Impact of glucokinase activators on the gut microbiota of high-fat diet-induced obese and type 2 diabetic mice.

Introduction: Glucokinase activators (GKAs) enhance glucose phosphorylation by activating glucokinase (GK) expressed in key metabolic organs (such as the liver, pancreas and intestine), thereby initiating cellular glucose metabolism and contributing to improved glycemic control. Among various GKAs under development, dorzagliatin and cadisegliatin (TTP399) are currently the most promising. The gut microbiota plays a critical role in the pathogenesis and progression of metabolic disorders, including obesity and type 2 diabetes. Substantial evidence indicates that long-term administration of oral glucose-lowering agents, such as metformin, can modulate the composition and function of the gut microbiota. Nevertheless, whether GKAs-as emerging oral hypoglycemic agents-also influence gut microbial homeostasis remains unexplored. This study aims to investigate the effects of oral GKAs on intestinal barrier integrity and gut microbiota composition in high-fat diet (HFD)-induced obese/type 2 diabetic mice. In addition, we compare the differential impacts of distinct GKA agents on glycemic regulation and gut microbial communities. Methods: Mice were randomly assigned to receive oral gavage of either a vehicle, dorzagliatin, or TTP399 for four consecutive weeks following 5 weeks of HFD feeding. Throughout the study, changes in key metabolic parameters, intestinal barrier integrity, and inflammatory markers were evaluated. Additionally, fecal samples were collected and subjected to 16S-rRNA gene sequencing for analysis of the gut microbiota composition. Results: Both dorzagliatin and TTP399 exerted beneficial hypoglycemic effects in HFD mice. Furthermore, results also showed that both dorzagliatin and TTP399 regulated the gut microbiota structure in HFD mice, specifically increasing the relative abundance of short-chain fatty acids-producing and anti-inflammatory bacteria. Notably, under the conditions of this study, neither activator exhibited significant effects on intestinal barrier integrity or inflammatory markers. Discussion: Dorzagliatin and TTP399 are associated with alterations in gut microbiota composition at the genus level in HFD-fed mice, with a concomitant increase in the abundance of beneficial genera, and no significant association with changes in intestinal barrier integrity or inflammation. Further investigation is warranted to elucidate the association between long-term GKAs treatment and microbial communities, as well as the potential relationship between microbial changes and hypoglycemic effects.