Unraveling the Antihyperglycemic Effects of Dipeptyl Peptidase-4 Inhibitors in Rodents: A Multi-Faceted Approach Combining Effects on Glucose Homeostasis, Molecular Docking, and ADMET Profiling

<b>Background/Objectives:</b> Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. <b>Methods</b>: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (<i>Mus musculus</i>). <b>Results</b>: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. <b>Conclusions</b>: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus.

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Journal
Pharmaceuticals
Published
2025-10-21
DOI
https://doi.org/10.3390/ph18101589
Primary Topic
Diabetes Treatment and Management
Type
article
Field-Weighted Citation Impact
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article

Unraveling the Antihyperglycemic Effects of Dipeptyl Peptidase-4 Inhibitors in Rodents: A Multi-Faceted Approach Combining Effects on Glucose Homeostasis, Molecular Docking, and ADMET Profiling

Matheus Nunes da Rocha, Marisa Jádna Silva Frederico, Fátima Regina Mena Barreto Silva, Ariclécio Cunha de Oliveira et al.
Pharmaceuticals
Diabetes Treatment and Management
article

Unraveling the Antihyperglycemic Effects of Dipeptyl Peptidase-4 Inhibitors in Rodents: A Multi-Faceted Approach Combining Effects on Glucose Homeostasis, Molecular Docking, and ADMET Profiling

Matheus Nunes da Rocha, Marisa Jádna Silva Frederico, Fátima Regina Mena Barreto Silva, Ariclécio Cunha de Oliveira, Kirley Marques Canuto, Lı́dia Moreira Lima, Walter José PELÁEZ, Hélcio Silva dos Santos, Claudia Johana Pérez Cardozo, Raimundo Rigoberto Barbosa Xavier Filho, Nylane Maria Nunes de Alencar, Gisele F. P. Rangel, Deysi Viviana Tenazoa Wong, Lyanna Rodrigues Ribeiro, Jane Eire Silva Alencar de Menezes, Emmanuel Silva Marinho, Gisele da Silva, Tiago Lima Sampaio, Leon Pereira, Carlos Otávio Damas Martins, Isabelle de Fátima Vieira Camelo Maia, Márcia Machado Marinho, Eduardo Reina, Daniele O. B. Sousa, Gabriela Araújo Freire, Raquel N. S. Roriz
article en

Abstract

<b>Background/Objectives:</b> Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. <b>Methods</b>: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (<i>Mus musculus</i>). <b>Results</b>: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. <b>Conclusions</b>: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus.

PharmaceuticalsVol. 18(10)
Universidade Estadual do Ceará (BR), Universidade Federal do Rio de Janeiro (BR), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Brazilian Agricultural Research Corporation (BR), Universidade Federal do Ceará (BR), Universidade Federal de Santa Catarina (BR)
Australian Government, Embrapa Agroindústria Tropical
Openalex Percentile: Top 60%
Diabetes Treatment and Management
DOIOpen Access PDFOpenAlex
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