Enhanced mitigation of diabetic myocardial injury in rats via modulating the adiponectin/IRS-1/PI3K/p-AKT/FOXO-1 signaling by combining methotrexate and insulin.

Mohamed S Elsayed, Mahmoud Elshal, Manar G Helal, Tarek Ibrahim

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Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 authors.

Mohamed S ElsayedDepartment of Pharmacology and Toxicology Dep. Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Mansoura, 35516, Egypt. docmido2233@std.mans.edu.eg.ORCID https://orcid.org/0000-0001-7815-0509

Mahmoud ElshalDepartment of Pharmacology and Toxicology Dep. Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Mansoura, 35516, Egypt.

Manar G HelalDepartment of Pharmacology and Toxicology Dep. Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Mansoura, 35516, Egypt.

Tarek IbrahimDepartment of Pharmacology and Toxicology Dep. Faculty of Pharmacy, Mansoura University, El Gomhoria Street, Mansoura, 35516, Egypt.

Funding

The Deanship of Postgraduate Studies and Research, Research Unit, Mansoura University, Mansoura, Egypt Mu-Phar-23-29

6 · The paper itself

Abstract

purposeThe present study aimed to explore the impact of combining methotrexate (MTX) and insulin (INS) to mitigate diabetes-associated myocardial injury and investigate the potential underlying mechanisms.

methodDiabetes was induced in rats by a single low-dose streptozotocin (STZ) injection (35 mg/kg, i.p.) after a four-week period of administration of a high-fat diet (HFD) feeding and fructose administration in water.

resultsOur data revealed that the diabetic rats had elevated serum cardiac injury biomarkers and a disturbed lipid profile in parallel with marked inflammation and distortion of normal cardiomyocyte architecture. Moreover, diabetes was associated with reduced levels of adiponectin, insulin receptor substrate (IRS)-1, phosphatidylinositol-3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase (p-GSK)-3β. Our findings showed that combining low doses of MTX and INS exerted superior ameliorative effects on serum cardiac injury biomarkers and the lipid profile, as well as histopathological abnormalities. Moreover, MTX enhanced the stimulatory effect of INS on adiponectin levels and the IRS-1/PI3K/p-AKT/FOXO-1 signaling pathway in the heart. MTX combined with INS also demonstrated a superior suppressive effect on cardiac FOXO-1 levels and the autophagy-associated biomarkers microtubule-associated protein 1A/1B-light chain (LC3-B) and beclin-1. Interestingly, the enhancement of cardiac INS signaling by MTX was accompanied by the inhibition of biomarkers of oxidative stress and the apoptotic executor caspase-3.

conclusionLow doses of MTX offer added therapeutic value against diabetic cardiac injury when combined with INS. This effect may be attributed, at least in part, to the modulation of the adiponectin/IRS-1/PI3K/p-AKT/FOXO-1 signaling cascade.

Indexed as

Diabetes Mellitus, ExperimentalDiabetic CardiomyopathiesInsulinMethotrexateAdiponectinAnimalsForkhead Box Protein O1Insulin Receptor Substrate ProteinsMaleMyocardiumPhosphatidylinositol 3-KinasePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleySignal TransductionAdiponectinForkhead Box Protein O1Foxo1 protein, ratInsulinInsulin Receptor Substrate ProteinsIrs1 protein, ratMethotrexatePhosphatidylinositol 3-KinasePhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktDiabetic myocardial injuryDrug repurposingInsulinMethotrexatep-GSK-3β autophagyPI3K/p-AKT/FOXO-1

Identifiers

PMID42631883

DOI10.1007/s12265-010-9200-z

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