Investigation of roles of hepatic glucose uptake in the pathogenesis of lifestyle-related diseases

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H04102
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Kanazawa University
• Principal Investigator: Inoue Hiroshi 金沢大学, 新学術創成研究機構, 教授 (50397832)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肝臓 / 糖取り込み / 生活習慣病

Outline of Final Research Achievements

The master regulator of hepatic glucose uptake is glucokinase, a hepatic enzyme which converts glucose to glucose-6-phosphate. We have found that impaired hepatic glucose uptake is causes by impeded activation of glucokinase in obesity and insulin resistance and that this impediment to glucokinase activation is induced by an acetylation of GKRP, a glucokinase-binding protein. We have also identified K126 as the acetylation site of GKRP. Here, we generated mice with K126R or K126Q mutation of GKRP as deacetylation- or acetylation mimicking mutant, respectively, to investigate the role of hepatic glucose uptake and GKRP in the pathogenesis of obesity-induced insulin resistance. K126Q mutation resulted in glucose tolerance, and K126R mice resisted insulin resistance and hepatic steatosis under the condition of high-fat diet induced obesity. These findings indicate that the regulatory mechanism of GKRP acetylation is a therapeutic target of insulin resistance in obesity.

Free Research Field

健康科学および栄養代謝内分泌学

Academic Significance and Societal Importance of the Research Achievements

GKRPのK126非アセチル化が、高脂肪食摂餌肥満マウスでの耐糖能異常・インスリン抵抗性を軽減することは、GKRP-K126のアセチル化制御機構が、肥満に伴う耐糖能異常・インスリン抵抗性の治療標的となることを示唆している。グルコキナーゼの恒常的活性化は、脂肪肝を増悪させ、インスリン抵抗性を増悪することから、今日では、グルコキナーゼは肥満・インスリン抵抗性の治療標的分子と考えられていない。GKRP-K126非アセチル化は、肥満でのGK活性化障害を抑止するが、その恒常的活性化は起こさない。本研究の知見は、グルコキナーゼおよびGKRPの肥満・インスリン抵抗性治療標的としての再評価へとつながる。