Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study

Area of Science:

• Genetics and Epidemiology
• Metabolic Diseases
• Liver Disease

Background:

• A consistent association exists between liver dysfunction and type 2 diabetes (T2D).
• The causal relationship and its direction between liver function and T2D remain unclear, potentially confounded by other factors.
• Nonalcoholic fatty liver disease (NAFLD) is linked to both liver dysfunction and T2D.

Purpose of the Study:

• To investigate the causal relationship between liver function markers and T2D risk using Mendelian randomization.
• To determine the directionality of the association between liver function and T2D.
• To explore the role of insulin resistance in the link between liver function and T2D.

Main Methods:

• Employed Mendelian randomization analysis with large-scale genetic data from up to 64,094 T2D cases and 607,012 controls.
• Utilized genetic variants associated with liver function biomarkers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyl transferase (GGT).
• Assessed the effect of T2D predisposition and insulin resistance on liver function using genetic variants.

Main Results:

• Genetically predicted higher levels of ALT and AST were associated with an increased risk of T2D.
• A modest negative association was observed between genetically predicted ALP and T2D risk; no significant association was found for GGT.
• Genetic predisposition to higher fasting insulin, a marker of insulin resistance, was linked to increased circulating ALT, but T2D predisposition was not.

Conclusions:

• Findings support a causal role for elevated ALT and AST in increasing T2D risk.
• Suggests that insulin resistance may lead to NAFLD (indicated by ALT/AST), which subsequently elevates T2D risk.
• Highlights the potential mediating role of NAFLD in the pathway from insulin resistance to T2D.