Diabetes can give rise to a serious condition known as diabetic cardiomyopathy.
This progressive illness leads to deteriorating heart function, which is not directly linked to hypertension or other cardiac diseases.
Often overlooked, diabetic cardiomyopathy is a critical contributor to mortality among those with diabetes, affecting individuals with both type 1 and type 2 forms of the disease.
Currently, there are no drug therapies approved for its treatment, nor are there specific clinical guidelines to address it.
A Promising Approach to Treatment
A recent study published in Pharmacological Research sheds light on a promising approach for developing new therapies for diabetic cardiomyopathy.
Researchers examined the beneficial effects of activating the nuclear receptor known as PPARβ/δ, a protein found in every body cell and especially abundant in the heart, liver, skeletal muscle, and adipose tissue—areas with high metabolic activity.
This research was spearheaded by Manuel Vázquez-Carrera and Xavier Palomer from the University of Barcelona’s Faculty of Pharmacy and Food Sciences, alongside the Institute of Biomedicine (IBUB) and the Sant Joan de Déu Research Institute (IRSJD).
The team collaborated with various experts, including Fátima Crispi of the Faculty of Medicine and Health Sciences at the University of Barcelona, Francisco Nistal from the University of Cantabria, and Walter Wahli from the University of Lausanne in Switzerland.
Mechanisms of Diabetic Cardiomyopathy
Diabetic cardiomyopathy arises from a mix of factors, including metabolic disturbances, inflammation, fibrosis, and the death of cardiac cells.
The study’s findings suggest that activating the PPARβ/δ receptor can significantly reduce inflammation and fibrosis in both animal models and human cardiac cells subjected to high glucose levels.
Among the PPAR family, PPARβ/δ is the most common receptor in the heart.
Vázquez-Carrera pointed out that, despite having limited energy reserves, the heart primarily depends on fatty acid oxidation for about 70% of its energy needs, with glucose and lactate also playing a role.
The genes that PPARβ/δ regulates are critical for lipid and glucose metabolism and are linked to metabolic disorders associated with chronic inflammation.
Vázquez-Carrera emphasized that a decrease in PPARβ/δ function correlates with various heart diseases, given its key role in managing inflammation and tissue remodeling.
In conditions like diabetes or obesity, reduced insulin sensitivity in the heart shifts energy reliance to fatty acid mitochondrial oxidation, leading to the buildup of lipids within the myocardium.
This accumulation can cause lipotoxicity, putting an increased demand for oxygen on the heart, which subsequently triggers inflammatory and fibrotic responses through specific transcription factors.
Such mechanisms contribute to structural changes in the heart, resulting in stiffness that hampers the organ’s ability to relax after each contraction.
Future Implications
The activated pathways of NF-кB and AP-1, along with the actions of mitogen-activated protein kinases (MAPK), can lead to cardiomyocyte death, worsening the contractile dysfunction typical of diabetic cardiomyopathy.
Professor Xavier Palomer provided insights into how these interconnected effects result in changes to the heart’s extracellular structure, diminishing contractility, causing left ventricular hypertrophy, and potentially leading to heart failure.
Earlier studies hinted that stimulating PPARβ/δ could help prevent metabolic disruptions related to diabetes and obesity, possibly reducing the risk of heart failure by enhancing the heart’s efficiency in circulating blood.
This recent research advances our understanding of how PPARβ/δ benefits diabetic cardiomyopathy.
It demonstrates that this receptor can inhibit the MAPK signaling pathway, based on experiments conducted on cultured human cardiac cells.
Elevated glucose levels, oxidative stress, and lipotoxicity worsen inflammation, fibrosis, and apoptosis in cardiomyocytes, primarily through MAPK activation, which also interferes with tissue remodeling after myocardial infarction.
Vázquez-Carrera noted that inhibiting MAPKs could offer protective benefits against inflammation and fibrosis not just in the heart but across other vital organs, including the liver, lungs, kidneys, and skeletal muscle, under various pathological conditions.
Interestingly, in August 2024, the U.S. Food and Drug Administration approved seladelpar, a selective PPARβ/δ agonist, for treating primary biliary cholangitis, a rare chronic condition affecting bile ducts that can cause significant liver damage.
A marketing authorization application for this drug is currently under review in the European Union.
The researchers concluded that, given current global health trends, there may be a heightened interest from pharmaceutical companies in exploring and developing drugs specifically targeting diabetic cardiomyopathy.
Source: ScienceDaily