Comparative Effects of Different Sugar Substitutes in a Mice Model of Type 2 Diabetes Induced Renal Injury

ABSTRACT The global incidence of diabetic kidney disease (DKD) due to type 2 diabetes is rising and is becoming one of the most threatening complications. Excessive sugar intake accelerates DKD progression, highlighting safe, low‐calorie sugar substitutes as potential intervention. This study aimed to elucidate the effects of different sugar substitutes on DKD and explore their underlying mechanisms. We established a mouse model of DKD using a high‐fat diet and streptozotocin and systematically compared the effects of Mogroside V (MOG), stevioside (ST), sucralose (TGS), erythritol (ERT), and sucrose (SUC). DKD mice exhibited typical renal injury characteristics along with increased renal oxidative stress and inflammatory responses. MOG and ST interventions significantly improved insulin levels; reduced blood urea nitrogen, serum creatinine, and urinary microalbumin levels; restored renal tissue structure; and alleviated oxidative‐inflammatory damage in DKD mice. ERT and TGS also mitigated oxidative‐inflammatory damage but had weaker effects, whereas SUC failed to improve DKD. Combined metabolomics, quantitative polymerase chain reaction, and western blot analyses indicated that different sugar substitutes exert comprehensive metabolic protection by regulating glycerophospholipid metabolism, linoleic acid metabolism, AMPK, MAPK signaling pathways, and FcεRI signaling pathways. Specifically, MOG significantly alleviated oxidative stress and inflammatory responses in DKD mouse kidneys by suppressing the mRNA expression of Alox5 , Pla2g4 , Raf1 , Hras , Ma2pk1 , Mapk1 , and Cysltr1 , as well as p‐ERK and 5‐lipoxygenase protein expression. These findings provide scientific evidence supporting the nutritional value of sugar substitutes in DKD.