Effect of orally administered dipterinyl calcium pentahydrate on oral glucose tolerance in diet-induced obese mice

Abstract

Calcium pterins have been shown to be significant immunotherapeutic agents in models of breast cancer, hepatitis B, and tuberculosis (Bacillus Calmette-Guérin mycobacteria). These compunds modulate the immuno-enzyme indoleamine 2,3-dioxygenase (IDO) and the blood levels of several identified inflammatory cytokines. Recent research into the pathology of diabetes implicates inflammatory factors in the progression of the disease, leading the authors to study its possible control by one of the calcium pterins, dipterinyl calcium pentahydrate (DCP). The investigators tested DCP as a novel therapeutic for type 2 diabetes. Female C57BL/6 J mice with diet-induced obesity were fed a high-fat diet and were administered DCP in 0.4% carboxymethylcellulose for 21 days. Blood glucose was followed during the dosing period, and an oral glucose tolerance test (OGTT) was carried out on day 21. Measurements of plasma indoleamine 2,3-dioxygenase metabolites (tryptophan and kynurenine) and certain cytokines and chemokines were also taken. DCP 7 mg/kg/day reduced OGTT area under the curve (OGTT/ AUC) by 50% (P < 0.05). A significant multivariate regression (P = 0.013; R² = 0.571) of OGTT/ AUC was derived from DCP dosage and plasma Trp. Elevated plasma Trp concentration, likely from heterogeneity in diet and/or indoleamine 2,3-dioxygenase activity, was found to correlate with higher OGTT/AUC diabetic measures, possibly via inhibition of histamine degradation. In conclusion, an optimum dose of DCP 7 mg/kg/day significantly improved the OGTT diabetic state in these female diet-induced obese mice.

Keywords:

• diabetes
• immunotherapy
• oral glucose tolerance test
• tryptophan
• kynurenine

Acknowledgments

Phillip Moheno is grateful to Dr David Schubert of the Salk Institute for Biological Studies for his insight and discussions related to this study.

Disclosures

All the authors conducted the research. Phillip Moheno and Svetlana E Nikoulina performed the data analysis and wrote the manuscript. Phillip Moheno holds stock, and all authors hold stock options, in SanRx Pharmaceuticals, Inc, which has been assigned patent rights to DCP.