The incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations.

Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Cardiovascular issues associated with diabetes, such as diabetic cardiomyopathy (DCM), can lead to heart failure. DCM is etiologically related to myocardial inflammation and can stem from a complex interplay of different cell types. Cardiomyocyte as an active mediator of the inflammatory response is an emerging concept with limited mechanistic understanding. Purpose We aimed to address the knowledge gap of cardiomyocyte endoplasmic reticulum (ER) dysfunction-mediated macrophage response and provide functional evidence for the therapeutic feasibility of managing inflammatory paracrine signals in response to diet-induced metabolic stress. Methods In vivo mouse model of high fat high sucrose diet-induced diabetes, cardiomyocyte-specific p21-activated kinase 2 (PAK2) knockout model, echocardiography, histology, 3D imaging, qPCR, co-culture of H9c2 culturing medium and bone-marrow derived macrophages, immunoblotting, macrophage isolation from myocardium, flow cytometry and AAV9-gene therapy. Results In a time-course study, diet-induced diabetic mice demonstrated an association between cardiac ER stress and sustained myocardial inflammation, with a maladaptive shift in myocardial ER stress response over time. Furthermore, as a cardiac ER dysfunction model, mice with cardiac-specific PAK2 deletion exhibited heightened myocardial inflammatory response in diabetes. Using human and mice diabetic heart samples, we show that ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) is a novel transcriptional regulator of high mobility group box-1 (HMGB1). Cardiac stress-induced active release of HMGB1 facilitated M1 macrophage polarization, and aggravated myocardial inflammatory signatures. Therapeutically, sequestering the extracellular HMGB1 using Glycyrrhizin conferred cardioprotection through its anti-inflammatory action. Also, as functional evidence, we showed that un-mitigated cardiac ER response due to PAK2 loss under diabetes may account as a barrier for leveraging the anti-inflammatory potential of Vildagliptin. Conclusion Collectively, we introduce an ER stress-mediated cardiomyocyte-macrophage link, altering the macrophage response in the myocardium, thereby providing insight into therapeutic prospects for diabetes-associated cardiac dysfunction.

Metabolic syndrome is a chronic systemic disease that is particularly manifested by obesity, diabetes, and hypertension, affecting multiple organs. The increasing prevalence of metabolic syndrome poses a threat to public health due to its complications, such as liver dysfunction and cardiovascular disease. Impaired adipose tissue plasticity is another factor contributing to metabolic syndrome. Emerging evidence demonstrates that fibroblast growth factors (FGFs) are critical players in organ crosstalk via binding to specific FGF receptors (FGFRs) and their co-receptors. FGFRs activation modulates intracellular responses in various cell types under metabolic stress. FGF21, in particular is considered as the key regulator for mediating systemic metabolic effects by binding to receptors FGFR1, FGFR3, and FGFR4. The complex of FGFR1 and beta Klotho (β-KL) facilitates endocrine and paracrine communication networks that physiologically regulate global metabolism. This review will discuss FGF21-mediated FGFR1/β-KL signaling pathways in the liver, adipose, and cardiovascular systems, as well as how this signaling is involved in the interplay of these organs during the metabolic syndrome. Furthermore, the clinical implications and therapeutic strategies for preventing metabolic syndrome and its complications by targeting FGFR1/β-KL are also discussed.

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