ArticleFrontiers in endocrinology2025
Dorzagliatin shows potential in preventing cognitive impairment in diabetes: evidence from Mendelian randomization analysis and animal study.
Article in Frontiers in endocrinology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Aim: Dorzagliatin is a glucokinase (GK) activator, restoring glucose homeostasis in type 2 diabetes. We investigated the effects of dorzagliatin on cognitive traits using Mendelian randomization (MR), with validation in a spontaneous diabetic rat model. Methods: A two-sample MR study was conducted to investigate the causal effects of GK activation on neurodegenerative traits. Utilizing genome-wide association study summary statistics, we selected independent genetic variants of Results: Genetically mimicked GK activation causally decreased risk of memory loss (OR 0.21 per 1% lower HbA1c, 95% CI 0.05-0.91) and was associated with higher scores of prospective memory task, symbol digit substitution task and intelligence. MR results also implied that GK activation had cognitive protective effects not solely attributed to glucose-lowering. Low-dose dorzagliatin treatment in young Goto Kakizaki rats prevented spatial memory impairment occurred in adulthood in the MWM test. It also significantly prevented the reduced expression of insulin receptors, glucose transporters, and synaptic proteins in the brains of Goto Kakizaki rats. Conclusions: Dorzagliatin protects against cognitive impairment under diabetes conditions. Maintaining glucose homeostasis directly regulates insulin pathway and glucose uptake, as well as enhances neurotransmission processes in the hippocampus. These findings not only highlight dorzagliatin as a promising therapeutic option for preventing diabetes-associated cognitive decline but also provide critical mechanistic insights into the role of GK modulated glucose homeostasis in preserving brain function, offering a potential translational strategy for clinical intervention.
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