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Diabetes mellitus (DM) and cardiovascular complications are two unmet medical emergencies that can occur together. The rising incidence of heart failure in diabetic populations, in addition to apparent coronary heart disease, ischemia, and hypertension-related complications, has created a more challenging situation. Diabetes, as a predominant cardio-renal metabolic syndrome, is related to severe vascular risk factors, and it underlies various complex pathophysiological pathways at the metabolic and molecular level that progress and converge toward the development of diabetic cardiomyopathy (DCM). DCM involves several downstream cascades that cause structural and functional alterations of the diabetic heart, such as diastolic dysfunction progressing into systolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis, and subsequent heart failure over time. The effects of glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular (CV) outcomes in diabetes have shown promising results, including improved contractile bioenergetics and significant cardiovascular benefits. The purpose of this article is to highlight the various pathophysiological, metabolic, and molecular pathways that contribute to the development of DCM and its significant effects on cardiac morphology and functioning. Additionally, this article will discuss the potential therapies that may be available in the future.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 μm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

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