Genetically Mediated Lipid Metabolism and Risk of Insulin Resistance: Insights from Mendelian Randomization Studies

ABSTRACT

Dysregulated lipid metabolism, characterized by higher levels of circulating triglycerides, higher levels of small, low density lipoprotein, and accumulation of intracellular lipids, is linked to insulin resistance and related complications such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Considering that various metabolic, genetic, and environmental factors are involved in the development of T2DM and CVD, the causalities of these diseases are often confounded. In recent years, Mendelian randomization (MR) studies coupling genetic data in population studies have revealed new insights into the risk factors influencing the development of CVD and T2DM. This review briefly conceptualizes MR and summarizes the genetic traits related to lipid metabolism by evaluating their effects on the indicators of insulin resistance based on the results of recent MR studies. The data from the MR study cases referred to in this review indicate that the causal associations between lipid status and insulin resistance in MR studies are not conclusive. Furthermore, available data on Asian ethnicities, including Korean, are very limited. More genome-wide association studies and MR studies on Asian populations should be conducted to identify Asian- or Korean-specific lipid traits in the development of insulin resistance and T2DM. The present review discusses certain studies that investigated genetic variants related to nutrient intake that can modify lipid metabolism outcomes. Up-to-date inferences on the causal association between lipids and insulin resistance using MR should be interpreted with caution because of several limitations, including pleiotropic effects and lack of information on genotype and ethnicity.