Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats

Journal Article · Mon Mar 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.11.025· OSTI ID:21344891

Minor, Robin K ^[1]; Smith, Daniel L ^[2]; Sossong, Alex M ^[1]; Kaushik, Susmita ^[3]; Poosala, Suresh ^[4]; Spangler, Edward L ^[1]; Roth, George S ^[5]; Lane, Mark ^[6]; Allison, David B ^[7]; Cabo, Rafael de ^[1]

---

1. Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 (United States)
2. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)
3. Departments of Developmental and Molecular Biology and of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461 (United States)
4. Research Resources Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224 (United States)
5. GeroScience, Inc., Pylesville, MD 21132 (United States)
6. Medimmune, LLC, Gaithersburg, MD 20878 (United States)
7. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294 (United States)

Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.

• OSTI ID: 21344891
• Journal Information: Toxicology and Applied Pharmacology, Vol. 243, Issue 3; Other Information: DOI: 10.1016/j.taap.2009.11.025; PII: S0041-008X(09)00498-0; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS
BODY TEMPERATURE
CATHEPSINS
DOSES
GLUCOSE
GLYCOGEN
IN VIVO
INGESTION
INSULIN
LABORATORY ANIMALS
MORTALITY
NEOPLASMS
RATS
TOXICITY
ALDEHYDES
ANIMALS
CARBOHYDRATES
DISEASES
ENZYMES
HEXOSES
HORMONES
HYDROLASES
INTAKE
MAMMALS
MONOSACCHARIDES
ORGANIC COMPOUNDS
PEPTIDE HORMONES
PEPTIDE HYDROLASES
POLYSACCHARIDES
PROTEINS
RODENTS
SACCHARIDES
SH-PROTEINASES
VERTEBRATES