GENETIC VARIATION IN GCKR AND PNPLA3 REGULATE METABOLIC BALANCE ACROSS THE LIVER

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-05-07 DOI:10.2337/db24-0923

Yunyun Ma, Shiqi Zuo, Therlinder Lo, David Phan, Tyler Finley, Adrienne Mackay, Enrique Trigo, Jaana A. Hartiala, Hooman Allayee, Anny H. Xiang, Thomas A. Buchanan, Richard M. Watanabe

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Abstract

We tested genetic variants in GCK, GCKR, and PNPLA3 for association with type 2 diabetes-related phenotypes under the hypothesis they may regulate metabolic balance across the liver and contribute to hepatic steatosis and insulin resistance in a large sample of self-identified Mexican Americans from the BetaGene Study. 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.

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GCKR和pnpla3的遗传变异调节整个肝脏的代谢平衡

我们测试了GCK、GCKR和PNPLA3基因变异与2型糖尿病相关表型的相关性，假设它们可能调节肝脏的代谢平衡，并有助于肝脂肪变性和胰岛素抵抗，这是来自BetaGene研究的大量自我鉴定的墨西哥裔美国人样本。我们进一步测试了与膳食果糖和总糖的相互作用是否有助于观察到的关联。GCK rs1799831与任何2型糖尿病相关表型无关，无论是单独还是与任何相互作用测试。我们重复了先前报道的GCKR rs780094和PNPLA3 rs738409的关联。我们还发现GCKR rs780094和膳食果糖之间的相互作用与葡萄糖有效性和零胰岛素时的葡萄糖有效性相关，这些指标反映了肝脏葡萄糖摄取。我们进一步表明，GCKR rs780094和PNPLA3 rs738409之间的相互作用与2型糖尿病相关性状相关，包括胰岛素敏感性。我们得出结论，GCKR和PNPLA3的变化及其相互作用和膳食果糖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的改变。这些发现表明GCKR和PNPLA3都是缓解肝代谢功能障碍的重要治疗靶点。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.