Ma Yunyun, Zuo Shiqi, Lo Therlinder, Phan David, Finley Tyler, Mackay Adrienne, Trigo Enrique, Hartiala Jaana A, Allayee Hooman, Xiang Anny H, Buchanan Thomas A, Watanabe Richard M
Department of Population and Public Health Sciences, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Diabetes and Obesity Research Institute of USC, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA.
Diabetes. 2025 Jul 1;74(7):1300-1309. doi: 10.2337/db24-0923.
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.
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.
在来自“β基因研究”的大量自我认定为墨西哥裔美国人的样本中，我们检测了葡萄糖激酶（GCK）、葡萄糖激酶调节蛋白（GCKR）和帕他汀样磷脂酶域蛋白3（PNPLA3）中的基因变异与2型糖尿病相关表型的关联，基于它们可能调节肝脏代谢平衡并导致肝脂肪变性和胰岛素抵抗的假设。我们进一步检测了与膳食果糖和总糖的相互作用是否会导致观察到的关联。GCK基因的rs1799831位点无论是单独还是与所检测的任何相互作用均与任何2型糖尿病相关表型无关。我们重复了先前报道的GCKR基因rs780094位点和PNPLA3基因rs738409位点的关联。我们还表明，GCKR基因rs780094位点与膳食果糖之间的相互作用与葡萄糖效能以及零胰岛素状态下的葡萄糖效能均相关，这两个指标反映肝脏葡萄糖摄取情况。我们进一步表明，GCKR基因rs780094位点与PNPLA3基因rs738409位点之间的相互作用与2型糖尿病相关特征有关，包括胰岛素敏感性。我们得出结论，GCKR和PNPLA3基因的变异及其相互之间以及与膳食果糖的相互作用是肝脏脂肪的部分决定因素，可能是由于肝脏中不同代谢途径的相对贡献发生了改变。这些发现表明GCKR和PNPLA3均是减轻肝脏代谢功能障碍的重要治疗靶点。
我们研究了GCKR和PNPLA3基因的遗传变异与无糖尿病的墨西哥裔美国人中2型糖尿病相关特征的关联。我们探讨了三个问题：这些基因座是否与2型糖尿病相关特征有关？这些基因座之间是否存在相互作用？是否与膳食糖存在相互作用？这些基因座单独以及相互作用时均与2型糖尿病相关特征有关；这些基因座还与膳食果糖相互作用以改变肝脏葡萄糖摄取。我们的研究结果支持这样的假设，即这些基因座与膳食果糖和总糖一起改变肝脏代谢平衡，并可能导致肝脏脂肪和胰岛素抵抗。
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