Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction in the absence of hypertension or coronary artery disease, making it a significant cardiovascular complication affecting 30–40% of diabetic patients. DCM is characterized by pathological systolic and diastolic dysfunctions, ventricular dilatation, interstitial fibrosis, and cardiomyocyte hypertrophy. Among these, diastolic dysfunction is the most prominent feature of DCM, estimated to be present in 40–60% of diabetic individuals without significant coronary artery involvement.
Persistent hyperglycemia induces alterations in cardiac structure and function, typified by fibrosis, myocardial inflammation, and free radical generation via activation of specific signal transduction pathways. Multiple factors, including glucotoxicity, lipotoxicity, epigenetic alterations, disrupted calcium signaling, and mitochondrial dysfunction, promote adverse cardiomyocyte hypertrophy and extracellular matrix remodeling, leading to systolic and diastolic dysfunction. Passive stiffness of the heart increases secondary to metabolic derangement and structural alterations, resulting in abnormal myocardial relaxation. Despite its established incidence and pathological progression, DCM remains largely undiagnosed and may only become evident upon the presentation of symptoms. It is critical to identify structural and serological biomarkers to support reliable detection and timely diagnosis of DCM to improve prevention and progression monitoring.
Despite effective glycemic control using established pharmacological and lifestyle therapies, the incidence of cardiovascular disease in diabetes continues to escalate, and there are no specific evidence-based treatments for DCM. Furthermore, because of the adverse side effects of some available drugs, there is an urgent need to explore natural therapeutic alternatives to ameliorate complications associated with diabetes and support improved patient management and prognosis. In this context, there is significant research interest in medicinal plants, which confer therapeutic effects, both in modern medicine and allopathy, due to their pronounced antioxidant and antihyperglycemic properties, reduced side effects, and low cost. Indeed, further to experimental studies highlighting the potential of natural extracts for the management of hyperglycemia, identification of such compounds that can selectively inhibit DCM progression via imposing antihyperglycemic and cardioprotective effects would be of great therapeutic interest.
In this regard, dates (Phoenix dactylifera), which belong to the Arecaceae family of palm and are abundantly cultivated in Middle Eastern countries and North Africa, hold exciting promise. There are more than 200 types of dates, with Egypt being the largest producer. Pakistan, which has the highest global rate of diabetes (26.7%) among its adult population, is also a major producer. Dates are enriched in phenolics, flavonoids, procyanidins, carotenoids, and phytosterols, which are likely to underlie the reported therapeutic benefits, including antitumor, antioxidant, hepatoprotective, antiatherogenic, neuroprotective, antihyperlipidemic, nephroprotective, antimicrobial, and gastrointestinal protection. This article explores the potential impact of Phoenix dactylifera in experimental DCM, with specific analysis of the functional, serological, histological, and gene expression endpoints, to assess whether dates may hold therapeutic significance for this devastating condition.
Discussion
Type 2 diabetes mellitus (T2DM) is a complex, polygenic, and heterogeneous disorder characterized by insulin resistance and pancreatic β-cell dysfunction, leading to poor glycemic control as a major risk factor correlating with poor metabolic and cardiovascular outcomes. Current treatments are suboptimal. This investigation focused on the methanolic extract of Phoenix dactylifera (PD) as a potential regulator of glucolipid metabolic and cardiovascular dysfunction in experimental T2DM, both in vivo and in vitro.
