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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus

by
Alma N. Díaz-Herreros
1,2,
Elba Reyes-Maldonado
3,
Erika Rosales-Cruz
3,
Fernando Gómez-Chávez
4,
Amaranta Sarai Valdez-Guerrero
5,
Octavio Rodríguez-Cortés
6,
Juan C. Cancino-Díaz
7 and
Mario E. Cancino-Díaz
1,*
1
Laboratorio de Inmunología Aplicada, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
2
Centro de Investigación Científica Serendipia A.C., Tláhuac, Mexico City 13210, Mexico
3
Laboratorio de Hematología, Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
4
Laboratorio de Enfermedades Osteoarticulares e Inmunológicas, Sección de Estudios de Posgrado e Investigación, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, Mexico City 07320, Mexico
5
Laboratorio de Bioquímica Aplicada, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
6
Laboratorio de Inflamación y Obesidad, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
7
Laboratorio de Inmunomicrobiología, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(10), 4640; https://doi.org/10.3390/ijms27104640
Submission received: 1 April 2026 / Revised: 12 May 2026 / Accepted: 14 May 2026 / Published: 21 May 2026
(This article belongs to the Special Issue Molecular Biology of Hypoxia: 2nd Edition)
Versions Notes

Abstract

The VHL–HIF-1α–VEGF axis regulates angiogenesis and metabolism. Beyond oncology, pVHL is essential for pancreatic β-cell function and is reduced in hypercaloric diet (HCD)-induced type 2 diabetes mellitus (T2DM). This study aimed to overexpress pVHL in pancreatic tissue and evaluate its effects on blood glucose levels and the expression of proteins related to glucose metabolism in the pancreas. HCD-induced diabetic C57BL/6 and BALB/c mice received a single intrapancreatic injection of an adenoviral vector (1 × 1012 viral particles) encoding the murine Vhlh gene (AdVHL) to induce transient pVHL overexpression. The glycemic delta (post-load glucose minus fasting) and net incremental area under the curve (niAUC) were determined on days 3, 6, 9, 12, and 15 post-treatment, as the peak in GFP overexpression (used as a surrogate reporter of transduction efficiency) was detected between days 9 and 12. Immunohistochemistry (IHC) and immunofluorescence (IF) were used to assess the expression of pVHL, HIF-1α, GLUT-1, GLUT-2, and insulin in pancreatic tissue. AdVHL treatment significantly decreased the glycemic delta and niAUC in mice with T2DM (p < 0.01). On day 15 after treatment, HIF-1α and GLUT-1 expression were markedly reduced in AdVHL-treated mice (p < 0.01), while GLUT-2 and insulin were significantly increased (p < 0.01). These results were reproduced in both mouse strains. Transient overexpression of pVHL in pancreatic tissue of mice with T2DM was associated with decreased glucose levels and changes in the expression of proteins related to glucose metabolism in the pancreas, resembling a healthier phenotype than that of mice with T2DM. These findings support an important functional role of the pVHL–HIF-1α axis in pancreatic physiology, provide a proof-of-concept for further mechanistic and translational studies, and implicate pVHL in the altered glucose metabolism observed in T2DM.
Keywords: pVHL; HIF-1α; type 2 diabetes mellitus; pancreatic tissue; adenoviral vector; GLUT-1; GLUT-2; insulin; VHL–HIF-1α axis pVHL; HIF-1α; type 2 diabetes mellitus; pancreatic tissue; adenoviral vector; GLUT-1; GLUT-2; insulin; VHL–HIF-1α axis

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MDPI and ACS Style

Díaz-Herreros, A.N.; Reyes-Maldonado, E.; Rosales-Cruz, E.; Gómez-Chávez, F.; Valdez-Guerrero, A.S.; Rodríguez-Cortés, O.; Cancino-Díaz, J.C.; Cancino-Díaz, M.E. Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus. Int. J. Mol. Sci. 2026, 27, 4640. https://doi.org/10.3390/ijms27104640

AMA Style

Díaz-Herreros AN, Reyes-Maldonado E, Rosales-Cruz E, Gómez-Chávez F, Valdez-Guerrero AS, Rodríguez-Cortés O, Cancino-Díaz JC, Cancino-Díaz ME. Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences. 2026; 27(10):4640. https://doi.org/10.3390/ijms27104640

Chicago/Turabian Style

Díaz-Herreros, Alma N., Elba Reyes-Maldonado, Erika Rosales-Cruz, Fernando Gómez-Chávez, Amaranta Sarai Valdez-Guerrero, Octavio Rodríguez-Cortés, Juan C. Cancino-Díaz, and Mario E. Cancino-Díaz. 2026. "Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus" International Journal of Molecular Sciences 27, no. 10: 4640. https://doi.org/10.3390/ijms27104640

APA Style

Díaz-Herreros, A. N., Reyes-Maldonado, E., Rosales-Cruz, E., Gómez-Chávez, F., Valdez-Guerrero, A. S., Rodríguez-Cortés, O., Cancino-Díaz, J. C., & Cancino-Díaz, M. E. (2026). Transient Overexpression of pVHL Mediated by Adenoviral Vector Injection in Pancreatic Tissue Decreases Blood Glucose Levels in a Hypercaloric Diet-Induced Mouse Model of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 27(10), 4640. https://doi.org/10.3390/ijms27104640

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