Doxycycline in Extremely Low Dose Improves Glycemic Control and Islet Morphology in Mice Fed a High-Fat Diet

Purpose: Chronic low-grade inflammation is detected in obese and diabetic individuals. Tetracyclines, used as antibiotics for years, have been demonstrated to have diverse non-bactericidal effects, including anti-tumor and anti-inflammatory activities. This study aimed to investigate whether doxycycline at sub-antimicrobial concentrations could improve glycemic control in mice fed a high-fat diet, through its anti-inflammatory activities. Methods: C57BL/6J mice were fed with a high-fat diet to induce diabetic and obese conditions. Three sub-antimicrobial dosages of doxycycline (200, 20, and 2 mu g/mL) were added to drinking water for 23 weeks during the housing phase. Results: Doxycycline at 200 mu g/mL tended to increase body weight, islet mass, and the percentage of large islets (diameter >350 mu m). At 20 mu g/mL, doxycycline significantly improved glucose tolerance and decreased fasting blood glucose. At 2 mu g/mL, doxycycline increased the percentage of small islets (diameter <80 mu m). Serum C-reactive protein and lipopolysaccharide levels significantly decreased while the beta-cell ratio increased in all doxycycline-administered mice. Conclusion: Our results suggest that doxycycline, even at an extremely low dose, could improve glycemic control and islet morphology via its anti-inflammatory activities.