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Mendelian Randomization Analyses Indicate a Causal Association Between Sodium-Glucose Cotransporter-1 Inhibition and

Gang Fan1,2,3, Zi-Han Qu2

  • 1Cardiology Department of Xianyang Central Hospital, Xianyang, Shaanxi Province, 712000, P.R. China.

Current Medicinal Chemistry
|March 15, 2026
PubMed
Abstract

Insights

Sodium-glucose cotransporter-1 (SGLT1) inhibition causally impacts mitochondrial biology. This Mendelian randomization study reveals SGLT1

Area of Science:

  • Genetics and Molecular Biology
  • Mitochondrial Function
  • Metabolic Pathways

Background:

  • The precise role of sodium-glucose cotransporter-1 (SGLT1) in mitochondrial biology is not well understood.
  • Investigating the link between SGLT1 activity and mitochondrial function is crucial for understanding cellular metabolism.
  • Mendelian randomization (MR) offers a robust approach to explore causal relationships between genetic predispositions and biological functions.

Purpose of the Study:

  • To investigate the causal association between SGLT1 inhibition and mitochondrial biology function.
  • To utilize Mendelian randomization (MR) analysis to establish a genetic link between SGLT1 and mitochondrial processes.
  • To identify specific mitochondrial components affected by SGLT1 inhibition.

Main Methods:

  • A two-sample Mendelian randomization (MR) study design was employed.
  • Genetic variants associated with SGLT1 inhibition (via SLC5A1 gene expression and HbA1c) were used as instrumental variables.
  • Inverse variance weighted (IVW) algorithm was the primary analytical method, supplemented by weighted median and MR-Egger methods for sensitivity analysis.

Main Results:

  • Genetically predicted SGLT1 inhibition showed a positive association with the upregulation of mitochondrial components, including Serine tRNA ligase and NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8.
  • Conversely, SGLT1 inhibition was negatively associated with the downregulation of mitochondrial components such as Glutaredoxin-2, Pyruvate carboxylase, and Mitochondrial glutamate carrier 2 in the European population.
  • These findings suggest a significant, bidirectional impact of SGLT1 inhibition on various mitochondrial proteins.

Conclusions:

  • This study provides the first genetic evidence causally linking SGLT1 inhibition to a diverse array of mitochondrial biology processes in the European population.
  • SGLT1 inhibition influences mitochondrial function through the regulation of specific proteins, including NDUFB8, GRX2, and PC.
  • Further basic and clinical research is warranted to fully elucidate the underlying mechanisms of this causal relationship and its therapeutic implications.
Keywords:
SGLT1glucose.hemoglobinmendelian randomizationmetabolismmitochondria

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