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

Abstract

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.

2-Deoxy-d-Glucose Ameliorates PKD Progression

“…Chronic ingestion for 6 months of high doses of 2DG (250 mg/kg per day) were reported to cause mortality and heart vacuolization in the rat. 22 On the contrary, a second study reported that chronic treatment. The power of the study was 0.93.…”

“…20,21 However, one study has reported signs of toxicity in the heart when high doses of 2DG are ingested by the rat. 22 Thus, we designed a study similar to the one conducted in the cystic animals on wild-type mice with the aim of testing the toxicity of this compound in our conditions (i.e., intraperitoneal administration of 100 mg/kg 5 days a week for 2.5 months). In these animals, we did not observe any major sign of kidney toxicity (measured as BUN), liver toxicity (measured as alanine amino transferase, aspartate aminotransferase, lactate dehydrogenase, and albumin), or heart toxicity (CK) (Supplemental Table 2).…”

Caloric Restriction Mimetic 2-Deoxyglucose Antagonizes Doxorubicin-induced Cardiomyocyte Death by Multiple Mechanisms

“…In addition, 2-DG was shown to substantially reduce ischemic brain injury (17). However, long term use of high dose 2-DG in rats can cause cardiac injury, casting doubt on the potential of 2-DG being used as a CR mimetic to prolong life in animals (18) despite evidence that 2-DG can significantly extend the life span in Caenorhabditis elegans (19). Regardless of this discrepancy, it remains formally possible that 2-DG may produce beneficial effects on the heart under more acute conditions such as ischemia/reperfusion and chemotherapy-induced cardiac damage.…”

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

“…Despite these promising preliminary findings, the case of 2DG emphasizes the need for progressive screening of interventions through several species because our laboratory has recently reported that 2DG feeding in rats produces negative cardiotoxic effects and increased mortality associated with a deregulation of protein degradation and clearance (25). Although 2DG may still have therapeutic value over the short term in targeted applications such as chemotherapy and brain imaging, its prospects as an aging intervention are seriously diminished in light of its chronic effects in rats.…”