Glucolipid Metabolic Profiling
Elevated levels of fasting blood glucose (FBG), HbA1C, serum glucose, insulin, total cholesterol, triglycerides, and LDL-c were observed in the DCM control rats compared to healthy controls. This model is characterized by STZ-induced β-cell destruction and insufficient insulin action, combined with high-fat diet-mediated insulin resistance and suppression of postprandial fatty acid release, a key driver of elevated triglycerides and lipoprotein dysregulation. Notably, metabolic alterations in circulating lipids pose the highest risk for cardiovascular complications in T2DM. These detrimental changes were largely restored by treatment with both PD and metformin, the comparator drug control, which acts to reduce lipid secretion from intestinal epithelial cells by AMPK and GLP-1 activation. The reduction in glucolipid parameters and increase in HDL-c observed in DCM rats subjected to PD treatment are likely due to the antihyperglycemic efficacy of PD extract, as indicated by α-amylase inhibition assay. PD extract mediates its significant antihyperglycemic effects through inhibition of α-amylase and glucosidase and stimulation of endogenous release of insulin from extra-islet sources, possibly due to dietary fibers of PD extract reducing carbohydrate gastrointestinal absorption and enhancing glucose uptake by skeletal muscles. The evident antihyperlipidemic effect of PD extract may be mediated through direct or indirect inhibition of endogenous cholesterol synthesis, thus reducing the cardiac risk ratio and conferring strong cardioprotection in experimental DCM.
Pancreatic Tissue Function and Gene Expression
The impact of PD extract on pancreatic tissue function and expressions of genes and transcriptional factors central to insulin signaling and maintenance of β-cell regeneration, proliferation, and secretion was explored using qRT-PCR mRNA analysis. Reduced expressions of INS-I, INS-II, MAFA, GLUT-2, and PDX-1 in the DCM control rats versus healthy controls were observed, confirming STZ-induced β-cell destruction, supported by histopathology. Metformin treatment upregulated expression levels of these genes in DCM rats, associated with β-cell restoration, consistent with its role as both an insulin sensitizer and promoter of insulin secretion. Similar effects on pancreatic gene expression and morphology were observed in the PD-treated DCM rats, likely due to flavonoid-mediated regulation of insulin signaling and secretion, carbohydrate digestion, and tissue glucose uptake. The high phenolic and flavonoid contents of the PD extract were confirmed, along with significant α-amylase inhibitory activity, indicating the antihyperglycemic efficacy of PD and its capability of supporting normal β-cell structure and functioning. These data strongly indicate that PD extract preserves pancreatic islet insulin signaling in experimental T2DM, highlighting its emerging therapeutic potential.
Cardiac Remodeling and Oxidative Stress
Given that uncontrolled or chronically elevated glycemia typically leads to adverse cardiac remodeling, the efficacy of PD extract on T2DM rat hearts was investigated. Cardiomyocytes have low innate antioxidants, such as glutathione and superoxide dismutase, making the myocardium more prone to deleterious effects of free radicals. Hyperglycemia promoted increased myocardial reactive oxygen species (ROS) generation, as depicted by high total oxidant status (TOS) and malondialdehyde (MDA) levels in the DCM versus control rats, with concomitant increased levels of myocardial enzymes (LDH, CK-MB, and AST). These changes were associated with elevated pro-BNP, decreased heart rate, and QRS complex widening, indicating myocardial stress and functional deterioration. The antioxidant activity of PD extract was shown to be superior to that of metformin, despite equivalent metabolic effects, suggesting that PD confers direct cardioprotective benefits via divergent mechanisms. Metformin indirectly suppresses oxidative stress by reducing activity of antioxidants, whereas the antioxidant activity of PD extract is mediated via various phenolic compounds, reinforcing myocardial antioxidative defense in the experimental DCM model, leading to additional functional benefit.
Inflammation and Cardiac Fibrosis
T2DM is characterized by chronic low-grade inflammation, triggering the release of various fibrotic mediators and promotion of cardiac fibrosis. The expression levels of proinflammatory genes, TNF-α and NF-κB, and the profibrotic gene, TGF-β, were quantified in myocardial tissue. These targets were selected as NF-κB pathway activation represents a central convergence point for numerous cytokines and chemokines in T2DM, increasing the production of proinflammatory cytokines, including TNF-α, resulting in a cycle of chronic low-grade inflammation and upregulation of TGF-β, a key mediator of cardiovascular fibrosis. Under inflammatory stimulation, abnormal deposition of extracellular matrix is increased with concomitant increase in collagen fibers, aggravating myocardial fibrosis. The mRNA expressions of NF-κB, TNF-α, and TGF-β were markedly increased in the DCM controls, parallel with immune cell infiltration and myocardial histopathology characterized by inter-fiber edema and prominent fibrosis. These impacts were significantly reduced by both interventions, with PD showing superior efficacy versus metformin. The superior inhibitory effect of PD extract on pro-inflammatory and profibrotic signals in myocardial tissue could be due to its high polyphenol content, modulating cyclo-oxygenase and lipo-oxygenase activity and downstream NF-κB and TNF-α. The pronounced downregulation of TGF-β and improved myocardial histopathology observed with the PD extract likely occurred secondary to its combined inhibitory actions on inflammation and free radical production, established drivers of fibrosis.
