Organic vs. inorganic nitrates: Metabolic and vascular outcomes in STZ-induced diabetes in mice.

Abstract

Background: Diabetic animals often display dysregulated nitric oxide (NO) metabolism, contributing to vascular dysfunction. This study evaluates the metabolic and vascular effects of organic nitrate isosorbide mononitrate (ISMN) versus inorganic sodium nitrate (NaNO3) in mice with type 1 diabetes mellitus (T1DM) induced by streptozotocin (STZ).

Experimental approach: T1DM was induced in male C57Bl6 mice with STZ ip and confirmed by fasting glucose. Mice were treated with ISMN (10 mg·kg^-1) or NaNO3 (85 mg·L^-1) for 14 days. A combination of in vivo, in vitro, and ex vivo studies assessed cardiometabolic benefits.

Results: Both nitrates reduced blood and urinary hyperglycemia in T1DM mice, with ISMN exhibiting more significant reductions in blood glucose. ISMN and NaNO3 similarly reduced water and food intake, urinary volume, glucose intolerance, and insulin resistance while increasing insulin and nitrite levels in serum and urine. Both nitrates improved endothelium-independent vascular function and attenuated reactive oxygen species (ROS) while increasing NO levels in the aortic rings of T1DM mice. Furthermore, both nitrates similarly reduced mean arterial pressure in T1DM mice.

Conclusion and implications: ISMN and NaNO₃ have demonstrated comparable hypotensive and antioxidant effects, offering metabolic and vascular benefits in STZ-TDM1 mice. The more pronounced reduction in blood glucose with ISMN treatment compared to NaNO₃ is particularly promising. The antihyperglycemic effects of both nitrates were linked to increased serum insulin levels and enhanced insulin sensitivity. These results provide a foundation for future clinical studies to evaluate the potential of ISMN or NaNO3 as antidiabetogenic and antihypertensive adjuvant therapies in diabetic patients.