University of Barcelona (UB), along with colleagues from the UB Institute of Biomedicine (IBUB) and the Sant Joan de Déu Research Institute (IRSJD), spearheaded the study as part of the Centre for Biomedical Research Network (CIBER) focused on Diabetes and Associated Metabolic Diseases (CIBERDEM).
Other contributors to this research include Fátima Crispi from the UB’s Faculty of Medicine and Health Sciences, BCNatal (IRSJD and Hospital ClÃnic – IDIBAPS), and the Centre for Biomedical Research Network on Rare Diseases (CIBERER); Francisco Nistal from the University of Cantabria and the Marqués de Valdecilla University Hospital and CIBERCV; and Walter Wahli from the University of Lausanne in Switzerland, among other specialists.
The role of a key protein in heart diseases
Metabolic disruptions, inflammation, abnormal tissue growth (fibrosis), and cardiac cell death through apoptosis all contribute to the onset of diabetic cardiomyopathy. The study illustrates that activating the PPARβ/δ receptor may help mitigate the inflammatory and fibrotic processes in laboratory animal models and human heart cells experiencing high sugar levels.
Among the peroxisome proliferator-activated receptors (PPARs), PPARβ/δ is the most prevalent in the heart. However, Vázquez-Carrera explains that “the energy reserves it maintains are only enough to support heart function for about ten seconds, relying heavily on a continuous supply of energy derived from fatty acid oxidation (70%) and, to a lesser degree, from other substrates like glucose or lactate provided via the bloodstream.”
“Many genes regulated by PPARβ/δ are crucial in lipid and glucose metabolism. This protein is associated with metabolic disorders that have an inflammatory component, such as insulin resistance caused by obesity or diabetes, abnormal fat levels in the blood, and metabolic fatty liver disease (MASLD),” notes Vázquez-Carrera.
“Most of these conditions are linked to a reduction in PPARβ/δ’s transcriptional activity, leading to suggestions that enhancing its activity could be beneficial for treatment. A decrease in this protein’s activity is also associated with various heart disorders,” adds Vázquez-Carrera. “Moreover, it plays a significant role in managing inflammation and tissue restructuring.”
Inflammation, fibrosis, and diabetic cardiomyopathy
In cases of diabetes or obesity, insulin resistance in the heart forces it to primarily rely on breaking down fatty acids for energy. This leads to lipid buildup in heart tissue, causing toxicity that requires the heart muscle to draw more oxygen. High blood sugar levels and lipotoxicity trigger inflammation and fibrosis in the heart by activating pro-inflammatory and profibrotic transcription factors, like NF-Ò›B and AP-1. Once activated, these factors initiate cardiac remodeling processes that increase heart stiffness and affect its relaxation after contraction.
The combined activation of NF-Ò›B and AP-1 alongside mitogen-activated protein kinase (MAPK) activity instigates cell death in heart muscle cells, contributing further to contractile issues in diabetic cardiomyopathy. Professor Xavier Palomer emphasizes that “these interconnected processes can lead to heart remodeling, decreased contractile ability, left ventricular thickening, and eventually heart failure.”
Mechanism of PPARβ/δ in diabetic cardiomyopathy
It was previously understood that activating PPARβ/δ in the heart could help prevent metabolic imbalances during diabetes and obesity. This action could play a pivotal role in averting heart failure, which is characterized by the heart’s inability to efficiently pump blood throughout the body.
The findings indicate that the beneficial properties of the PPARβ/δ protein in diabetic cardiomyopathy stem from its ability to inhibit the MAPK pathway, as shown in experiments with cultured human heart cells.
It is well-known that oxidative stress, high blood sugar levels, and lipotoxicity can exacerbate inflammation, fibrosis, and apoptosis in heart cells during diabetic cardiomyopathy through the activation of MAPKs, which also influence tissue remodeling following a heart attack.
According to Vázquez-Carrera, “It is not surprising that inhibiting these MAPKs can help reduce inflammation and fibrosis in not just the heart, but also in other organs and tissues such as the liver, lungs, kidneys, and even skeletal muscles under various pathological conditions.”
Exploring new treatment avenues
In August 2024, the US Food and Drug Administration (FDA) approved a new selective PPARβ/δ agonist called seladelpar for treating primary biliary cholangitis, a rare and chronic disease affecting the bile ducts that can lead to substantial liver damage. As of February, its marketing authorization application in the European Union is currently under review.
“Given the global health landscape, it would be reasonable to expect that pharmaceutical companies would be increasingly keen on researching and developing such drugs to treat diabetic cardiomyopathy,” conclude the researchers.
