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BackgroundInsulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brain cortical structure in this association.MethodsThe publicly available data sources for insulin resistance (fasting insulin, homeostasis model assessment beta-cell function and homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time) were obtained from the MAGIC, ENIGMA, and UK Biobank datasets, respectively. We first conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine the susceptibility of insulin resistance on cognitive phenotypes. Additionally, we applied a two-step MR to assess the mediating role of cortical surficial area and thickness in the pathway from insulin resistance to cognitive impairment. The primary Inverse-variance weighted, accompanied by robust sensitivity analysis, was implemented to explore and verify our findings. The reverse MR analysis was also performed to evaluate the causal effect of cognition on insulin resistance and brain cortical structure.ResultsThis study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, p=0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, p=0.009). The surface area of the rostral middle frontal mediated 20.97% (95%CI=1.44% to 40.49%) of the total effect of proinsulin on reaction time. No evidence of heterogeneity, pleiotropy, or reverse causality was observed.ConclusionsBriefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure.

Ethnopharmacology relevance:Dichondra repens J.R.Forst. and G.Forst (DRF; Convolvulaceae, called Matijin in Chinese), has been traditionally used to treat jaundice, bacillary dysentery, urinary tract infection, edema, contusions, and strains and sprains based on traditional Chinese medicine (TCM) concepts.Aim of study: This paper intends to provide a comprehensive and critical analysis of research on DRF focusing on a relationship between traditional uses and pharmacological effects, evaluating the therapeutic potential of this plant.Methods: Relevant data on DRF were retrieved from available databases.Results: The heat-clearing and detoxifying, and removing the phlegm and turbid urine effects of DRF are linked to its anti-hepatitis B virus (HBV), anti-inflammatory, and hepatoprotective activities. Especially, the hepatoprotective effects of DRF are mainly based on anti-HBV activities of phenylalanine dipeptides Matijin-Su (MTS) and its derivatives derived from this plant. Further, a phase I anti-HBV clinical trial of a candidate compound named bentysrepinine (Y101, Chinese name Tifentai) has been completed. Also, anti-tumor, analgesic, and antibacterial properties have been reported in the extracts and compounds from DRF. Although pharmacy, pharmacodynamics, toxicology, and pharmacokinetics of bentysrepinine have been systemically reported, no studies have reported chemistry, safety, pharmacology of other compounds or extracts systemically.Conclusion: Phenylalanine dipeptide compounds are main components and MTS is a characteristic substance of DRF. The main pharmacological effect of DRF is anti-HBV activity, which is coherent with the traditional use of this plant in China. Except bentysrepinine, few studies have been conducted on toxicities of the extracts or compounds from DRF. Thus, it is still necessary to evaluate safety, chemistry, pharmacology of the extracts or compounds from DRF regarding the link between traditional uses and modern applications before the future clinical trials. Bacterial sepsis, cholecystitis and tumors may be prior therapeutic targets of this plant in the future.