Genetic Variations in GCKR and PNPLA3 Regulate Metabolic Balance Across the Liver

Abstract

We tested genetic variants in GCK, GCKR, and PNPLA3 in a large sample of self-identified Mexican Americans from the BetaGene Study for association with type 2 diabetes-related phenotypes under the hypothesis that they may regulate metabolic balance across the liver and contribute to hepatic steatosis and insulin resistance. We further tested whether interactions with dietary fructose and total sugar contributes to the observed associations. GCK rs1799831 was not associated with any type 2 diabetes-related phenotypes either alone or with any interaction tested. We replicated previous associations reported for GCKR rs780094 and PNPLA3 rs738409. We also show the interaction between GCKR rs780094 and dietary fructose is associated with both glucose effectiveness and glucose effectiveness at zero insulin, measures reflective of hepatic glucose uptake. We further show the interaction between GCKR rs780094 and PNPLA3 rs738409 is associated with type 2 diabetes-related traits, including insulin sensitivity. We conclude variations in GCKR and PNPLA3 and their interactions with each other and dietary fructose are partial determinants of hepatic fat, likely due to alterations in relative contributions of different metabolic pathways in the liver. These findings point to both GCKR and PNPLA3 as important therapeutic targets to mitigate hepatic metabolic dysfunction.

Article highlights: We examined genetic variation in GCKR and PNPLA3 for association with type 2 diabetes-related traits in Mexican Americans without diabetes. We addressed three questions: Are these loci associated with type 2 diabetes-related traits? Is there interaction between these loci? Is there interaction with dietary sugars? These loci individually, and in an interaction, are associated with type 2 diabetes-related traits; these loci also interact with dietary fructose to alter hepatic glucose uptake. Our findings support the hypothesis that these loci, coupled with dietary fructose and total sugars, alter hepatic metabolic balance and may contribute to hepatic fat and insulin resistance.