A novel glucokinase activator TMG-123 causes long-lasting hypoglycemia and impairs spermatogenesis irreversibly in rats

• Published in: Journal of toxicological sciences Vol. 46; no. 3; pp. 115 - 123
• Main Authors: Kobayashi, Taiki, Shimomoto, Takasumi, Tamura, Azusa, Namekawa, Junichi, Iijima, Takeshi, Ochiai, Hideharu
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 01.01.2021; Japan Science and Technology Agency
• Subjects: Abnormalities; Animals; Body weight; Copulation; Copulation - drug effects; Degeneration; Dosage; Enzyme Activators - toxicity; Female; Fertility; Fertility - drug effects; Food consumption; Germ cell; Germ cells; Germ Cells - drug effects; Germ Cells - pathology; Glucokinase; Glucokinase - metabolism; Glucokinase - toxicity; Glucose; Histopathology; Hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - pathology; Hypoglycemic Agents - toxicity; Male; Necropsy; Organ weight; Rats; Rats, Sprague-Dawley; Reproductive organs; Seminiferous Tubules - cytology; Seminiferous Tubules - drug effects; Seminiferous Tubules - pathology; Sperm; Spermatogenesis; Spermatogenesis - drug effects; Spermatozoa - drug effects; Spermatozoa - pathology; Testes; Testicular toxicity; Testis; Tubules; Weight measurement; Germ cell; Testis; Reproductive organs; Hypoglycemia; Sperm; Testicular toxicity
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.46.115

The importance of glucose is well known as an energy source in testes. In order to evaluate the effects of long-lasting hypoglycemia on testes, a novel glucokinase activator, TMG-123, was dosed to rats at 5, 20 and 100 mg/kg for 13 weeks. As a result, plasma glucose levels decreased for several hours with increasing doses over the dose range of 5 to 100 mg/kg. No toxicological findings attributable to the test article were observed in clinical observation, measurements of body weight and food consumption, necropsy, and organ weight measurement. Histopathology showed scattered degeneration of seminiferous tubules in testes, and exfoliation of germ cells related to the degeneration of seminiferous tubules was observed in the lumen of both epididymides in the same animals at the end of the dosing period. Similar histopathological findings were noted at the end of the recovery period. In addition, a fertility study was conducted at the same doses for 13 weeks for males and 5 weeks for females. Sperm analysis showed decreases in the sperm concentration and the motility index and an increase in the incidences of sperm malformations. However, there were no abnormalities in the copulation or fertility rate. These results suggest that long-lasting hypoglycemia in rats is harmful to spermatogenesis and the testicular damage does not recover.