Li Zhao, Freiberg Sydney, Music Meredith L, Gu Lina, Nacos Sarah, Phillips Joseph P, Hassan Adil, Shibbani Kamel, Munir Sanah S, Kumar Vooha K, Halligan Luke, Michel Mia E, London Benjamin F, Bui Ngan, Cicha Michael, Buffard Valerie, Abel E Dale, Ahmad Ferhaan
Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USA.
Department of Pharmaceutical Sciences, University of St. Joseph, West Hartford, CT, USA.
Basic Res Cardiol. 2025 Sep 11. doi: 10.1007/s00395-025-01136-7.
Diabetes mellitus can lead to a cardiomyopathy independent of other risk factors such as coronary artery disease and hypertension, in up to 75% of patients. The prevalence of diabetic cardiomyopathy in the population is 1.1%. We previously showed that SGLT1 is expressed in cardiomyocytes and is further upregulated in diabetic cardiomyopathy and other forms of heart failure. In this study, we sought to determine the mechanisms by which cardiac SGLT1 contributes to the pathophysiology of heart failure in diabetes, obesity, and insulin resistance. We determined whether transgenic mice with cardiomyocyte-specific knockdown of SGLT1 (TG) had attenuation of cardiomyopathy after induction of obesity and insulin resistance by exposure to a high fat diet (HFD) from ages 8-28 weeks. TG mice and wildtype (WT) littermates exhibited similar increases in body weight and blood glucose after exposure to HFD. Nevertheless, TG mice exhibited attenuation of cardiomyopathy, manifested by less hypertrophy, systolic and diastolic dysfunction, fibrosis, nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) activation, and reactive oxygen species (ROS) production. In vivo hyperinsulinemia and in vitro exposure of cardiomyocytes to high glucose or insulin led to an increase in SGLT1 expression by increasing binding of the transcription factors HNF-1 and Sp1 to the SGLT1 gene (Slc5a1), and the transcript stabilizer HuR to SGLT1 mRNA. SGLT1 may contribute to cardiac injury in obesity and insulin resistance by stimulating ROS through its interaction with EGFR. SGLT1 may represent a therapeutic target for inhibition to prevent or to reverse diabetic cardiomyopathy.
糖尿病可导致一种独立于冠状动脉疾病和高血压等其他风险因素的心肌病，在高达75%的患者中出现。人群中糖尿病性心肌病的患病率为1.1%。我们之前表明，SGLT1在心肌细胞中表达，并且在糖尿病性心肌病和其他形式的心力衰竭中进一步上调。在本研究中，我们试图确定心脏SGLT1促成糖尿病、肥胖和胰岛素抵抗中心力衰竭病理生理学的机制。我们确定了通过从8至28周龄暴露于高脂饮食（HFD）诱导肥胖和胰岛素抵抗后，心肌细胞特异性敲低SGLT1的转基因小鼠（TG）是否减轻了心肌病。暴露于HFD后，TG小鼠和野生型（WT）同窝小鼠体重和血糖出现了相似的增加。然而，TG小鼠表现出心肌病减轻，表现为较少的肥大、收缩和舒张功能障碍、纤维化、烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（Nox2）激活和活性氧（ROS）产生。体内高胰岛素血症以及体外将心肌细胞暴露于高葡萄糖或胰岛素导致SGLT1表达增加，这是通过增加转录因子HNF-1和Sp1与SGLT1基因（Slc5a1）的结合以及转录稳定因子HuR与SGLT1 mRNA的结合实现的。SGLT1可能通过其与表皮生长因子受体（EGFR）的相互作用刺激ROS，从而促成肥胖和胰岛素抵抗中的心脏损伤。SGLT1可能代表一种用于抑制以预防或逆转糖尿病性心肌病的治疗靶点。
