Targeting the PI3K/Akt/mTOR and Nrf2 signaling axis with berberine: a novel strategy for attenuating diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a major contributor to heart failure in patients with diabetes. Although berberine (BBR) exhibits broad metabolic and cardiovascular benefits, its mechanistic role in DCM remains incompletely defined. Cardiovascular function was assessed using arterial blood pressure (ABP), electrocardiography (ECG), and echocardiography. Biochemical analyses included glycemic indices, lipid profile, oxidative stress markers, inflammatory cytokines, and cardiac injury biomarkers. Cardiac and aortic tissues were evaluated for calcium (Ca2⁺) content, gene expression by RT-PCR, and immunohistochemical changes. DCM rats exhibited significant increases in ABP, left ventricular internal diameter, fasting glucose, HbA1c, cholesterol, triglycerides, LDL-C, malondialdehyde, tumor necrosis factor-α, interleukin-17, cardiac enzymes, Caspase-3 expression, and myocardial and aortic fibrosis, accompanied by marked ECG abnormalities. Conversely, ejection fraction, fractional shortening, serum insulin, HDL-C, superoxide dismutase activity, interleukin-10 levels, cardiac Ca2⁺ content, and expression of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (Nrf2), and PTEN-induced putative kinase protein 1 (PINK1) were significantly reduced. Combined insulin and BBR treatment produced greater improvement in cardiac structure, function, and molecular signaling than either treatment alone. Berberine, particularly as an adjunct to insulin therapy, effectively attenuates DCM by reducing hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis, while enhancing mitophagy and cardiac Ca2⁺ homeostasis. These effects are mediated, at least in part, through the coordinated modulation of the PI3K/Akt/mTOR and Nrf2 signaling pathways.