Myocardial Structure and Function
The myocardium is particularly prone to the deleterious effects of glucotoxicity and lipotoxicity, promoting myofibril disorganization and disarray, commonly observed in failing hearts. Treatment with PD extract resulted in a more normalized structure of myofibers in DCM tissue with less fibrosis compared to the metformin treatment group, which continued to exhibit myofiber disarray. This term refers to nonparallel organization of cardiac myocytes, associated with regions of myocardial scarring. Its presence in metformin-treated hearts indicates that this established antihyperglycemic drug confers some protection against cardiovascular damage, while reduced myofiber disarray seen in PD extract provides evidence of superior cardioprotective efficacy.
The relative heart weight index was significantly higher in the DCM control, suggestive of pathological hypertrophy in response to hyperglycemia and associated oxidative stress, and was restored by treatment with both the PD extract and metformin. Such protective effects are likely due to the ability of the PD extract to enhance endogenous antioxidants in the myocardium, leading to a reduction in injury markers, edema, and myonecrosis, and restoration of structure. Despite the increased relative heart weight in the DCM controls, the cardiomyocyte diameter significantly increased compared to the healthy control and treatment groups, potentially due to long-standing metabolic derangements leading to cardiomyocyte hypertrophy, atrophy, and degeneration.
In Vitro Studies and Bioactive Constituents
Although in vivo data clearly indicate that PD extract conferred more marked cardioprotection versus metformin, likely mediated via more pronounced anti-inflammatory and antioxidant effects, these experiments did not allow conclusions on whether these effects were due to direct actions of PD extract on the heart or mediated by indirect glucometabolic alterations. Complementary in vitro studies assessed the impact of p-coumaric acid (PCA), a bioactive constituent of PD extract detected in HPLC, on cultured human cardiac fibroblasts (HCFs) exposed simultaneously to hyperglycemic and profibrotic stimuli to promote phenotypic change and differentiation to activated myofibroblasts. mRNA and protein expression of myofibroblast markers, α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF), which promote extracellular matrix deposition and fibrosis, were markedly increased after 48 hours stimulation with high glucose and TGF-β and significantly reduced by PCA treatment. These data support in vivo findings, indicating that PD extract reduces profibrotic signaling via its bioactive constituent, PCA, providing evidence that PD extract exerts direct cardiac benefits in DCM in parallel to metabolic improvement. These results suggest that methanolic extract of Phoenix dactylifera can offer significant cardioprotection by orchestrating adverse cardiac remodeling in experimental DCM by modulating both glucolipid metabolism and fibroblast activation.
Conclusion
Diabetic cardiomyopathy remains a critical complication of diabetes, contributing significantly to cardiovascular morbidity and mortality among diabetic patients. Current treatments, primarily focused on glycemic control, do not adequately address the complex metabolic and structural changes associated with DCM. The methanolic extract of Phoenix dactylifera emerges as a promising natural therapeutic agent, demonstrating significant cardioprotective, antihyperglycemic, and anti-inflammatory effects in experimental models. The bioactive constituents of PD, such as phenolics and flavonoids, contribute to its efficacy in mitigating oxidative stress, inflammation, and fibrosis, thereby preserving cardiac structure and function. Further research is warranted to translate these findings into clinical practice, potentially offering a novel approach to managing diabetic cardiomyopathy and improving patient outcomes.
resource : https://www.mdpi.com/2073-4409/13/14/1196