The Impact of SGLT1 Inhibition on Frailty and Sarcopenia: A Mediation Mendelian Randomization Study

Figures

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  FIGURE 1. A flowchart illustrating the methodological framework and sources of GWAS databases utilized in the study. FI, frailty index; GWAS, genome‐wide association study; SGLT1, sodium‐glucose co‐transporter 1.

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  FIGURE 2. Causal effect of SGLT1 inhibition on FI, as well as low grip strength in both male and female individuals aged 60 years and older under both FNIH and EWGSOP criteria. (A) In the primary analysis, genetic variants demonstrating significant associations with both HbA1c levels and mRNA expression of the SLC5A1 gene were identified as instrumental variables for MR analysis to investigate the causal relationship between SGLT1 inhibition and outcomes. (B) In the validation analysis, functionally damaging missense variants within the SLC5A1 gene, previously documented in literature, were employed to mimic the effect of SGLT1 inhibition in the MR analysis. CI, confidence interval; EWGSOP, European Working Group on Sarcopenia in Older People; FI, frailty index; FNIH, Foundation for the National Institutes of Health; IVW, inverse variance weighted; MR, Mendelian randomization; pval, p value; SGLT1, sodium‐glucose co‐transporter 1.

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  FIGURE 3. Causal effect of plasma proteins and metabolites on FI, as well as low grip strength aged 60 years and older under both FNIH and EWGSOP criteria. (A) Volcano gram illustrating the association between plasma proteins and FI. (B) Volcano gram illustrating the association between plasma proteins and low grip strength (60 years and older) under EWGSOP criteria. (C) Volcano gram illustrating the association between plasma proteins and low grip strength (60 years and older) under FNIH criteria. (D) Volcano gram illustrating the association between plasma metabolites and FI. (E) Volcano gram illustrating the association between plasma metabolites and low grip strength (60 years and older) under EWGSOP criteria. (F) Volcano gram illustrating the association between plasma metabolites and low grip strength (60 years and older) under FNIH criteria. EWGSOP, European Working Group on Sarcopenia in Older People; FI, frailty index; FNIH, Foundation for the National Institutes of Health.

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  FIGURE 4. Roadmap suggesting potential mechanisms of SGLT1 inhibition on attenuating frailty through mediators. SGLT1 inhibition led to increased expression of PCSK1 which in turn up‐regulated the GLP1 levels. The interaction between GLP1 and its receptor in skeletal muscle could attenuate the insulin resistance. Moreover, GLP1 acted as a stimulus for insulin secretion which could activate the CPT expression, consequently inhibiting the insulin resistance in skeletal muscle induced by long chain saturated fatty acid, such as palmitoylcarnitine and arachidate. In addition, the activation of GLP1 increased the MANF level, facilitating the repair of skeletal muscle damage and promoting the survival of pancreatic β cells, which were responsible for insulin secretion. Meanwhile, GLP1 also increased the expression levels of PON3, which could protect the skeletal muscle by anti‐inflammation, anti‐oxidation and anti‐apoptosis. In addition, SGLT1 inhibition suppressed the level of kynurenine, a molecule participating in the biological process of inflammation, oxidative stress and insulin resistance, thereby safeguarding skeletal muscle health. CPT, carnitine palmitoyltransferase; GLP1,…

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  FIGURE 5. Roadmap suggesting potential mechanisms of SGLT1 inhibition on attenuating sarcopenia through mediators. GLP1 activation, promoted by SGLT1 inhibition, decreased the level of sphingomyelin that was widely recognized as a trigger of insulin resistance in skeletal muscle. In addition, the activation of GLP1 promoted the insulin secretion and CPT upregulation, thereby mitigating palmitoylcarnitine‐induced insulin resistance in skeletal muscle. Additionally, GLP1 was demonstrated to be related to higher level of p53 which in turn increased the RRM2B expression, facilitating the DNA repair of skeletal muscle. In particular, p53 also showed the ability of attenuating palmitoylcarnitine‐induced insulin resistance in skeletal muscle. CPT, carnitine palmitoyltransferase; DNA, deoxyribonucleic acid; GLP1, glucagon‐like peptide‐1; SGLT1, sodium‐glucose co‐transporter 1.